CN108078984B - Composition of 5-hydroxytryptamine and norepinephrine reuptake inhibitor and cannabidiol and application thereof - Google Patents
Composition of 5-hydroxytryptamine and norepinephrine reuptake inhibitor and cannabidiol and application thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
A composition and application thereof in preventing and/or treating mental diseases, in particular to a combination of 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SNRI) and Cannabidiol (CBD) and application thereof in preventing and/or treating depression.
Description
Technical Field
The invention relates to a composition and application thereof in preventing and/or treating depression, in particular to a combination of 5-hydroxytryptamine and a norepinephrine reuptake inhibitor (SNRI) or pharmaceutically acceptable salt thereof and Cannabidiol (CBD) and application thereof in preventing and/or treating depression.
Background
Depression refers to a serious medical condition that affects a person's mind, feeling, behavior, mood, and physical health. Major depression, also known as clinical depression, major depressive disease, major affective disorder, and unipolar mood disorder, may involve some combination of the following symptoms: depressed mood, poor attention, insomnia, fatigue, appetite disorders, excessive guilt, and thought of suicide. Left untreated, depression can cause severe impairment of daily function, even suicide. Researchers believe that more than half of the suicidal deaths experience depression.
Depression occurs in 5-10% of adults worldwide. Even more people have experienced mood disorders associated with depression such as dysthymia, seasonal affective disorder and post-partum depression, bipolar disorder, anxiety, post-traumatic stress disorder, panic disorder and obsessive compulsive disorder.
The socio-economic costs associated with depression and the human costs of individuals and families are enormous. Within 15 months after being diagnosed with depression, patients with depression are 4 times more likely to die than those who do not have depression. Almost 60% of the suicide roots are major depression, with about 15% of people admitted to the hospital for psychiatric treatment due to depression ultimately suiciding. The world health organization estimates that major depression is the fourth major cause of disability-adjusted life year (disability-adjusted life years) loss worldwide, and will be the second major cause by 2020.
There are a number of pharmacological substances that are useful in the treatment of depression. Significant success has been achieved through the use of 5-hydroxytryptamine (5-HT) reuptake inhibitors (SRI), norepinephrine reuptake inhibitors (NERI), dual 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAQI), phosphodiesterase-4 (PDE4) inhibitors, or other compounds. However, even with these options available, many patients still do not respond or only partially respond to treatment. In addition, many of these substances exhibit a delayed effect of activity, so that the patient must be treated weeks or months before receiving benefit. Most currently available antidepressants require 2-3 weeks or more to elicit a response.
The most important mechanism of 5-hydroxytryptamine (5-HT) inactivation is reuptake by nerve endings and storage in vesicles for recycling, followed by metabolism to 5-hydroxyindoleacetic acid (5-hydroxyandioic acid) via monoamine oxidase. Most of the prior novel antidepressant drugs have the action mechanism of inhibiting the consumption of 5-HT, and the antidepressant drug selective 5-HT reuptake inhibitor (SSRis) which is most widely applied clinically has the effect of selectively inhibiting the uptake of 5-HT, so that the 5-HT content in synaptic cleft is increased, the level of the 5-HT in vivo is improved, and the antidepressant drug is suitable for various types of depression.
Norepinephrine (NE), the scientific name 1- (3, 4-dihydroxyphenyl) -2-aminoethanol, is a substance formed by removing the N-methyl group from epinephrine, and also belongs to catecholamines in chemical structure. It is both a neurotransmitter, synthesized and secreted primarily by the postsympathetic neurons and by the intracerebral adrenergic nerve endings, the major transmitter released by the latter, and a hormone, synthesized and secreted by the adrenal medulla, but in minor amounts.
