CN116920101A - New pharmaceutical composition for treating major depressive disorder - Google Patents
New pharmaceutical composition for treating major depressive disorder Download PDFInfo
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- CN116920101A CN116920101A CN202310250280.0A CN202310250280A CN116920101A CN 116920101 A CN116920101 A CN 116920101A CN 202310250280 A CN202310250280 A CN 202310250280A CN 116920101 A CN116920101 A CN 116920101A
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- Prior art keywords
- benzodiazepine
- dextromethorphan
- pharmaceutically acceptable
- major depressive
- injection
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- 208000024714 major depressive disease Diseases 0.000 title claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 9
- 229960001985 dextromethorphan Drugs 0.000 claims abstract description 43
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000004480 active ingredient Substances 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 14
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims abstract 17
- 239000004615 ingredient Substances 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims description 30
- 229940049706 benzodiazepine Drugs 0.000 claims description 19
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 claims description 13
- 229960003120 clonazepam Drugs 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
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- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Abstract
The invention discloses a novel pharmaceutical composition for treating major depressive disorder, which is characterized by comprising dextromethorphan active ingredient and benzodiazepineAn active-like ingredient; the dextromethorphan active ingredient and the benzodiazepineThe weight ratio of the similar active ingredients is 45-180:1. the invention uses dextromethorphan and benzodiazepineSynergistic combination of the classes by dextromethorphan and benzodiazepineThe combined action of class and active metabolite dextrorphan, acting against target points such as NMDA receptor, sigma-1 receptor agonism, GABA-A receptor agonism and multiple mechanisms can greatly improve the treatment effect on major depressive patients (MDD), especially refractory depression (TRD), and simultaneously the benzodiazepine
Description
Technical Field
The invention belongs to the technical field of pharmaceutical compositions, and particularly relates to a novel pharmaceutical composition for treating major depressive disorder.
Background
Depression is a common mental disorder, 3 hundred million people are ill worldwide, and serious harm is caused to physical and psychological health life quality, occupation and social functions of patients, and is an important cause for suicide of human beings. Depression has become one of the leading causes of global disease burden, amounting to $2000 per year in the united states alone. The burden of social disease caused by depression is expected to rise at the beginning of this century to be second only to coronary heart disease. Epidemiological surveys conducted in 17 developed countries around the world show that on average, one person out of every 20 has experienced over the past year a depression. The pathogenesis of depression is currently unknown, and there are numerous hypotheses that none of them fully explain the pathogenesis of depression and the mechanism of antidepressant action.
In month 8 2022, axsome Therapeutics compound sustained release tablets "Auvey (dextromethorphan 45 mg+bupropion 105 mg") were approved by the FDA in the United states and became the only oral N-methyl-D-aspartate (NMDA) receptor antagonist currently used to treat Major Depressive Disorder (MDD).
However, it is undeniable that bupropion carries the risk of inducing epilepsy and is forbidden to patients with depression who have had a history of epilepsy, and Axsome Therapeutics compound sustained-release tablets cannot reduce the risk of transition to manic phase in patients with depression, which limits the use of the drug. .
Refractory Depression (TRD) is an important public health problem and requires a great deal of intensive experimentation to teach clinical practice [ Stimpson et al The British Journal of Psychiatry, (2002) 181:284-294]. There remains a need to develop effective treatments for mood disorders, particularly Major Depressive Disorder (MDD).
Disclosure of Invention
In order to solve the technical problems, the invention provides a novel pharmaceutical combination for treating major depressive disorder, which is prepared from dextromethorphan and benzodiazepineSynergistic combination of the classes by dextromethorphan with benzodiazepine->Synergistic combination of the classes by dextromethorphan, benzodiazepine +.>The combined action of class and active metabolite dextrorphan, acting on antagonism of target points such as NMDA receptor, sigma-1 receptor agonism, GABA-A receptor agonism and the like and multiple mechanisms can greatly improve the treatment effect on patients suffering from severe depression (MDD), especially refractory depression (TRD), and simultaneously the benzodiazepine>The compound reduces the dosage of dextromethorphan, reduces the abuse probability possibly possessed by dextromethorphan, and has the advantages of multiple targets, quick action and low abuse probability.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a new pharmaceutical composition for the treatment of major depressive disorder comprises dextromethorphan as active ingredient and benzodiazepineAn active ingredient.
Preferably, the dextromethorphan active ingredient is dextromethorphan or a pharmaceutically acceptable salt thereof.
Preferably, the benzodiazepineThe active ingredients are clonazepam or pharmaceutically acceptable salts of clonazepam.
