CN108078984A - The composition and its application of serotonin and norepinephrine reuptake inhibitors and cannabidiol - Google Patents
The composition and its application of serotonin and norepinephrine reuptake inhibitors and cannabidiol Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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Abstract
A kind of composition and its application in prevention and/treatment mental disorder, more particularly to a kind of 5 hydroxytryptamines and norepinephrine reuptake inhibitors (SNRI) are combined with cannabidiol (CBD) and its application in prevention and/or treatment depression.
Description
Technical field
A kind of application the present invention relates to composition and its in preventing and/or treating depression, more particularly to a kind of 5-
The combination of hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI) or its pharmaceutically useful salt and cannabidiol (CBD) and its
Application in preventing and/or treating depression.
Background technology
Depression refers to the serious medical conditions for influencing the thought of people, impression, behavior, mood and health.Principal characteristic
Depression is also referred to as clinical depression, major depressive disorder, the principal characteristic disturbance of emotion and unipolarity emotional conditions, can be related to following
Some combinations of symptom：It is depressed, pay attention to force difference, insomnia, fatigue, appetite disorder, excessive guilt and want to commit suiside.It does not treat
If, depression can cause serious daily life function to be damaged or even commit suiside.Researcher believe committed suicide people more than half
Live through depression.
Worldwide the adult of 5-10% suffers from depression.Even more people lives through relevant with depression
Mood disorder, after depression, seasonal Emotional Disorders and post-natal depression, bipolar disorder, anxiety disorder, wound
Stress disorders, paranoid fears and obsession etc..
Social economy's cost relevant with depression and individual and the manpower cost of family are huge.It is being diagnosed as pressing down
In 15 months after strongly fragrant disease, the possibility of patients with depression death wants 4 times high compared with the people that those do not suffer from depression.
Almost 60% suicide has its source in Serious depression, has 15% or so in the people being hospitalized for treatment due to depression in mental hospital
It is final to commit suiside.World Health Organization's estimation Serious depression is worldwide Disability adjusted life years (disability-
Adjusted life years) loss the 4th major reason, the reason for the year two thousand twenty will being second important.
It can be used for treating depression there are many pharmacological agents.By using serotonin (5-HT) reuptaking inhibitor
(SRI), norepinephrine reuptake inhibitors (NERI), serotonin and norepinephrine reuptake double inhibitor
(SNRI), monoamine oxidase inhibitors (MAQI), phosphodiesterase-4 (PDE4) inhibitor or other compounds have been obtained for
Great success.But even if there is these available selections, still treatment is not responded to by many patients or only partial response.
In addition, many of these substances show the delayed-action of activity, so that patient must just receive after treatment several weeks or several months
To benefit.Major part is currently available that antidepressants need 2-3 weeks or the longer time can just cause response.
The most important mechanism of serotonin (5-HT) inactivation is by nerve endings reuptake and is stored in vesica repeatedly profit
With followed by drawing indolylbutyric acid (5-hydroxyindoleacetic acid, 5-HIAA) into 5- hydroxyls through monoamine oxidase metabolism.It is existing
In the mechanism of action of most novel antidepressants, significant portion puts forth effort on the consumption for inhibiting 5-HT, clinically most widely used
Antidepressants selectivity 5-HT reuptaking inhibitors (SSRIs) are exactly selective depression 5-HT this intake effect, are made between cynapse
The rise of gap 5-HT contents is so as to improve the level of internal 5-HT, and so as to reach antidepressant curative effect, which is suitable for various types
Depression.
Norepinephrine (NE), scientific name 1- (3,4- dihydroxyphenyl) -2- ethylaminoethanols, are that adrenaline removes N- methyl
The substance formed afterwards, falls within catecholamine in chemical constitution.It is both a kind of neurotransmitter, mainly by neural after sympathetic section
Member and the synthesis of intracerebral adrenergic nerve tip and secretion, are the primary transmitter of the latter's release and a kind of hormone, by kidney
Gland medullary substance synthesizes and secretion, but content is less.