Duloxetine (Duloxetine) is an antidepressant drug developed by american gifts and german brilin invar. Duloxetine is a 5-hydroxytryptamine and norepinephrine reuptake inhibitor. As mentioned above, 5-hydroxytryptamine and norepinephrine are central neurotransmitters and play an important role in the regulation of emotion and sensitivity to pain. Duloxetine inhibits the reuptake of 5-hydroxytryptamine and norepinephrine by neurons, thereby increasing the concentration of these two central neurotransmitters in the brain and spinal cord, and is useful for the treatment of depression. Venlafaxine (Venlafaxine) is also an SNRI reuptake inhibitor, and has the strongest inhibition effect on reuptake of 5-hydroxytryptamine and stronger inhibition effect on reuptake of norepinephrine.
As noted above, recent developments in 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI), such as duloxetine and venlafaxine, have demonstrated that the neuroscience market is already trending 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI) as the first line of treatment for a variety of conditions. Although the side effects of SNRI are less severe than earlier tricyclic antidepressant compounds, adverse side effects still remain. Binding to these receptors can produce side effects such as dry mouth, lethargy, appetite stimulation and several cardiovascular risk factors. The higher noradrenaline activity of SNRI also involves a number of side effects, thus limiting its use. For example, currently available SNRIs have limited application for the treatment of Irritable Bowel Syndrome (IBS) because of the constipation side effects associated with higher NE activity. In addition, potential overdose situations are associated with excessive adrenergic stimulation of seizures, arrhythmia, bradycardia, hypertension, hypotension and even death.
Clearly, there is an important need for effective treatments that can prevent or treat depression without causing side effects. In particular, it is important to have products that address the side effects of dry mouth, lethargy, anorexia, cardiovascular disease, constipation, seizures, arrhythmia, bradycardia, hypertension, hypotension, etc., as the damage from these side effects may be so great as to stop the patient from taking the drug to reduce the physical harm.
Existing studies suggest that cannabis is also demonstrated in adult and neonatal acute and chronic neurodegenerative animal models that are presumed to replicate as an important neuroprotective agent, and are thought to be involved in its vasodilation, inhibition of excitatory amino acid and cytokine release, inhibition of oxidative stress and toxic products of nitric oxide, modulation of certain activities of cannabinoids. CN101939017A discloses phytocannabinoids in combination with aripiprazole for use in the prevention or treatment of psychosis or psychotic disorders to reduce or eliminate the adverse side effects of aripiprazole, wherein the adverse side effects reduced or eliminated are selected from catalepsy and ptosis.
The use of cannabis as a medicine has long been known and in the 19 th century, cannabis products have been recommended as hypnotic sedatives which are useful in the treatment of hysteria, confusion, epilepsy, neurological insomnia, migraine and dysmenorrhea.
In the 40 s of the 20 th century, researchers isolated Cannabidiol (CBD) from cannabis sativa, and in vivo experiments found that CBD not only antagonized the psychotropic activity of THC agonizing cannabinoid type I receptor (CB1R), but also had anticonvulsant, anxiolytic, antipsychotic, sedative-hypnotic, anti-inflammatory and neuroprotective effects. Preclinical and clinical studies show that CBD has good pharmacokinetic properties, can rapidly penetrate blood-brain barrier (BBB) after injection, and has remarkable cerebral neuroprotective effect. CBD can exert neuroprotective effect through multiple pathways, and has weak toxicity and few side effects.
Therefore, the inventor of the present invention tried to prepare a composition of 5-hydroxytryptamine and a norepinephrine reuptake inhibitor (SNRI) or a pharmaceutically acceptable salt thereof and CBD for the prevention and/or treatment of depression, which received a good effect, not only in the prevention and/or treatment of depression, but also in the alleviation or elimination of side effects.
Disclosure of Invention
The invention aims to provide a composition, and provides a composition of the composition and application of the composition in preventing and/or treating depression.
The invention provides a composition for treating depression, which comprises 5-hydroxytryptamine, a norepinephrine reuptake inhibitor or pharmaceutically acceptable salts thereof and CBD.
