WO2015192772A1 - Medical application of nmda receptor antagonist and pharmaceutical composition thereof - Google Patents

Abstract

A pharmaceutical application of an NMDA receptor antagonist. The NMDA receptor antagonist and a pharmaceutically acceptable salt or a pharmaceutical composition thereof are used to prepare drugs for treating or preventing central nervous system diseases and/or mental diseases, and the NMDA receptor antagonist is conveyed to the human central nervous system through targeted drug delivery. Also provided is a pharmaceutical composition containing the NMDA receptor antagonist. The composition is a nasal in-situ gel, nasal drops, nasal spray or nasal powder.

Description

Medical use of NMDA receptor antagonists and pharmaceutical compositions thereof Technical field

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.

Background technique

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.

About 120 million people worldwide suffer from depression. The WHO predicts that depression will be the leading cause of disability by 2020. From the Asian Psychiatric Summit (APNS) hosted by the Chinese Medical Association Psychiatric Branch in June 2005, it was learned that more than 26 million people in China currently suffer from depression, but less than 10% of patients have received related drugs. Treatment, the total economic burden of depression to China reached 62.2 billion yuan.

At present, depression is mainly treated by two strategies: drug therapy and non-drug therapy. 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. Currently, 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. 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. For example, 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.

N-methyl-D-aspartate receptor (NMDAR) is a class of ionotropic glutamate receptors whose function is mainly involved in the refinement of neural circuits during development and triggers various forms of synaptic plasticity. Play an important physiological role in the process of learning, memory and emotional regulation. More and more studies have found that NMDAR is involved in a variety of pathological processes, including brain cell death caused by stroke, neurological disease and schizophrenia, depression and other gods. Menstrual / mental illness. 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.

There is increasing evidence that NMDARs modulators show great potential for antidepressants. The most important and direct evidence comes from studies of 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.

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. Studies have also shown that GLYX-13 easily crosses the blood-brain barrier. Therefore, the main bottleneck of GLYX-13 entering the brain is the high clearance rate in the systemic circulation. At present, 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.

Currently, NMDA receptor antagonists such as GYLX-13 are mainly administered by intravenous injection. In addition, WO201104089A2 discloses various possible administration modes of GLYX-13: 1. By oral administration, for example, the drug is tableted. , capsules, granules, powders and syrups. 2. By parenteral administration, such as injection, intravenous, intramuscular, subcutaneous, intravenous drip. 3. By eye administration, such as eye ointment and eye drops. 4. By topical administration, buccal administration, sublingual administration, rectal administration, vaginal administration. 5. An ointment or the like is prepared by transdermal absorption administration.

It is worth noting that 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. In addition, 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.

Therefore, it is very necessary to solve the problem of high drug elimination rate and poor drug compliance caused by current administration methods by new administration methods and preparations.

Summary of the invention

In order to overcome the deficiencies of the prior art, the inventors have intensively studied to find a new application of 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.

As a further preferred embodiment, 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.

As a further preferred embodiment, the targeted administration method is intraventricular injection, nasal administration.

Other targeted modes of administration also include carotid injections, which, like direct ventricular injections, are invasive and may present poor patient compliance and risk of infection. Nasal administration allows the absorbed drug to bypass the blood-brain barrier and directly enter the central nervous system, which is beneficial to increase the concentration of NMDA receptor antagonists such as GLYX-13 in brain tissue, greatly reducing the amount of drugs and reducing systemic side effect.

After nasal administration, the drug molecules are retained in the olfactory mucosa and easily absorbed into the cerebrospinal fluid, thereby bypassing the blood-brain barrier and entering the central nervous system to exert therapeutic effects. 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.

As a further preferred embodiment, 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.

As a still further preferred embodiment, the NMDA receptor antagonist is selected from the group consisting of GLYX-13. As a further preferred embodiment, 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.

As a further preferred embodiment, 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 Or by applying the device to the nasal cavity, 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. In addition, 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. 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. 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). In addition, NMDA receptors are also involved in certain types of spatial learning.