Duloxetine (Duloxetine) is that Lilly Co., Eli. resists with what Bo Linyin lattice company of Germany researched and developed jointly
Antidepressant agents.Duloxetine is a kind of serotonin and norepinephrine reuptake inhibitors.As described above, 5- hydroxyl colors
Amine, norepinephrine belong to central neurotransmitter, play an important role in terms of regulation and control emotion and to the susceptibility of pain.Degree
Duloxetine can inhibit reuptake of the neuron to serotonin and norepinephrine, thus improve both nervous centralis and pass
Concentration of the matter in brain and spinal cord, therefore can be used for treating depression.Venlafaxine (Venlafaxine) is equally a kind of SNRI
Reuptaking inhibitor, wherein it is most strong to serotonin reuptake transporter inhibitory action, to norepinephrine reuptake inhibitory action
It is relatively strong.
As described above, the serotonins such as Duloxetine and Venlafaxine and norepinephrine reuptake inhibitors (SNRI)
Recent development proved that the market of Neuscience has tended to inhibit serotonin and norepinephrine reuptake
The First Line that agent (SNRI) is used as various illnesss is treated.Although the side effect of SNRI and tricyclic antidepressant compound earlier
It compares, severity is lower, but still there are adverse side effects.Side effect can be generated by being combined with these receptors, such as dry, thermophilic
It sleeps, appetite stimulation and some cardiovascular risk factors.The higher norepinephrine activity of SNRI is directed to many side effects,
Therefore its application is limited.For example, it is currently available that SNRI for irritable bowel syndrome
The treatment of (irritablebowelsyndrome, IBS) has limited application, this is because in the presence of related to higher NE activity
Constipation side effect.In addition, potential excess dose situation and excess adrenergic stimulation epileptic attack, cardiac arrhythmia, heartbeat Xu
Slow, hypertension, low blood pressure are even dead related.
Undoubtedly, for that can prevent or treat depression, without causing effective treatment of side effect, there are important demands.
Particularly, obtain for dry, drowsiness, loss of appetite, angiocardiopathy, constipation, epileptic attack, cardiac arrhythmia, areocardia,
The product of the side effects such as hypertension, low blood pressure is very important, and is made because the injury that these side effects are brought may arrive greatly
Patient cuts out this drug and is injured with mitigating it caused by body.
Existing research is thought it is assumed that adult that hemp is replicated as important neuroprotective agent and newborn acute, slow
It also confirms that, and thinks and its vasodilator, inhibition excitatory amino acid and cell factor in nerve degeneration animal model
Release, inhibition oxidative stress and nitric oxide production toxic product, some activity of modulation cannboid are related.CN101939017A is public
It has opened plant cannabinoids to combine to prevent or treat mental disease or phrenoblabia with Aripiprazole, to reduce or eliminate A Li piperazines
The adverse side effect of azoles, wherein the adverse side effect reduced or eliminated is selected from catalepsy and ptosis.
Hemp knows already as the application of medicine, and in 19th century, hemp products is proposed as hypnosis sedative,
It can be used for treatment hysteria, amentia, epilepsy, nerve insomnia, antimigraine and dysmenorrhoea.
In the 1940s, researcher's isolated cannabidiol (CBD) from hemp, experiment in vivo finds CBD not
But the psychotropic activity that energy antagonism THC excitement cannboid I receptors (CB1R) are triggered, and with anticonvulsion, antianxiety, anti-essence
Refreshing disease, tranquilizing soporific, anti-inflammatory and neuroprotection.Preclinical and clinical research shows that CBD pharmacokinetics are good, injection
After can penetrate blood-brain barrier (blood-brain barrier, BBB) rapidly, neuroprotection effect is notable.CBD can pass through
Multipath plays neuroprotection, and its toxicity is weak, few side effects.
Therefore, the present inventor attempt by serotonin and norepinephrine reuptake inhibitors (SNRI) or its
Composition is made in pharmaceutically useful salt and CBD, for the prevention and/or treatment of depression, has received good effect, not only can be with
Prevention and/or treatment depression, can also be mitigated or eliminated side effect.
The content of the invention
The present invention is intended to provide a kind of composition, and provide the composition of said composition and its preventing and/or treating
Application in depression.
Provided by the present invention for treating the composition of depression, press down including serotonin and norepinephrine reuptake
Preparation or its pharmaceutically useful salt and CBD.
The method for preparing above-mentioned composition, includes the following steps：By the serotonin and norepinephrine reuptake
Inhibitor or its pharmaceutically useful salt are mixed in proportion with CBD, obtain the composition.