The method for preparing the composition comprises the following steps: and uniformly mixing the 5-hydroxytryptamine and the norepinephrine reuptake inhibitor or the pharmaceutically acceptable salt thereof with CBD according to a proportion to obtain the composition.
Pharmaceutically acceptable salts of 5-hydroxytryptamine and norepinephrine reuptake inhibitors according to the present invention include acid addition salts formed with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, tertiaryvaleric acid, tertiarybutylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, naphthoic acid, salicylic acid, stearic acid, and the like.
The compositions of the present invention may be formulated into specific dosage forms for administration by any suitable route, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, preferably oral routes. It will be appreciated that the preferred route will depend, inter alia, on the general condition and age of the patient to be treated, the nature of the disease to be treated and the specific active ingredient.
Compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.
Compositions for oral administration also include liquid dosage forms such as solutions, emulsions, suspensions, syrups and elixirs.
Compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use.
Other suitable dosage forms for administration include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like.
The composition of the invention or produced according to the invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups and the like, or parenterally in the form of solutions. To prepare such compositions, methods known in the art may be employed, and any pharmaceutically acceptable carrier, diluent, excipient, or other additive commonly used in the art may be employed.
For parenteral administration, sterile aqueous solutions, aqueous propylene glycol solutions, aqueous vitamin E solutions or solutions of sesame or peanut oil of one or more of the active ingredients may be employed. If necessary, such aqueous solutions should be suitably buffered and the liquid diluent first rendered isotonic with sufficient salt or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed is readily prepared by standard techniques known to those skilled in the art.
Injectable solutions may be prepared by dissolving one or more active ingredients and possible additives in a portion of the injectable solvent (preferably sterile water), adjusting the solution to the desired volume, sterilizing the solution and filling it in suitable ampoules or vials. Any appropriate additive commonly used in the art may be added, such as tonicity agents, preservatives, antioxidants, and the like.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like.
Any other adjuvants or additives conventionally used for coloring, flavoring, preserving, etc. may be used, provided that they are compatible with the active ingredient or ingredients already used.
Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may comprise any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
Compositions formed by admixing one or more active ingredients of the present invention with a pharmaceutically acceptable carrier may then be conveniently administered in a variety of dosage forms suitable for the disclosed route of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
The active ingredients of the present invention may be formulated as similar or dissimilar pharmaceutical compositions and unit dosage forms thereof.
If solid carriers are employed for oral administration, the formulations may be in the form of tablets, powders or pellets placed in hard gelatin capsules, or may be in the form of lozenges or pastilles.
If a liquid carrier is employed, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution. The pharmaceutical preparations may conveniently be presented in unit dosage form according to standard procedures for pharmaceutical formulations. The amount of active compound per unit dose may vary depending on the nature of the active compound and the intended dosage regimen. Typically, this will be in the range of 0.1mg to 5000mg per unit dose.
The CBD used in the present invention may be a chemically synthesized product, a biologically synthesized product, a plant extract or prepared in other ways. Preferably, the cannabidiol of the invention is a plant extract, and the plant may be a stem core, a flower, a leaf, a seed and/or a shell of a seed of Cannabis sativa l.
The dosage of the drug used in the present invention is determined by considering the drug properties of each ingredient to be combined, the properties of the drug combination and the symptoms of the patient.
The 5-hydroxytryptamine and norepinephrine reuptake inhibitor, or pharmaceutically acceptable salts thereof, are generally used in an amount of about 20-60mg once a day (or about 10-30mg twice a day), more preferably about 30-40mg once a day (or about 10-20mg twice a day).