According to a second aspect of the present invention, 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. Powder, nasal microspheres, nasal microcapsules, nasal nanoparticles, nasal liposomes, nasal emulsions, nasal creams, nasal films or nasal cyclodextrins; preferably nasal drops Nasal, nasal spray, nasal in situ gel and nasal powder.

Preferably, 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.

As a further preferred embodiment, the aforementioned other pharmaceutical excipients are selected from the group consisting of permeation enhancers, osmotic pressure regulators, pH adjusters or preservatives.

As a still further preferred embodiment, 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, cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sodium lauryl sulfate, Tween -80, octanoic acid monoglyceride, azone, cholate, sodium taurodeoxycholate, sodium glycocholate, sodium deoxycholate, sodium glycoacetate, fusidic acid, salicylate, N - acetyl-L-cysteine, sodium edetate, citrate, collagen N-acetyl derivative, lysolecithin, palmitoyl lysolecithin, stearoyl lysolecithin, sodium glycyrrhizinate, Dipotassium glycyrrhizinate, carbene oxydisodium, dihydropyridinium sodium, bezoar dihydro puromycin sodium, octanoyl carnitine, lauroyl carnitine, chitosan, cetylpyridinium chloride, borneol , poly L- lysine or a combination thereof, preferably from azone, sodium oxydeoxycholate or a combination thereof; the osmotic pressure adjusting agent is selected from the group consisting of glycerin, sodium chloride, potassium chloride, glucose or a combination thereof; preferably chlorinated Sodium; the pH adjusting agent is selected from the group consisting of hydrochloric acid, sodium hydroxide, potassium hydroxide, acetic acid, sodium acetate, citric acid, sodium citrate, phosphoric acid, dihydrogen phosphate , disodium hydrogen phosphate, sodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate or a combination thereof; preferably sodium dihydrogen phosphate, disodium hydrogen phosphate or a combination thereof; the preservative is selected from the group consisting of chlorobutanol , benzalkonium chloride, benzalkonium bromide, potassium sorbate, methyl salicylate, sodium salicylate, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, benzyl p-hydroxybenzoate, isophthalic acid Phenol, phenylethyl alcohol, benzoic acid, sodium benzoate, benzyl alcohol, phenol, m-cresol, thimerosal or a combination thereof; preferably ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate or a combination thereof.

In a still further preferred embodiment, 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, and 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. In addition, the drug is absorbed through the nasal cavity, avoiding The systemic circulation is eliminated, so that the dosage can be drastically reduced. In addition, the patient can be administered autonomously and is painless, and thus has good patient compliance.

As a most preferred embodiment, the composition and content (W/V) of each component of the nasal gel is:

As a most preferred embodiment, the composition and content (W/V) of each component of the nasal gel is:

Preferably, 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.

As a further preferred embodiment, 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.

As a still further preferred embodiment, 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, mannitol, sorbitol, cyclodextrin, or a combination thereof; Oleohydrin, lauryl alcohol, cetyl alcohol, linoleic acid, polyoxyethylene lauryl ether, isopropyl palmitate, isopropyl myristyl ester, lanolin, eucalyptol, menthol, saponin, Dodecane nitrogen

Ketone, camphor, liquid paraffin, dimethicone, glycerin, polyethylene glycol, cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sodium lauryl sulfate, Tween -80, octanoic acid monoglyceride, azone, cholate, sodium taurodeoxycholate, sodium glycocholate, sodium deoxycholate, sodium glycoacetate, fusidic acid, salicylate, N - acetyl-L-cysteine, sodium edetate, citrate, collagen N-acetyl derivative, lysolecithin, palmitoyl lysolecithin, stearoyl lysolecithin, sodium glycyrrhizinate, Dipotassium glycyrrhizinate, carbene oxydisodium, dihydropyridinium sodium, bezoar dihydropurin sodium, octanoylcarnitine, lauroyl carnitine, chitosan, cetylpyridinium chloride, poly L-Cylin or a combination thereof.