Serotonin of the present invention and the pharmaceutically useful salt of norepinephrine reuptake inhibitors include with inorganic acid or
The acid-addition salts that organic acid is formed, the inorganic acid is such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid；The organic acids
As acetic acid, propionic acid, caproic acid, enanthic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid,
Citric acid, benzoic acid, o- (4- hydroxy benzoyls) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, trimethylacetic acid, uncle
Butylacetic acid, dodecyl sulphate, gluconic acid, glutamic acid, naphthoic acid, salicylic acid, stearic acid etc..
Composition of the present invention can be made into specific dosage form, for example oral by any appropriate approach, rectum,
Nose, lung, part (including oral cavity and sublingual), in transdermal, brain pond, intraperitoneal, vagina and parenteral (including subcutaneous, intramuscular, sheath
It is interior, intravenous and intracutaneous) approach administration is preferably oral route.It is to be understood that optimization approach depends on the general of patient to be treated
Situation and age, the property of disease to be treated and concrete activity ingredient etc..
The composition of oral medication includes solid dosage forms, such as capsule, tablet, sugar coated tablet, pill, pastille, powder agent
And granule.
The composition of oral medication further includes liquid dosage form, such as solution, emulsion, suspension, syrup and elixir.
The composition of parenteral includes sterile aqueous and non-aqueous injectable solutions, dispersion liquid, suspension or breast
Liquid and the aseptic powdery for being redissolved in sterile injectable solution or dispersion liquid before use.
The suitable form of administration of others includes suppository, spray, ointment, cream, gelling agent, inhalant, skin paste
Piece, implants etc..
The composition or composition produced by the invention of the present invention can be given by any appropriate approach, such as with
The forms such as tablet, capsule, powder agent, syrup take orally or parental injection as a solution.In order to prepare this combination
Methods known in the art can be used in object, and in the art usually used any pharmaceutically acceptable carrier, dilute can be used
Release agent, excipient or other additives.
For parenteral, can use the aseptic aqueous solutions of one or more active ingredients, aqueous propylene glycol solution,
Aqueous vitamin e solution or sesame oil or peanut oil solution.If it is necessary, this aqueous solution should be buffered appropriately, and liquid
Body diluent is made isotonic of enough salt or glucose first.Aqueous solution be particularly suitable for it is intravenous, intramuscular, subcutaneous and
Intraperitoneal administration.Sterile aqueous media used by being easily made by standard technique well known by persons skilled in the art.
It is (preferably sterile by the way that one or more active ingredients and possible additive are dissolved in a part of solvent for injection
Water), to required volume, sterile solution is simultaneously filled into appropriate ampoule or bottle adjustment solution, and it is molten can to prepare injection
Liquid.Common any appropriate additive in the art, such as tonicity agents, preservative, antioxidant etc. can be added in.
Appropriate pharmaceutical carrier includes inert solid diluent or filler, aseptic aqueous solution and various organic solvents.
The example of solid carrier has lactose, carclazyte, sucrose, cyclodextrin, talcum powder, agar, pectin, Arabic gum, tristearin
Acid, the lower alkyl ether of cellulose, cornstarch, potato starch, talcum powder, magnesium stearate, gelatin, lactose, glue etc..
The auxiliary material or additive of any other the purpose of being commonly used in coloring, flavoring, anti-corrosion can be used, as long as them and work
Property ingredient or used ingredient are compatible.
The example of liquid-carrier has syrup, peanut oil, olive oil, phosphatide, aliphatic acid, fatty acid amine, polyoxyethylene and water.
Similar, carrier or diluent can include any slow-release material known in the art, such as mix individually or with wax
Glycerin monostearate or distearin.
By the way that the active ingredient of one or more present invention to be mixed to the composition to be formed with pharmaceutically acceptable carrier,
Then can easily be given with the various dosage forms of suitable open administration route.It can be facilitated by known method in pharmaceutical field
Ground makes preparation exist with unit dosage forms.
The active ingredient of the present invention can be formulated as similar or dissimilar pharmaceutical composition and its unit dosage forms.
If oral medication, using solid carrier, preparation can be tablet, the powder or piller that are placed in hard gelatin capsule
Form can be lozenge or lozenge form.
If using liquid carrier, preparation can be syrup, emulsion, Perle or sterile injection liquid, example
Such as aqueous or non-aqueous liquid suspension or solution.Pharmaceutical preparation can be conveniently fabricated unit according to the standardization program of pharmaceutical formulation
Dosage form.The amount of the reactive compound of per unit dose may change according to the property and expected dosage of reactive compound
Become.In general, this can be in the range of per unit dose 0.1mg~5000mg.