Generally, the weight ratio of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor, or pharmaceutically acceptable salt thereof, to the CBD is determined in view of the pharmaceutical properties of the two components, the properties of the pharmaceutical combination, and the patient's symptoms, preferably, the weight ratio of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor, or pharmaceutically acceptable salt thereof, to the CBD is about 1:0.2-60, more preferably, the weight ratio of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor, or pharmaceutically acceptable salt thereof, to the CBD is about 1:0.5-30, in embodiments of the invention the weight ratio of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor, or pharmaceutically acceptable salt thereof, to the CBD is 1:0.2, 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 present invention also relates to a composition for use in the prevention and/or treatment of depression or psychosis, the composition comprising an antidepressant or antipsychotic effective amount of a first compound selected from one or more of 5-hydroxytryptamine and a norepinephrine reuptake inhibitor, or a pharmaceutically acceptable salt thereof; the second compound is cannabidiol; optionally, one or more pharmaceutically acceptable carriers may also be included.
Further, depression includes psychogenic depression, endogenous depression, hypochondriasis type depression, anxious depression, pseudodementia type depression, chronic depression.
Further, the 5-hydroxytryptamine and norepinephrine reuptake inhibitor, or a pharmaceutically acceptable salt thereof, is selected from one of duloxetine, venlafaxine, milnacipran, and combinations thereof.
In an embodiment of the invention, the weight ratio of 5-hydroxytryptamine and norepinephrine reuptake inhibitor or pharmaceutically acceptable salt thereof to cannabidiol in the composition is 1: 0.2-60; preferably 1: 0.5-30.
Further, the composition is selected from one of capsules, tablets, sugar-coated tablets, pills, troches, powders, granules, solutions, emulsions, suspensions, syrups, sterile injectable solutions, sterile powders for dispersion, suppositories, sprays, ointments, creams, gels, inhalants, skin patches or implants.
Also, the present invention relates to a use for the preparation of a medicament for the prevention and/or treatment of depression or psychosis, comprising administering to said patient orally, intramuscularly, intravenously, intraperitoneally or parenterally an antidepressant or antipsychotic effective amount of the composition.
Further, a use for the manufacture of a medicament for reducing side effects after administration in a patient with depression or psychosis, comprising administering to the individual a composition in the form of an oral or parenteral formulation in an amount effective to reduce the side effects.
The patient is selected from human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate.
The invention also relates to the pharmaceutical use of a cannabidiol pharmaceutical composition for reducing or eliminating the side effects of dry mouth, lethargy, anorexia, cardiovascular disease, constipation, seizures, arrhythmia, bradycardia, hypertension, hypotension, and the like, induced by the use of 5-hydroxytryptamine and a norepinephrine reuptake inhibitor, or a pharmaceutically acceptable salt thereof, alone.
One embodiment of the present invention relates to a kit for preventing and/or treating depression or psychosis, the kit comprising the composition.
Further, the present invention relates to a method for the prevention and/or treatment of depression comprising administering to a patient in need thereof a therapeutically effective amount of a combination of cannabidiol and 5-hydroxytryptamine and a norepinephrine reuptake inhibitor, or a pharmaceutically acceptable salt thereof.
Unless otherwise indicated, the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired prophylactic or therapeutic effect during the course of therapy, in association with a required pharmaceutical carrier.
In certain embodiments, the term "patient" refers to a human.
The term "administering" as used herein refers to either directly administering a compound or composition to a patient or administering a prodrug derivative or analog of a compound to a patient that will form an equivalent amount of the active compound or substance in the patient.
The term "pharmaceutically acceptable adjuvant" means, unless otherwise indicated, that the ingredient is free of biologically or otherwise undesirable active impurities, e.g., the ingredient may be incorporated into a disclosed pharmaceutical formulation and administered to a patient without causing a significant undesirable biological effect or interacting in a deleterious manner with other ingredients contained in the formulation.
Unless otherwise indicated, the term "treating" includes inhibiting, delaying, alleviating, attenuating, limiting, alleviating, or resolving a disease, disorder, condition, or state, its occurrence and/or progression, and/or its symptoms.
Unless otherwise indicated, the term "preventing" includes reducing the following risks: a disease, disorder, condition or state, its occurrence and/or progression, and/or its symptoms is suffered, infected or experienced.