According to a third aspect of the present invention, 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.

Preferably, 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.

As a further preferred embodiment, 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), Phenothiazines, thiazepines, butyrylbenzenes, opioid receptor agonists, opioid receptor partial agonists, opioid receptor antagonists, glutamate receptor antagonists, acetylcholine receptor antagonists, neuropeptides Receptor antagonists, k-receptor agonists, tricyclic antidepressants (such as amitriptyline), selective serotonin reuptake inhibitors (such as fluphenoxybenzamine, fluphene, and sertraline) , tetracyclic antidepressants (such as maprotiline), and monoamine oxidase (MAO) inhibitors (such as phenelzine), drugs that excite the cerebral cortex, excite the medullary respiratory center drugs, and promote the recovery of brain function.

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.

In a further preferred embodiment, 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.

As a still further preferred embodiment, 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.

Compared with the prior 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. In particular, 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.

In addition, the drug is absorbed through the nasal cavity, which avoids the elimination of the drug in the systemic circulation. Compared with the existing preparation or administration mode, 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.

In summary, 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.

detailed description

The present invention is further described in detail with reference to the accompanying drawings, but by no way of limitation,

Example 1

1, the formulation of the preparation

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	/

2, the preparation method

Take 900ml of water for injection, add the prescribed amount of ethyl p-hydroxybenzoate, sodium chloride and azone, stir and dissolve solution. 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. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Pack and sell.

Example 2

1, the formulation of the preparation

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	/

2, the preparation method

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. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense into a squeeze nasal delivery device.

Example 3

1, the formulation of the preparation

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	/

2, the preparation method

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. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense into a nebulized nasal delivery device.

Example 4

1, the formulation of the preparation

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	/

2, the preparation method

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. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense to the pressure quantitative absorption device.

Example 5

1, the formulation of the preparation

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	/

Water for Injection

Add to 1000ml

/

2, the preparation method

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. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense to the pressure quantitative absorption device.

Example 6

1, the formulation of the preparation

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	/

2, the preparation method

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. Take a prescription amount of gellan gum, disperse it in the above solution, and make the inflation completely into a clear solution. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense into a nebulized nasal delivery device.

Example 7

1, the formulation of the preparation

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	/

2, the preparation method

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. Take a prescription amount of gellan gum, disperse it in the above solution, and make the inflation completely into a clear solution. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense into a spray nasal delivery device.

Example 8

1, the formulation of the preparation

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	/

2, the preparation method

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. Take a prescription amount of gellan gum, disperse it in the above solution, and make the inflation completely into a clear solution. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense to the pressure quantitative absorption device.

Example 9

1, the formulation of the preparation

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	/

Water for Injection

Add to 1000ml

/

2, the preparation method

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. Add the prescription GLYX-13 and oxazepam, dissolve and adjust the pH to 5.0-7.4. Dispense into a nebulized nasal delivery device.

Example 10

1, the formulation of the preparation

Component	Quality (g)	Composition (W/W, %)
			GLYX-13	55	55
Hydroxypropyl cellulose	twenty three	twenty three
			Sodium fulvate	5	5
lactose	17	17

2, the preparation method

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.

Example 11

1, the formulation of the preparation

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	/

2, the preparation method

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. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense into a squeeze nasal delivery device.

Example 12

1, the formulation of the preparation

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	/

2, the preparation method

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. Add the prescription GLYX-13, dissolve and adjust the pH to 5.0-7.4. Dispense into a nebulized nasal delivery device.

Example 13

1, the formulation of the preparation

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	/

2, the preparation method

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. Add the prescribed amount of GLYX-13 and estazolam, dissolve and adjust the pH to 5.0-7.4. Dispense into a squeeze nasal delivery device.

Example 14

1, the formulation of the preparation

Component	Quality (g)	Composition (W/V, %)
			GLYX-13	30	3

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	/

2, the preparation method

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.

