CN108785298A - A kind of pharmaceutical composition, preparation method and the usage for treating epilepsy - Google Patents
A kind of pharmaceutical composition, preparation method and the usage for treating epilepsy Download PDFInfo
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- CN108785298A CN108785298A CN201710288379.4A CN201710288379A CN108785298A CN 108785298 A CN108785298 A CN 108785298A CN 201710288379 A CN201710288379 A CN 201710288379A CN 108785298 A CN108785298 A CN 108785298A
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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Abstract
The pharmaceutical composition of the invention discloses a kind of cannabidiol (CBD) and tetrahydrocannabinol (THCV) containing special ratios, preparation method and its purposes in epilepsy therapy.Specifically, for the pharmaceutical composition using cannabidiol or its pharmaceutically acceptable salt and tetrahydrocannabinol or its pharmaceutically acceptable salt as active constituents of medicine, the wherein weight proportion between cannabidiol or its pharmaceutically acceptable salt and tetrahydrocannabinol or its pharmaceutically acceptable salt is 600:1-3.The pharmaceutical composition is particularly useful in the therapeutic process of epilepsy, especially partial seizures.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of pharmaceutical composition for treating epilepsy, preparation side
Method and its purposes in treating epilepsy, especially partial seizures.
Background technology
Epilepsy (epilepsy) is a kind of brain diseases chronic caused by Different types of etiopathogenises, is led with brain neuron over-discharge
Cause that repeatability, ictal and transience central nervous system function is not normal is characterized.
Epilepsy has morbidity in the crowd of any age, area and race, but higher with Children and teenager incidence.
Recently as China human mortality aging, the incidence of cerebrovascular disease, dementia and nervous system degenerative disease increases, the elderly
Has there is the trend risen in epilepsy invasion rate in group.Epilepsy brings serious negative effect, epilepsy for personal, family and society
It breaks out and causes huge physiology and psychological pain to patient, seriously affect the quality of life of patient and family；It takes for a long time
Antiepileptic and other diagnosis and treatment expenses bring heavy financial burden to family.
The partial seizures (partial seizure) of epilepsy are also referred to as focal seizure (focal seizure).Face
Bed and electroencephalogram initially change prompt, and cerebral hemisphere partial nerve member is activated first, then occurs simultaneously and rapidly discharging, fast
Speed is spread to surrounding normal brain area, generates a series of electro physiologies and neurochemistry variation, until neuronal energy is exhausted and metabolism drop
It is low that breaking-out is made to terminate automatically.According to episode process whether with the disturbance of consciousness, it is divided into simple partial seizure (unconscious barrier when breaking-out
Hinder) and complex partial seizures (having the different degrees of disturbance of consciousness).Almost all of antiepileptic all there may be adverse reaction,
Its severity has very big difference in Different Individual.The adverse reaction of antiepileptic is to lead to another main original for the treatment of failure
Cause.Most of adverse reaction is slight, but also has a small number of entail dangers to life.Most common adverse reaction includes Central nervous
The influence (calm, drowsy, dizzy, mutual aid obstacle, cognition, memory etc.) of system, to whole body multisystem influence (hematological system,
Digestive system, weight change, fertility Issue, bone health etc.) and idiosyncrasy reaction.
Hemp knows already as the application of medicine, and in 19th century, hemp products is proposed as hypnosis sedative,
It can be used for treating hysteria, amentia, epilepsy, nerve insomnia, migraine and dysmenorrhoea.In the 1940s, research
Personnel's isolated cannabidiol (CBD) from hemp, experiment in vivo find CBD not only can antagonism THC excitements cannboid I types by
The psychotropic activity that body (CB1R) is caused, and with anticonvulsion, antianxiety, antipsychotic, tranquilizing soporific, anti-inflammatory and neural guarantor
Shield acts on.Preclinical and clinical research shows that cannabidiol (CBD) pharmacokinetics are good, can penetrate blood brain after injection rapidly
Barrier, neuroprotection effect are notable.Cannabidiol (CBD) can play neuroprotection, and its poison by multipath
The weak, few side effects of property.Currently, FDA authorized three kinds of the drug containing cannabidiol it is rare disease (the ictal epilepsy LGS of children,
Dravet epileptic syndromes, hypoxic ischemic encephalopathy of newborn (NHIE)) drug qualification.