Preferably, the dextromethorphan active ingredient and the benzodiazepineThe weight ratio of the similar active ingredients is 45-180:1.
dextromethorphan is the dextrorotatory isomer of levomethafene, the active metabolite dextrorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as glutamate receptor modulator, a novel antidepressant mechanism of action, meaning that its effect is different from most depressive drugs currently available, while dextromethorphan is also a sigma-1 receptor agonist'
BenzodiazepinesAs a broad spectrum antiepileptic, chinese CFDA has been approved for the control of treatment of various epileptic conditions, meaning that the drug can minimize the conversion of depressed patients to seizures by other drugs. At the same time, benzodiazepine->The GABA-A receptor is an agonist and can promote the effect of dextromethorphan.
The invention innovatively combines and synergistically compounds the two medicaments, achieves a relatively comprehensive anti-depression treatment effect through the combined action of target points such as antagonism of an NMDA receptor, agonism of a sigma-1 receptor, agonism of a GABA-A receptor and the like and multiple mechanisms, and takes effect within one week on average according to clinical data published by the FDA in the United states, namely, axsome Therapeutics compound slow-release tablets (dextromethorphan 45 mg+bupropion 105 mg), and can reasonably predict that the compound pharmaceutical preparation takes effect as fast as or even faster than Axsome Therapeutics compound slow-release tablets.
The preparation method of the oral tablet is not limited at all, and conventional technical means are adopted.
Compared with the prior art, the invention has the following advantages and effects:
(1) The composition provided by the invention comprises dextromethorphan active ingredient and benzodiazepineThe active ingredients can greatly improve the treatment effect on Major Depressive Disorder (MDD), especially refractory depression (TRD), and simultaneously treat benzodiazepines by acting on target points such as antagonism of NMDA receptor, agonism of sigma-1 receptor, agonism of GABA-A receptor and the like and multiple mechanisms>The compound reduces the dosage of dextromethorphan, reduces the abuse probability possibly possessed by dextromethorphan, and has the advantages of multiple targets, quick action and low abuse probability.
(2) The medicine for treating major depressive disorder prepared by the composition has the advantages of high bioavailability, high effect taking efficiency, low dosage, less side effect and the like, and is more suitable for clinical application.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention are further described in detail below.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The raw materials adopted by the invention are all common commercial products unless specified.
Experimental example, a novel pharmaceutical composition for treatment of major depressive disorder
1. Experimental animal
Experimental animal CFW mice
2. Animal modeling
The model establishment is carried out by referring to a construction method of a chronic unpredictable depression mouse model given by SuWJ et al and Li M et al, and the specific operation is as follows:
mice were randomly divided into a model group and a normal control group according to body weight, wherein 10 normal control groups were administered without any stimulus, and 7 different chronic stress stimulators were administered to the mice within 35 days. Chronic stressors include: (1) water withdrawal for 24h, (2) fasting for 24h, (3) wet padding for 24h (squirrel cage poured into tap water for 200 ml), (4) tail clamping for 1min, (5) squirrel cage tilting (45 °,24 h), (6) on-ice stimulation for 5min, (7) electrical stimulation (50 v,0.3 s), which is repeated 5 times, in random order but the same stressor is not applied continuously, so that the mice cannot predict the stimulus given.
3. Grouping and dosing
After 35 days of modeling, model group mice were randomly divided into model control groups and drug groups according to body weight, 10 mice per group,
wherein the medicine components are as follows:
the mass ratio of dextromethorphan hydrobromide DXM to clonazepam in the drug group 1 is 45:1, wherein the specific dosage is 1.2 mug/kg of dextromethorphan hydrobromide and 0.0267 mug/kg of clonazepam;
the mass ratio of dextromethorphan hydrobromide DXM to clonazepam in the drug group 2 is 90:1, wherein the specific dosage is 1.2 mug/kg of dextromethorphan hydrobromide and 0.0134 mug/kg of clonazepam;
the mass ratio of dextromethorphan hydrobromide DXM to clonazepam in the drug group 3 is 135:1, wherein the specific dosage is 1.2 mug/kg of dextromethorphan hydrobromide and 0.0089 mug/kg of clonazepam;
the mass ratio of dextromethorphan hydrobromide DXM to clonazepam in the drug group 4 is 180:1, wherein the specific dosage is 1.2 mug/kg of dextromethorphan hydrobromide and 0.0067 mug/kg of clonazepam;
drug group 5 was administered at 1.2 μg/kg dextromethorphan hydrobromide DXM;
drug group 6 was administered at a dose of clonazepam of 0.0267 μg/kg.
The pharmaceutical composition was dissolved or suspended with sodium carboxymethylcellulose (0.5% cmc-Na) to the desired dosing concentration; the model control group and the normal control group were given equal volumes of 0.5% sodium carboxymethylcellulose (0.5% cmc-Na), administered once daily by gavage for 5 consecutive days, and the model control group and the drug group continued to be subjected to stress stimulation during the administration period.