CBD used in the present invention can be chemosynthesis product, biosynthetic products, plant extracts or using other
Mode is prepared.Preferably, cannabidiol of the present invention is plant extracts, and the plant can be hemp
The stalk core of Cannabis sativa L., flower, leaf, the shell of seed and/or seed.
By the pharmaceutical properties of each ingredient, the property of the pharmaceutical composition and the patient symptom for considering to combine, determine
Drug dose used in the present invention.
Serotonin and norepinephrine reuptake inhibitors or the commonly used about 20-60mg/ of its pharmaceutically useful salt
The amount of (or about 10-30mg/ is twice a day) once a day, more preferably application about 30-40mg/ (or about 10- once a day
20mg/ is twice a day) amount.
In general, serotonin and norepinephrine reuptake inhibitors or the weight ratio of its pharmaceutically useful salt and CBD are
Consider the pharmaceutical properties of two kinds of ingredients, the property of pharmaceutical composition and patient symptom and determine, it is preferable that serotonin and go first
Adrenaline reuptake inhibitors or the weight ratio of its pharmaceutically useful salt and CBD are about 1:0.2-60, it is highly preferred that 5- hydroxyl colors
Amine and norepinephrine reuptake inhibitors or the weight ratio of its pharmaceutically useful salt and CBD are about 1:0.5-30, in this hair
Serotonin and norepinephrine reuptake inhibitors or the weight ratio 1 of its pharmaceutically useful salt and CBD in bright embodiment:
0.2、1:0.3、1:0.4、1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:
8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:21、1:22、1:23、
1:24、1:25、1:26、1:27、1:28、1:29、1:30、1:31、1:32、1:33、1:34、1:35、1:36、1:37、1:38、1:
39、1:40、1:41、1:42、1:43、1:44、1:45、1:46、1:47、1:48、1:49、1:50、1:51、1:52、1:53、1:
54、1:55、1:56、1:57、1:58、1:59、1:60。
The invention further relates to a kind of composition, it is used to prevent and/or treats depression or mental disease, the composition bag
Containing a effective amount of first compound of antidepression or antipsychotic and second compound, first compound be selected from serotonin and
One or more in norepinephrine reuptake inhibitors or its pharmaceutically useful salt；The second compound is hemp two
Phenol；Optionally, one or more pharmaceutically acceptable carriers can also be included.
Further, it is depressed to include psychogenic depression, endogenous depression, hypochondriasis type depression and anxiety depression, pseudodementia
Type is depressed, chronic depression.
Further, serotonin and norepinephrine reuptake inhibitors or its pharmaceutically useful salt are selected from Du Luoxi
One kind in spit of fland, Venlafaxine, Milnacipran and combinations thereof.
In an embodiment of the present invention, in composition serotonin and norepinephrine reuptake inhibitors or its can medicine
The weight ratio of salt and cannabidiol is 1:0.2-60；Preferably 1:0.5-30.
Further, composition be selected from capsule, tablet, sugar coated tablet, pill, pastille, powder agent, granule, solution,
Emulsion, suspension, syrup, sterile injectable solution, the aseptic powdery of dispersion liquid, suppository, spray, ointment, cream,
One kind in gelling agent, inhalant, dermal patch or implants.
Meanwhile it is used to prepare prevention and/or treatment depression or the purposes of antipsychotic drugs, bag the present invention relates to a kind of
It includes and is taken orally to the patient, is intramuscular, in vein, peritonaeum or parenteral gives antidepression or a effective amount of composition of antipsychotic.
It is further, a kind of to be used to prepare the medicinal usage for reducing side effect after depression or mental patient's medication,
A effective amount of composition of side effect is reduced including being given in the form of oral formulations or parenteral administration to the individual.
Patient is selected from people, mouse, rat, cavy, dog, cat, horse, ox, pig or non-human primate.
The invention further relates to a kind of medicinal usage of cannabidiol pharmaceutical composition, said composition is used to that list to be mitigated or eliminated
Dry, the drowsiness, appetite solely excited using serotonin and norepinephrine reuptake inhibitors or its pharmaceutically useful salt is subtracted
Move back, angiocardiopathy, constipation, epileptic attack, the side effect of cardiac arrhythmia, areocardia, hypertension, low blood pressure etc..