Unless otherwise specified, the term "comprising" means "open" or "inclusive" such that they include the recited elements, but also allow for the inclusion of additional, unrecited elements.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
Example 1 formulation example achievable with the composition according to the invention
Some non-limiting formulation examples of 5-hydroxytryptamine and norepinephrine reuptake inhibitors with cannabidiol are given below.
1. Experiment 1
Formulation sample set 1
Tablets containing the above formulation were prepared according to methods well known to those of ordinary skill in the art.
Control group 1
Tablets containing the above formulation were prepared according to methods well known to those of ordinary skill in the art.
2. Experiment 2
Formulation sample set 2
Tablets containing the above formulation were prepared according to methods well known to those of ordinary skill in the art.
Control group 2
Tablets containing the above formulation were prepared according to methods well known to those of ordinary skill in the art.
3. Experiment 3
Formulation sample set 3
The above formulations are mixed and packaged in hard gelatin capsules according to methods well known to those of ordinary skill in the art.
Control group 3
The above formulations are mixed and packaged in hard gelatin capsules according to methods well known to those of ordinary skill in the art.
4. Experiment 4
Formulation sample set 4
The above formulations are mixed and packaged in soft capsules (soft capsule shell formulation gelatin: glycerol: water 100:55:75 by weight) according to a preparation method well known to those of ordinary skill in the art.
Control group 4
The above formulations are mixed and packaged in soft capsules (soft capsule shell formulation gelatin: glycerol: water 100:55:75 by weight) according to a preparation method well known to those of ordinary skill in the art.
5. Experiment 5
Formulation sample set 5
The preparation method comprises the following steps: taking about 800ml of water for injection, adding a proper amount of 0.1mol/L HCl and hydroxypropyl-beta-cyclodextrin, stirring for dissolving, adding CBD and milnacipran for dissolving, adjusting the pH value to 6.2-6.5 by using 0.1mol/L HCl, adding water for injection to the full volume, stirring uniformly, filtering, filling and sealing in an ampoule, and sterilizing for 30min by using circulating steam at 100 ℃.
Control group 5
The preparation method comprises the following steps: taking about 800ml of water for injection, adding a proper amount of 0.1mol/L HCl and hydroxypropyl-beta-cyclodextrin, stirring for dissolving, adding milnacipran for dissolving, adjusting the pH value to 6.2-6.5 by using 0.1mol/L HCl, adding water for injection to the full amount, stirring uniformly, filtering, filling and sealing in an ampoule, and sterilizing for 30min by using circulating steam at 100 ℃.
EXAMPLE 25 synergistic antidepressant Effect of serotonin and norepinephrine reuptake inhibitors with CBD
The first, experimental principle:
the forced swimming experiment is also called behavior despair experiment, is a credible depression animal model, is widely applied to screening antidepressant drugs and researching the action mechanism of the antidepressant drugs, and a large number of researches show that the model is proved to be sensitive to most antidepressant drugs.
II, an experimental method:
110 rats (about 200g) were randomly divided into 11 groups according to sex and body weight, 10 rats in each group, male and female halves, room temperature 22 + -1 deg.C, humidity 50 + -10%, natural light, free intake of drinking water. All animals were acclimated in the feeding environment for 5 days before starting the experiment, fasted for 12-16 hours and had free food and water.
Formulation sample set (combination set) formulation sample sets 1-5 in example 1 (experiments 1-5); wherein the dosage of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor group is 7mg/kg body weight, and the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD are in proportion to the components in the formula sample groups 1-5.
Control group (5-hydroxytryptamine and norepinephrine reuptake inhibitor use group): control groups 1-5 in example 1 (experiments 1-5).
A control group (control group 6) was also set up, and an equal volume of physiological saline was administered only.