Example 15

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:

(1) Drug configuration: 58.2 mg of GLYX-13 was accurately weighed and dissolved in 0.29 ml of a solvent (see Example 1 for a solvent formulation) to prepare a solution having a final concentration of 200 mg/ml.

(2) Administration: SD rats were starved overnight, randomly grouped, and 3 rats were selected at each time point. 10 microliters of drug solution was instilled into one nostril with a micro-injector, and the rats were observed to ensure large The mouse sucks all the drops into the nostrils.

(3) Sample collection and preservation: After different time of administration, blood was collected and collected for plasma preservation; rats were suffocated with CO2, cerebrospinal fluid (CSF) was collected, brain was dissected, and brain tissue was collected. The collected biological samples were all stored at -80 degrees.

(4) Analysis of sample drug concentration: The concentration of GLYX-13 in plasma samples, cerebrospinal fluid and brain tissue was measured by LC-MS/MS. The method of using liquid and liquid is as follows:

After nasal administration of GLXY-13, the test results of brain tissue and plasma were as follows:

From the above experimental results, it can be seen that 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.

Intravenous contrast experiment

In this experiment, SD rats weighing 200-300 g were selected, and rats were intravenously injected with drugs at 10 mg/kg body weight. The experimental method is as follows:

(1) Drug configuration: 20.9 mg of GLYX-13 was accurately weighed and dissolved in 10.45 ml of 0.9% physiological saline to prepare a solution having a concentration of 1 mg/ml.

(2) Administration: SD rats were starved overnight, randomly divided into groups, and 3 rats were selected at each time point, and the drug was intravenously administered according to the body weight of the rats at 10 μl/g body weight.

(3) Sample collection and preservation: After different time of administration, blood was collected and collected for plasma preservation; rats were suffocated with CO2, cerebrospinal fluid (CSF) was collected, brain was dissected, and brain tissue was collected. The collected biological samples were all stored at -80 degrees.

(4) Analysis of sample drug concentration: The concentration of GLYX-13 in plasma samples, cerebrospinal fluid and brain tissue was measured by LC-MS/MS.

After GLXY-13 was administered intravenously, the test results of brain tissue and plasma were as follows:

It can be seen from the above experimental results that after intravenous injection of GLYX-13, it can be rapidly distributed to brain tissue. By intravenous administration, the drug can reach a peak in brain tissue for a short period of time, but its drug clearance is also faster; and the proportion of drug into brain tissue is relatively low compared with the high blood concentration in plasma, metabolic clearance Also faster.

Comparison of experimental data of GLYX-13 via nasal administration and intravenous administration

From the above experimental results, the following conclusions can be drawn:

(1) After nasal administration, 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.

(2) 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.

(3) From the experimental results, the same exposure (AUC) of intravenous administration for 4 hours can be achieved after 24 hours of nasal administration.

(4) Because 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. Compared with the application of intravenous administration, after nasal administration, 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.

(5) Compared with intravenous drip administration, 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.

It should be noted that the above embodiments are only intended to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art The technical solutions are modified or equivalent, and the technical solutions are not to be construed as falling within the spirit and scope of the present invention.

Claims (24)