One embodiment of the present of invention is related to a kind of for preventing and/or treating depression or the kit of mental disease, institute
Stating kit includes composition.
Further, the present invention relates to a kind of method prevented and/or treatment is depressed, controlled including giving patient in need
Treat a effective amount of cannabidiol and serotonin and norepinephrine reuptake inhibitors or its pharmaceutically useful salt combination.
Unless otherwise stated, term " unit dosage forms ", which refers to, is suitable as the single of people experimenter and other mammals
The physically discrete unit of dosage, each unit include combined with the pharmaceutical carrier of needs be computed can be during treatment
The active material of the predetermined amount of desired prevention or therapeutic effect is generated in the process.
In certain embodiments, term " patient " refers to people.
" application " of the present invention is directed to patient and directly applies compound or composition or apply compound to patient
Prodrug derivant or the like, the reactive compound or substance of equivalent amount will be formed in patient's body.
Unless otherwise stated, term " pharmaceutically acceptable auxiliary material " be meant that the ingredient do not have bioactivity or its
The impurity of his bad activity, such as the ingredient can be included in disclosed pharmaceutical preparation and give patient, but not cause significantly not
Good biological effect generates interaction with the other compositions included in said preparation in harmful manner.
Unless otherwise stated, term " treatment " includes inhibition, delay, mitigation, decrease, limitation, mitigation or regression disease
Disease, obstacle, illness or state, generation and/or process and/or its symptom.
Unless otherwise stated, term " prevention " includes reducing following risk：Suffer from, infect or undergo disease, obstacle,
Illness or state, generation and/or process and/or its symptom.
Unless otherwise stated, term "comprising" represents " opening " or " inclusive " term so that they include enumerating
Element, but also allow to include additional, unmentioned element.
Specific embodiment
It should be noted that in the case where there is no conflict, the feature in embodiment and embodiment in the application can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
The achievable formula of 1 composition of the present invention of embodiment is enumerated
Serotonin is given below and some of norepinephrine reuptake inhibitors and cannabidiol are nonrestrictive
Formulation Example.
1. experiment 1
It is formulated sample group 1
According to preparation method well known within the skill of those ordinarily skilled, the tablet containing above-mentioned formula is prepared.
Control group 1
According to preparation method well known within the skill of those ordinarily skilled, the tablet containing above-mentioned formula is prepared.
2. experiment 2
It is formulated sample group 2
According to preparation method well known within the skill of those ordinarily skilled, the tablet containing above-mentioned formula is prepared.
Control group 2
According to preparation method well known within the skill of those ordinarily skilled, the tablet containing above-mentioned formula is prepared.
3. experiment 3
It is formulated sample group 3
According to preparation method well known within the skill of those ordinarily skilled, above-mentioned formula is mixed and is packaged in hard gelatin capsule
In be made.
Control group 3
According to preparation method well known within the skill of those ordinarily skilled, above-mentioned formula is mixed and is packaged in hard gelatin capsule
In be made.
4. experiment 4
It is formulated sample group 4
According to preparation method well known within the skill of those ordinarily skilled, above-mentioned formula is mixed and to be packaged in soft capsule (soft
Capsule shells formula is gelatin by weight:Glycerine:Water is 100:55:75) it is made in.
Control group 4
According to preparation method well known within the skill of those ordinarily skilled, above-mentioned formula is mixed and to be packaged in soft capsule (soft
Capsule shells formula is gelatin by weight:Glycerine:Water is 100:55:75) it is made in.
5. experiment 5
It is formulated sample group 5
Preparation method：Water for injection about 800ml is taken, adds in appropriate 0.1mol/L HCl and hydroxypropyl-β-cyclodextrin, is stirred
Dissolving, then CBD and Milnacipran is added to be allowed to dissolve, it is 6.2-6.5 to adjust pH value with 0.1mol/L HCl, is injected water to complete
Amount stirs evenly, filtration, and embedding is in ampoule, with 100 DEG C of sterilizing 30min of flowing steam.
Control group 5
Preparation method：Water for injection about 800ml is taken, adds in appropriate 0.1mol/L HCl and hydroxypropyl-β-cyclodextrin, is stirred
Dissolving, adds Milnacipran to be allowed to dissolve, and it is 6.2-6.5 to adjust pH value with 0.1mol/L HCl, adds to the full amount of water for injection and stirs evenly,
Filtration, embedding is in ampoule, with 100 DEG C of sterilizing 30min of flowing steam.