24 hours before the formal test, the mice are placed in a glass round jar (height 25cm, diameter 10cm) with water depth 10cm, the water temperature is 24 +/-1 ℃, and forced swimming training is carried out for 15 minutes. After each group was administered, the mice were again placed in a glass round jar with a water depth of 10cm for forced swimming for 6min, and the immobility time of the mice within the last 4 minutes was observed and recorded. The time when the mouse stopped struggling, remained floating in the water, or just made some necessary slight movements to keep the head floating on the water surface was considered as swimming immobility time.
Thirdly, experimental results:
in the forced swimming test of mice, the formula sample groups (experimental groups) 1-5 and the control groups 1-5 respectively produce antidepressant effect. Formula sample groups 1-5 (combination group) and control groups 1-5 (5-hydroxytryptamine and norepinephrine reuptake inhibitor group) dose-dependently reduced the immobility time of mice in swimming experiments. Moreover, the results show that the combined use of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD can play a synergistic role, and obviously improve the anti-immobility effect (P is less than 0.05) of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor.
TABLE 15 Effect of serotonin and norepinephrine reuptake inhibitors and CBD on immobility time for swimming mice
Note: p < 0.05 compared to control; p < 0.01
Example 35-serotonin and norepinephrine reuptake inhibitors in combination with CBD alleviate the side effects of constipation
The first experiment method comprises the following steps:
taking 90 healthy Kunming mice with the weight of 20-25g, randomly dividing the mice into 9 groups according to the sex and the weight, wherein each group comprises 10 mice with half of the sex. The room temperature is 22 +/-1 ℃, the humidity is 50 +/-10 percent, and the drinking water can be freely taken under natural illumination. After all animals had acclimatized in the rearing environment for 5 days, the experiment was started, and the animals were reared in cages and given a constant amount of feed.
Formulation sample set (combination set) formulation sample sets 1-4 in example 1 (experiments 1-4); wherein the dosage of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor group is 7mg/kg body weight, and the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD are in proportion to the components in the formula sample groups 1-4.
Control group (5-hydroxytryptamine and norepinephrine reuptake inhibitor use group): control groups 1-4 in example 1 (experiments 1-4).
A control group (control group 6) was also set up, and an equal volume of physiological saline was administered only.
The first time of defecation of the first grain of 10 animals and the number and weight of the grains in 12h are recorded 1 day before the experiment, and the mice of each group are fasted for 16h without water prohibition, and when the measurement is carried out on the next day, the formula sample groups 1-4(7mg/kg) and the control groups 1-4 are respectively fed with stomach-irrigation and administration, and the control group 6 is fed with stomach-irrigation and administration with equal volume of physiological saline. After 30min, the animals are fed in a single cage with carbon liquid indicator (black), and are normally drunk and fed, and the black excrement discharge time of the first grains of each animal and the grain number and weight of the excrement discharge within 12h are recorded from the carbon liquid indicator (black).
The data were statistically processed using the sps.17.0 software and compared for significant differences between groups.
Second, experimental results
The experimental results show (see table 2) that the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD have a function of reducing the side effect of defecation of mice, and it can be seen that the simultaneous intake of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD can accelerate the first defecation time, increase the defecation frequency and defecation weight of mice compared with the single intake of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor, which indicates that the simultaneous intake of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD has a certain inhibition effect on the side effect of constipation caused by the single use of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor. Thus, the combination of 5-hydroxytryptamine and norepinephrine reuptake inhibitors with CBDs in a suitable ratio may reduce the side effects of constipation associated with 5-hydroxytryptamine and norepinephrine reuptake inhibitors.