1. Use of an NMDA receptor antagonist for the preparation of a medicament for treating or preventing a central nervous system disease and/or a psychotic disorder, the targeted administration of the NMDA receptor antagonist, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof Passed to the human central nervous system.
2. The use according to claim 1, wherein said central nervous system and/or mental illness is selected from the group consisting of depression, autism, Alzheimer's disease, Alzheimer's disease, seizures, neuralgia or detoxification. symptom.
3. The use according to claim 1, wherein the targeted administration directly enters the central nervous system of a person without undergoing systemic circulation or blood-brain barrier.
4. The use according to claim 3, wherein the targeted administration is intracerebroventricular administration or nasal administration.
5. The use according to claim 1 wherein said 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.
6. The use according to claim 5, wherein the NMDA receptor antagonist is selected from the group consisting of GLYX-13.
7. The use according to claim 1, wherein the targeted administration 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 It is 0.1-20 mg/kg/day.
8. The use according to claim 4, wherein the nasal administration is carried out by formulating an NMDA receptor antagonist, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a pharmaceutical excipient into a pharmaceutically acceptable form. In the pharmaceutical preparation, the pharmaceutical preparation is applied to the nasal cavity directly or through a device, and 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.
9. The use according to claim 8, wherein the pharmaceutically acceptable pharmaceutical preparation is selected from the group consisting of nasal drops, nasal in situ gels, nasal aerosols, nasal sprays, nasal powders. Aerosols, nasal microspheres, nasal microcapsules, nasal nanoparticles, nasal liposomes, nasal emulsions, nasal creams, nasal films or nasal sprays A cyclodextrin formulation; preferably a nasal nasal spray, a nasal spray, a nasal in situ gel, and a nasal powder.
10. A nasal in situ gelling agent comprising 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.
11. A nasal or nasal spray comprising an effective amount of an NMDA receptor antagonist, or a pharmaceutically acceptable salt thereof, water, and one or more other pharmaceutical excipients.
12. The nasal in situ gelling agent according to claim 10 or the nasal drop or nasal spray according to claim 11, wherein the other pharmaceutical excipient is selected from the group consisting of a penetration enhancer and an osmotic pressure adjusting agent. , pH adjuster or preservative.
13. The nasal in situ gelling agent according to claim 10, wherein the gel matrix is selected from the group consisting of poloxamer 407, poloxamer 188, sodium alginate, gellan gum, chitosan, and a derivative thereof, methyl cellulose, hydroxypropyl cellulose, polylactic acid-polyethylene glycol block copolymer, polycaprolactone polyethylene glycol block copolymer, poly N-isopropyl acrylamide or Combination thereof; preferably poloxamer 407, poloxamer 188, gellan gum or a combination thereof.
14. The nasal in situ gel, nasal drop or nasal spray according to claim 12, wherein the penetration enhancer is selected from the group consisting of oleyl alcohol, lauryl alcohol, cetyl alcohol, linoleic acid, and poly Oxyethylene lauryl ether, isopropyl palmitate, isopropyl myristate, lanolin, eucalyptol, menthol, saponin, dodecane nitrogen

    

    Ketone, camphor, liquid paraffin, dimethicone, glycerin, polyethylene glycol, cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sodium lauryl sulfate, Tween -80, octanoic acid monoglyceride, azone, cholate, sodium taurodeoxycholate, sodium glycocholate, sodium deoxycholate, sodium glycoacetate, fusidic acid, salicylate, N - acetyl-L-cysteine, sodium edetate, citrate, collagen N-acetyl derivative, lysolecithin, palmitoyl lysolecithin, stearoyl lysolecithin, sodium glycyrrhizinate, Dipotassium glycyrrhizinate, carbene oxydisodium, dihydropyridinium sodium, bezoar dihydropurin sodium, octanoylcarnitine, lauroyl carnitine, chitosan, cetylpyridinium chloride, poly L-Lactic acid or a combination thereof, preferably from azone, sodium oxydeoxycholate or a combination thereof; the osmotic pressure adjusting agent is selected from the group consisting of glycerin, sodium chloride, potassium chloride, glucose or a combination thereof; preferably sodium chloride; The pH adjusting agent is selected from the group consisting of hydrochloric acid, sodium hydroxide, potassium hydroxide, acetic acid, sodium acetate, citric acid, sodium citrate, phosphoric acid, sodium dihydrogen phosphate, phosphorus Dihydrogen sodium, sodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate or a combination thereof; preferably sodium dihydrogen phosphate, disodium hydrogen phosphate or a combination thereof; the preservative is selected from the group consisting of chlorobutanol and benzene Benzalkonium chloride, benzalkonium bromide, potassium sorbate, methyl salicylate, sodium salicylate, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, benzyl p-hydroxybenzoate, resorcinol, Phenylethanol, benzoic acid, sodium benzoate, benzyl alcohol, phenol, m-cresol, thimerosal or a combination thereof; preferably ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate or a combination thereof.
15. The nasal in situ gelling agent according to claim 10, which comprises an effective amount of an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof, wherein the gel matrix is selected from the group consisting of poloxamer 407, poloxa 188, gellan gum or a combination thereof, the penetration enhancer is selected from the group consisting of azone or sodium sulphate sodium, the osmotic pressure adjusting agent is selected from sodium chloride, the pH adjuster is selected from hydrochloric acid or sodium hydroxide, and the preservative is selected from the group consisting of Ethyl hydroxybenzoate with the balance being water.
16. The nasal in situ gelling agent according to claim 15, wherein the composition and content (W/V) of each component of the gelling agent are:

    
17. The nasal in situ gelling agent according to claim 15, wherein the composition and content (W/V) of each component of the gelling agent are:

    
18. A nasal in situ gel, nasal drop or nasal spray comprising an NMDA receptor antagonist according to any one of claims 10-17 for use in the preparation of a medicament for the treatment or prevention of diseases of the central nervous system and/or mental illness For use of the drug, the NMDA receptor antagonist, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is delivered to the central nervous system of a human by targeted administration.
19. An effective amount of an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof, and one or more A nasal powder for other pharmaceutical excipients.
20. The nasal powder according to claim 19, wherein the other pharmaceutical excipient is selected from the group consisting of a carrier powder, a penetration enhancer, an adhesive, a glidant, a surfactant, and/or a diluent.
21. The nasal powder according to claim 20, wherein the carrier powder is selected from the group consisting of starch, lactose, mannitol, sorbitol, pregelatinized starch, cyclodextrin or a combination thereof; The glidant is selected from the group consisting of sodium alginate, gum arabic, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, starch, sodium carboxymethyl starch, pregelatinized starch, cyclodextrin or Combining; the surfactant is selected from the group consisting of polysorbate, poloxamer, benzathon or a combination thereof; the diluent is selected from the group consisting of starch, lactose, mannitol, sorbitol, pregelatinized starch, cyclodextrin or Combining; the penetration enhancer is selected from the group consisting of oleyl alcohol, lauryl alcohol, cetyl alcohol, linoleic acid, polyoxyethylene lauryl ether, isopropyl palmitate, isopropyl myristyl ester, lanolin, eucalyptus oil , menthol, saponin, dodecane nitrogen

    

    Ketone, camphor, liquid paraffin, dimethicone, glycerin, polyethylene glycol, cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sodium lauryl sulfate, Tween -80, octanoic acid monoglyceride, azone, cholate, sodium taurodeoxycholate, sodium glycocholate, sodium deoxycholate, sodium glycoacetate, fusidic acid, salicylate, N - acetyl-L-cysteine, sodium edetate, citrate, collagen N-acetyl derivative, lysolecithin, palmitoyl lysolecithin, stearoyl lysolecithin, sodium glycyrrhizinate, Dipotassium glycyrrhizinate, carbene oxydisodium, dihydropyridinium sodium, bezoar dihydropurin sodium, octanoylcarnitine, lauroyl carnitine, chitosan, cetylpyridinium chloride, poly L-Cylin or a combination thereof.
22. The use of a nasal powder according to any one of claims 19 to 21 for the preparation of a medicament for treating or preventing a central nervous system disease and/or a psychiatric disease, the NMDA receptor antagonist, a pharmaceutically acceptable salt thereof or Its pharmaceutical composition is delivered to the human central nervous system by targeted administration.
23. A pharmaceutical composition comprising an NMDA receptor antagonist and any other one or more central nervous system drugs, said NMDA receptor antagonist being delivered to a human central nervous system by targeted administration; preferably, said targeting Administration is for intraventricular injection or nasal administration.
24. The pharmaceutical composition according to claim 23, wherein the central nervous system drug is selected from the group consisting of a sedative-hypnotic drug, an anti-epileptic drug, an antipsychotic drug, an antidepressant, an analgesic or a neurodegenerative disease therapeutic drug.