2 serotonin of embodiment and norepinephrine reuptake inhibitors cooperate with antidepressant effect with CBD's
First, experimental principle：
Forced swim test is also referred to as " behavioral despair " experiment, is a believable depressed animal model, is widely used
In screening antidepression class drug and the mechanism of action of research antidepressant, substantial amounts of research shows, it has already been proven that the model
It is sensitive for most of antidepressant.
2nd, experimental method：
Rat (about 200g) 110 is randomly divided into 11 groups by gender weight, every group 10, half male and half female, room temperature 22 ± 1
DEG C, humidity 50 ± 10%, natural lighting, drinking-water of freely ingesting.All animals start to test after adapting in feeding environment 5 days,
When fasting 12-16 is small before experiment, drinking water is free.
It is formulated sample group (combination group):Formula sample group 1-5 (in experiment 1-5) in embodiment 1；Wherein, serotonin and
Norepinephrine reuptake inhibitors group dosage is 7mg/kg weight, and serotonin and norepinephrine reuptake inhibit
Agent and CBD are according to each component ratio in formula sample group 1-5.
Control group (serotonin and norepinephrine reuptake inhibitors use group)：In embodiment 1 (in experiment 1-5)
Control group 1-5.
Control group one group (control group 6) is set up simultaneously, is given only isometric physiological saline.
Before official testing 24 it is small when, mouse is placed in glass circle cylinder (high 25cm, diameter 10cm) of depth of water 10cm, water temperature
24 ± 1 DEG C, make forced swimming and train 15 minutes.Mouse is placed in again after each group is administered strong in the glass circle cylinder of depth of water 10cm
System swimming 6min observes and records the dead time of mouse in last 4 minutes.It is floating to keep in water not when mouse stopping struggle
It is dynamic or only do the time that some necessary mild actions keep heads to float on the surface and be considered as non-swimming time.
3rd, experimental result：
In the forced swim test of mouse, formula sample group (experimental group) 1-5 and control group 1-5 generate antidepression respectively
Effect.Being formulated sample group 1-5 (combination group) and control group 1-5, (serotonin and norepinephrine reuptake inhibitors use
Group) dose-dependently reduce dead time of the mouse in swimming test.Also, use 5- from the results, it was seen that merging
Hydroxytryptamine and norepinephrine reuptake inhibitors and CBD can play synergistic effect, hence it is evident that improve serotonin and go first
Adrenaline reuptake inhibitors resist motionless effect (P ＜ 0.05).
The influence of 1 serotonin of table and norepinephrine reuptake inhibitors and CBD to mouse non-swimming time
Note：* P ＜ 0.05 compared with the control group；* P ＜ 0.01
3 serotonin of embodiment and norepinephrine reuptake inhibitors mitigate constipation side effect with CBD combinations
First, experimental method：
Healthy Kunming mouse 90, weight 20-25g is taken, is randomly divided into 9 groups by gender weight, every group 10, male and female are each
Half.22 ± 1 DEG C of room temperature, humidity 50 ± 10%, natural lighting, drinking-water of freely ingesting.All animals adapt to 5 days in feeding environment
After start to test, animal sub-cage rearing used quantitatively gives feeding.
It is formulated sample group (combination group):Formula sample group 1-4 (in experiment 1-4) in embodiment 1；Wherein, serotonin and
Norepinephrine reuptake inhibitors group dosage is 7mg/kg weight, and serotonin and norepinephrine reuptake inhibit
Agent and CBD are according to each component ratio in formula sample group 1-4.
Control group (serotonin and norepinephrine reuptake inhibitors use group)：In embodiment 1 (in experiment 1-4)
Control group 1-4.
Control group one group (control group 6) is set up simultaneously, is given only isometric physiological saline.
Before experiment 1 day 10 animals of record first grain row's melena time and in 12h defecation grain number and weight, and by each group
Mouse is deprived of food but not water 16h, and when measuring next day, formula sample group 1-4 (7mg/kg) and control group 1-4 difference gavages give food simultaneously
Administration, 6 gavage of control group, which gives to eat and give, waits capacity physiological saline.Again to carbon dust liquid indicator (black), animal single cage after 30min
It feeds, normal water and feed, from carbon dust liquid indicator (black) every animal of start recording first grain row's melena time and in 12h
The grain number and weight of defecation just.