On day 5 of dosing, mice were subjected to tail suspension and forced swimming experiments, 60min before the experiment, and moved to a quiet test room to reduce animal stress.
The tail suspension experiment of the mice, the tail end of the mice is stuck on a wood board 15cm away from the ground, the tail is in an inverted posture, the tail suspension of the mice is carried out for 6min, and the accumulated time within 4min after the tail suspension is recorded.
Forced swimming experiment: the mice were placed in open cylindrical beakers (diameter 15cm, height 25 cm) separately, warm water at 25+ -1deg.C was added to the beakers, the water depth was 10cm, the mice were forced to swim for 6min, and the accumulated time was recorded within 4 min. The mice stopped swimming, remained motionless in the water, or were considered motionless with only some slight movements necessary to maintain equilibrium. The experimental results are shown in tables 1 and 2.
TABLE 1
| Group of | Dosage of drug | Tail suspension immobility time/s | Forced swimming immobility time |
| Blank control group | 38.6±5.0 | 61.0±7.3 |
TABLE 2
Note that: p < 0.01 compared with the blank control group, indicating a very significant difference; comparison with the model control group showed significant differences in # P < 0.05, and significant differences in # P < 0.01.
As shown in the table above, the tail suspension immobility time and the forced swimming immobility time of the mice in the model control group are extremely remarkable (P < 0.01) compared with the blank control group, which indicates that the movable model of the invention is successful in modeling.
Compared with a model control group, the tail suspension immobility time and the forced swimming immobility time of mice in the drug groups 1-4 are obviously different, P is less than 0.05, and the drug groups 5 and 6 have no obvious difference, so that the composition for treating major depressive disorder can effectively treat the major depressive disorder.
Meanwhile, the tail suspension immobility time and forced swimming immobility time of mice in the drug groups 1-4 are extremely obviously reduced by P < 0.01, which indicates that when the dextromethorphan active ingredient and the benzodiazepine are contained in the compositionThe weight ratio of the similar active ingredients is 90-135:1, the composition of the present invention has a better effect of treating major depressive disorder.
The invention also provides an oral tablet and capsule for treating major depressive disorder, which comprises the following components in parts by weight: 45-180 parts of dextromethorphan hydrobromide and benzodiazepineClass 1 part and auxiliary materials 100-400 parts.
Preferably, the auxiliary materials include, but are not limited to, at least one of sorbitol, mannitol, lactose, sucrose, xylitol, dextrin, stevioside, polyvinyl alcohol (PVP), polyethylene glycol (PEG), cross-linked polyvinylpyrrolidone (PVPP), starch, carboxymethyl cellulose, and microcrystalline cellulose (CMCC). The preparation method of the oral tablet is not limited at all, and conventional technical means are adopted.
Preferably, the preparation method comprises the following steps: dextromethorphan hydrobromide and benzodiazepine are added in the formula amountSieving, mixing, adding appropriate amount of wetting adjuvant, making soft mass, sieving, granulating, oven drying, sieving again, granulating, adding tabletting adjuvant, and making into tablet or capsule with 45.25-46mg of active drug per tablet and 145.25-146mg of active drug per tablet, wherein the ratio is shown in Table 3.
TABLE 3 Table 3
| Dextromethorphan | Benzodiazepines | Auxiliary materials | |
| 1 | 45mg | 0.25mg | 100mg |
| 2 | 45mg | 0.5mg | 100mg |
| 3 | 45mg | 0.75mg | 100mg |
| 4 | 45mg | 1mg | 100mg |
The invention also provides an oral liquid for treating major depressive disorder, which comprises the following components in parts by weight: 45-180 parts of dextromethorphan hydrobromide and benzodiazepine1 part of auxiliary materials.
Preferably, the auxiliary materials include, but are not limited to, at least one of sorbitol, mannitol, lactose, sucrose, xylitol, dextrin, stevioside, polyvinyl alcohol (PVP), polyethylene glycol (PEG), cross-linked polyvinylpyrrolidone (PVPP), starch, carboxymethyl cellulose, and microcrystalline cellulose (CMCC). The preparation method of the oral liquid is not limited at all, and conventional technical means are adopted.
Preferably, the preparation method comprises the following steps: 450mg dextromethorphan hydrobromide and 2.5-10mg benzodiazepineThe quasi-drug is dissolved in water dissolved with auxiliary materials, and the volume is fixed to 100ml.
The invention also provides an injection for treating major depressive disorder, which comprises the following components in parts by weight: 45-180 parts of dextromethorphan hydrobromide and benzodiazepine1 part of auxiliary materials.
The preparation method of the injection is not limited at all, and conventional technical means are adopted.