TABLE 2 Effect of CBD in combination with 5-hydroxytryptamine and norepinephrine reuptake inhibitors on the duration of defecation in mice
*P＜0.05，**P＜0.01
Example 4: combination of 5-hydroxytryptamine and norepinephrine reuptake inhibitors with CBD to reduce dry mouth side effects
The first experiment method comprises the following steps:
taking 90 healthy Kunming mice with the weight of 20-25g, randomly dividing the mice into 9 groups according to the sex and the weight, wherein each group comprises 10 mice with half of the sex. The room temperature is 22 +/-1 ℃, the humidity is 50 +/-10 percent, and the drinking water can be freely taken under natural illumination. After all animals had acclimatized in the rearing environment for 5 days, the experiment was started, and the animals were reared in cages and given a constant amount of feed.
Formulation sample set (combination set) formulation sample sets 1-4 in example 1 (experiments 1-4); wherein the dosage of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor group is 7mg/kg body weight, and the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD are in proportion to the components in the formula sample groups 1-4.
Control group (5-hydroxytryptamine and norepinephrine reuptake inhibitor use group): control groups 1-4 in example 1 (experiments 1-4).
A control group (control group 6) was also set up, and an equal volume of physiological saline was administered only.
The frequency of drinking water and the amount of water of 10 animals are recorded 1 day before the experiment, and the mice in each group are fasted and are forbidden to drink water for 16 hours, and when the time of the day is measured, the formula sample groups 1-4(7mg/kg) and the control groups 1-4 are respectively administrated with the gavage, and the control group 6 is administrated with the normal saline with the equal volume. Animals in each group were fed in a single cage, and were allowed normal drinking and food, and the number of times each animal had drunk water and the amount of water recorded over 6 hours.
The data were statistically processed using the sps.17.0 software and compared for significant differences between groups.
TABLE 35 Effect of serotonin and norepinephrine reuptake inhibitors in combination with CBD on dry mouth side effects
Note: p < 0.05, P < 0.01
Second, experimental results
The experimental result shows that the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD have the effect of reducing the side effect of the mouse on the xerostomia, and compared with the method of taking the 5-hydroxytryptamine and norepinephrine reuptake inhibitor alone, the method can reduce the frequency and the amount of drinking water of the mouse by taking the 5-hydroxytryptamine and norepinephrine reuptake inhibitor and CBD simultaneously, and shows that the CBD has a certain effect of inhibiting the side effect of the 5-hydroxytryptamine and norepinephrine reuptake inhibitor on the xerostomia. Thus, the 5-hydroxytryptamine and norepinephrine reuptake inhibitors can be combined with the CBD at a suitable ratio to mitigate the side effects of dry mouth from the 5-hydroxytryptamine and norepinephrine reuptake inhibitors.
Claims (4)
1. Use of a cannabidiol pharmaceutical composition in the manufacture of a medicament for the prevention and/or treatment of depression while reducing or eliminating the side effects of dry mouth or constipation induced by the sole use of a 5-hydroxytryptamine and a norepinephrine reuptake inhibitor, or a pharmaceutically acceptable salt thereof; the pharmaceutical composition consists of an antidepressant effective amount of a first compound selected from one or more of 5-hydroxytryptamine and a norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof; the second compound is cannabidiol, and the 5-hydroxytryptamine and norepinephrine reuptake inhibitor or pharmaceutically acceptable salt thereof is selected from duloxetine, venlafaxine, milnacipran and pharmaceutically acceptable salt thereof; the weight ratio of the 5-hydroxytryptamine and the norepinephrine reuptake inhibitor or the pharmaceutically acceptable salt thereof to the cannabidiol in the composition is 1: 0.5-30.
2. The use of claim 1, wherein said depression comprises psychogenic depression, endogenous depression, hypochondriac depression, anxiogenic depression, pseudodementias depression, or chronic depression.
3. Use according to claim 1 or 2, wherein the composition is selected from one of capsules, tablets, pills, lozenges, powders, granules, emulsions, sterile injectable solutions, suppositories, sprays, ointments.
4. Use according to claim 1 or 2, characterized in that cannabidiol is an extract of a plant selected from the group consisting of the stem, flower, leaf, root and/or seed husks of Cannabis sativa l.
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| 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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| 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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