The data obtained carries out statistical disposition, and the significant difference between comparative group with spss.17.0 softwares.
2nd, experimental result
The experimental results showed that (referring to table 2), serotonin and norepinephrine reuptake inhibitors arrange mouse with CBD
Just side effect plays an important role of to mitigate, it can be seen that with individually intake serotonin and norepinephrine reuptake inhibitors phase
Absorbed simultaneously with CBD than, serotonin and norepinephrine reuptake inhibitors can accelerate for the first time defecation time, increase it is small
Mouse defecation frequency and defecation weight illustrate that serotonin and norepinephrine reuptake inhibitors are absorbed simultaneously with CBD to list
Solely using serotonin and norepinephrine reuptake inhibitors the side effect of constipation is caused to have certain inhibitory action.Therefore, may be used
Under suitable proportion, serotonin and norepinephrine reuptake inhibitors to be shared with CBD, serotonin can be mitigated
The side effect of the constipation brought with norepinephrine reuptake inhibitors.
Table 2CBD is combined the shadow to the mouse defecation duration with serotonin and norepinephrine reuptake inhibitors
It rings
* P ＜ 0.05, * * P ＜ 0.01
Embodiment 4：Serotonin and norepinephrine reuptake inhibitors mitigate dry side effect with CBD combinations
First, experimental method：
Healthy Kunming mouse 90, weight 20-25g is taken, is randomly divided into 9 groups by gender weight, every group 10, male and female are each
Half.22 ± 1 DEG C of room temperature, humidity 50 ± 10%, natural lighting, drinking-water of freely ingesting.All animals adapt to 5 days in feeding environment
After start to test, animal sub-cage rearing used quantitatively gives feeding.
It is formulated sample group (combination group):Formula sample group 1-4 (in experiment 1-4) in embodiment 1；Wherein, serotonin and
Norepinephrine reuptake inhibitors group dosage is 7mg/kg weight, and serotonin and norepinephrine reuptake inhibit
Agent and CBD are according to each component ratio in formula sample group 1-4.
Control group (serotonin and norepinephrine reuptake inhibitors use group)：In embodiment 1 (in experiment 1-4)
Control group 1-4.
Control group one group (control group 6) is set up simultaneously, is given only isometric physiological saline.
1 day record 10 drinking water for animals number and water before experiment, and by each group mouse 16h fasting for solids and liquids, surveyed in next day
Periodically, it is formulated sample group 1-4 (7mg/kg) and control group 1-4 and gives gastric infusion respectively, control group 6, which gives, waits capacity physiology salt
Water.Each group animal single cage is fed, normal water and feed, interior every drinking water for animals number and water when record 6 is small.
The data obtained carries out statistical disposition, and the significant difference between comparative group with spss.17.0 softwares.
3 serotonin of table and norepinephrine reuptake inhibitors are combined the influence to dry side effect with CBD
Note：* P ＜ 0.05, * * P ＜ 0.01
2nd, experimental result
The experimental results showed that serotonin and norepinephrine reuptake inhibitors and CBD are to mouse dry side effect
There is mitigation, it can be seen that compared with individually intake serotonin and norepinephrine reuptake inhibitors, 5- hydroxyls
Tryptamines and norepinephrine reuptake inhibitors absorb the number and quantity that can reduce mouse drinking-water, explanation with CBD simultaneously
CBD causes the side effect of dry to have certain inhibitory action serotonin and norepinephrine reuptake inhibitors.It therefore, can be with
Under suitable proportion, serotonin and norepinephrine reuptake inhibitors are shared with CBD, to mitigate serotonin and go
The side effect for the dry that methylepinephrine reuptaking inhibitor is brought.
Claims (12)
1. a kind of composition, it is used to prevent and/or treats depression or mental disease, the composition include antidepression or anti-essence
Refreshing sick a effective amount of first compound and second compound, first compound are selected from serotonin and norepinephrine again
One or more in uptake inhibitor or its pharmaceutically useful salt；The second compound is cannabidiol；Optionally, further include
One or more pharmaceutically acceptable carriers.
2. composition according to claim 1, which is characterized in that the depression includes psychogenic depression, endogenous presses down
Strongly fragrant, hypochondriasis type depression and anxiety depression, pseudodementia type are depressed, chronic depression.