Preferably, the preparation method comprises the following steps: 45mg dextromethorphan or dextromethorphan pharmaceutically acceptable salt is prepared into dry powder, and 0.25-1mg of benzodiazepineClass or benzodiazepine>The pharmaceutically acceptable salt is prepared into 1ml of injection with the concentration of 0.25-1mg/ml, and when in use, the dextromethorphan dry powder is dissolved in 100ml of injection for intravenous injection, and the benzodiazepine is added>Intramuscular injection, each pack containing 45mg of dextromethorphan dry powder and 1ml of benzodiazepine>And (3) injection-like liquid.
The composition provided by the invention comprises dextromethorphan active ingredient and benzodiazepineSynergistic combination of the active ingredients can greatly improve the treatment effect on patients suffering from Major Depressive Disorder (MDD), especially refractory depression (TRD), and simultaneously treat benzodiazepines by acting to antagonize NMDA receptors and reduce the combined action of target points such as agonism of sigma-1 receptors and multiple mechanismsThe class reduces the amount of dextromethorphan used, reducing the potential for abuse that dextromethorphan may have.
In summary, the novel pharmaceutical composition for treating major depressive disorder covers a plurality of action targets for resisting depression, can greatly improve the treatment effect on MDD patients, especially TRD, and has the advantages of multiple targets, quick action and low abuse probability.
Meanwhile, the medicine prepared by the composition has the advantages of improving the treatment effective rate, prolonging the acting time, reducing the dosage and improving the bioavailability, and is more suitable for clinical application.
It is emphasized that benzodiazepinesThe analogues have similar action mechanisms and similar clinical effects, so that the clonazepam can be considered to be treated by the same-titer chlorodiazepine and clorazone->Acid, diazepam, fluoazepam, flunitrazepam, lorazepam, oxazepam, temazepam, prazepam, harazepam, quartzepam, alprazolam, triazolam, eszomib.
It should be emphasized that the examples described herein are illustrative rather than limiting, and therefore the invention includes, but is not limited to, the examples described in the detailed description, as other embodiments derived from the technical solutions of the invention by a person skilled in the art are equally within the scope of the invention.
Claims (9)
1. A novel pharmaceutical combination for the treatment of major depressive disorder comprising benzodiazepineActive ingredients and benzodiazepine>An active-like ingredient; the dextromethorphan active ingredient and benzodiazepine>The weight ratio of the similar active ingredients is 45-180:1.
2. the composition of claim 1, wherein the dextromethorphan active ingredient is dextromethorphan or a pharmaceutically acceptable salt thereof; the benzodiazepineThe active component is benzodiazepine>Class or benzodiazepine>Pharmaceutically acceptable salts.
3. Benzodiazepines according to claims 1 and 2A drug-like substance comprising clodiazepine and clorazone->Acid, diazepam, fluoazepam, fluniterDiazepam, clonazepam, lorazepam, oxazepam, temazepam, prazepam, harazepam, quarazepam, alprazolam, triazolam, eszomib.
4. A novel pharmaceutical combination for the treatment of major depressive disorder comprising a composition according to claim 1 or 2 and pharmaceutically acceptable excipients.
5. The medicine according to claim 3, wherein the dosage form of the medicine is any one of an oral tablet, a capsule, an oral liquid and an injection.
6. The pharmaceutical combination oral tablet and capsule of claim 3, comprising the following components in parts by weight: 45-180 parts of dextromethorphan or dextromethorphan pharmaceutically acceptable salt and benzodiazepineClass or benzodiazepine>1 part of pharmaceutically acceptable salt and 100 parts of auxiliary materials.
7. The pharmaceutical combination oral liquid according to claim 3, which is characterized by comprising the following components in parts by weight: dextromethorphan or 450mg of dextromethorphan pharmaceutically acceptable salt, and benzodiazepineClass or benzodiazepine>2.5-10mg of pharmaceutically acceptable salt and liquid auxiliary materials are added to the mixture to fix the volume to 100ml.
8. The pharmaceutical combination injection according to claim 3, wherein 45mg of dextromethorphan or dextromethorphan is used in medicineThe acceptable salt is prepared into dry powder, 0.25-1mg of benzodiazepineClass or benzodiazepine>The pharmaceutically acceptable salt is prepared into 1ml of injection with the concentration of 0.25-1mg/ml, and when in use, the dextromethorphan dry powder is dissolved in 100ml of injection for intravenous injection, and the benzodiazepine is added>Intramuscular injection, each pack containing 45mg of dextromethorphan dry powder and 1ml of benzodiazepine>And (3) injection-like liquid.
9. Use of a composition according to claim 1 or 2 for the preparation of a medicament for the treatment of major depressive disorder.
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