3. composition according to claim 1 or 2, wherein the serotonin and norepinephrine reuptake inhibitors
Or its pharmaceutically useful salt is selected from Duloxetine, Venlafaxine, Milnacipran and its pharmaceutically useful salt.
4. according to claim 1-3 any one of them compositions, wherein serotonin and noradrenaline in the composition
Plain reuptaking inhibitor or the weight ratio of its pharmaceutically useful salt and cannabidiol are 1:0.2-60；Preferably 1:0.5-30.
5. according to claim 1-4 any one of them compositions, which is characterized in that the composition be selected from capsule, tablet,
It is sugar coated tablet, pill, pastille, powder agent, granule, solution, emulsion, suspension, syrup, sterile injectable solution, scattered
One in the aseptic powdery of liquid, suppository, spray, ointment, cream, gelling agent, inhalant, dermal patch or implants
Kind.
6. according to claim 1-5 any one of them compositions, which is characterized in that the cannabidiol is plant extract
Object, the plant are selected from the shell of the stalk core of hemp Cannabis sativa L., flower, leaf, root and/or seed.
7. a kind of be used to prepare the prevention of claim 1-6 any one of them and/or the medicine group for the treatment of depression or mental disease
The purposes of object is closed, including being taken orally to the patient, in intramuscular, vein, peritonaeum or parenteral gives antidepression or antipsychotic
A effective amount of claim 1-6 any one of them compositions.
8. a kind of claim 1-6 any one of them that is used to prepare reduces side effect after depression or mental patient's medication
Medicinal usage reduces a effective amount of power of side effect including being given in the form of oral formulations or parenteral administration to the individual
Profit requires 1-6 any one of them compositions.
9. according to claim 7-8 any one of them purposes, which is characterized in that the patient is selected from people, mouse, rat, globefish
Mouse, dog, cat, horse, ox, pig or non-human primate.
10. a kind of purposes of cannabidiol pharmaceutical composition, said composition for be mitigated or eliminated be used alone serotonin and
Norepinephrine reuptake inhibitors or the dry of its pharmaceutically useful salt excitation, drowsiness, anorexia, angiocardiopathy, just
Secret, epileptic attack, the side effect of cardiac arrhythmia, areocardia, hypertension, low blood pressure.
11. a kind of for preventing and/or treating depression or the kit of mental disease, the kit includes claim 1-6
Any one of them composition.
12. a kind of method prevented and/or treatment is depressed, this method includes the right for giving bacterium in need
It is required that 1-6 any one of them compositions.
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| WO2022221613A1 (en) * | 2021-04-16 | 2022-10-20 | Apnimed, Inc. (Delaware) | Combination of a norepinephrine reuptake inhibitor and a cannabinoid for use in treating sleep apnea |
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|---|---|---|---|---|
| WO2007052013A1 (en) * | 2005-11-01 | 2007-05-10 | Gw Pharma Limited | A combination of cannabinoids for the treatment of peripheral neurophatic pain |
| CN101939017A (en) * | 2008-01-04 | 2011-01-05 | Gw药品有限公司 | Anti-psychotic composition comprising cannabinoids and anti-psychotic medicament |
| WO2016141056A1 (en) * | 2015-03-02 | 2016-09-09 | Afgin Pharma, Llc | Topical regional neuro-affective therapy with cannabinoids |
| CN105943618A (en) * | 2016-06-14 | 2016-09-21 | 云南瑞酚生物科技有限公司 | Drug for treating depression |
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2016
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| WO2007052013A1 (en) * | 2005-11-01 | 2007-05-10 | Gw Pharma Limited | A combination of cannabinoids for the treatment of peripheral neurophatic pain |
| CN101939017A (en) * | 2008-01-04 | 2011-01-05 | Gw药品有限公司 | Anti-psychotic composition comprising cannabinoids and anti-psychotic medicament |
| WO2016141056A1 (en) * | 2015-03-02 | 2016-09-09 | Afgin Pharma, Llc | Topical regional neuro-affective therapy with cannabinoids |
| CN105943618A (en) * | 2016-06-14 | 2016-09-21 | 云南瑞酚生物科技有限公司 | Drug for treating depression |
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| WO2022221613A1 (en) * | 2021-04-16 | 2022-10-20 | Apnimed, Inc. (Delaware) | Combination of a norepinephrine reuptake inhibitor and a cannabinoid for use in treating sleep apnea |
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