Chinese patent application CN201280004572.6 discloses a kind of cannabidiol (CBD) with the agent higher than 300mg/ days
The purposes combined with the standard anti-epileptic drug by sodium or calcium channel effect for epilepsy is measured, and is disclosed in embodiment
The combination of the combination of CBD and valproate, phenobarbital, CBD and valproate can increase the incubation period that epileptic attack starts,
Reduce the percentage of tonic-clonic seizures, but the combination of CBD and phenobarbital is almost without apparent synergistic action effect,
Combination is meaningless for the treatment of epilepsy.
U.S. Patent Application Publication No. US2015359756A1 discloses cannabidiol (CBD) and one or more anti-epileptics
The combination of drug (AEDs), wherein the antiepileptic (AEDs) can be selected from：Clobazam, Clorazepate, goes first at Clonazepam
Clobazam, diazepam, ethymal, Felbamate, Gabapentin, high fat diet, drawing section amine, Lamotrigine, Levetiracetam, labor
West is dissolved, midazolam, N- remove first Clobazam, nordazepam, phenytoinum naticum, Stiripentol, Topiramate Trazodone, valproic acid, ammonia for drawing
Hexenoic acid, Zonisamide.However, the patent application does not disclose or implies cannabidiol (CBD) and tetrahydrocannabinol
(THCV) combination and its purposes in treating epilepsy, especially partial seizures.
It is following for treating in preparation that Chinese patent application 200580039064.1 discloses tetrahydrocannabinol (THCV)
Purposes in the drug of disease or situation：Obesity, schizophrenia, epilepsy, cognitive disorder such as Alzheimer disease, are coveted at osteopathy
It eats disease, abused with the relevant obesity of type-2 diabetes mellitus (Non-Insulin Dependent Diabetes Mellitus) and drug, alcohol and nicotine
Or dependence.However, the patent application is also without open or hint cannabidiol (CBD) and tetrahydrocannabinol (THCV) group
Conjunction and its purposes in treating epilepsy, especially partial seizures.
The present inventor is by experiment it was unexpectedly observed that when the cannabidiol (CBD) that will be matched containing specified weight
When being used for the treatment of epilepsy, especially partial seizures with the pharmaceutical composition of tetrahydrocannabinol (THCV), two kinds of work
Property ingredient between can generate unexpected synergy, at the same time can also mitigate two kinds of active components be used alone when
Side effect, improve the compliance of patient.
Invention content
It is a kind of with synergistic treatment effect the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide
At the same time fruit also has the treatment epilepsy for mitigating side effect, the especially pharmaceutical composition of partial seizures, prepare
Method and its purposes in treating epilepsy, especially partial seizures.
For this purpose, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition is comprising active constituents of medicine and pharmaceutically
Acceptable carrier or excipient, wherein the active constituents of medicine is：A) cannabidiol or its pharmaceutically acceptable salt, and
B) tetrahydrocannabinol or its pharmaceutically acceptable salt, and active constituents of medicine a) and b) between weight proportion be 600:
1-3。
Present inventor it was unexpectedly observed that in the pharmaceutical composition with specified weight match existing cannabidiol and
Tetrahydrocannabinol can generate unexpected collaboration effect in epilepsy, especially in the therapeutic process of partial seizures
At the same time fruit can also mitigate side effect when two kinds of active components are used alone, improve the compliance of patient.
In one embodiment of the invention, described two active constituents of medicine a) in described pharmaceutical composition and b)
Between weight proportion be 600:1.
In another embodiment of the present invention, described two active constituents of medicine a) in described pharmaceutical composition and
B) weight proportion between is 600:2.
In another embodiment of the present invention, described two active constituents of medicine a) in described pharmaceutical composition and
B) weight proportion between is 600:3.
Preferably, the active constituents of medicine a) in described pharmaceutical composition is cannabidiol.
Preferably, the active constituents of medicine b) in described pharmaceutical composition is tetrahydrocannabinol.
Cannabidiol used in the present invention and tetrahydrocannabinol can be chemosynthesis product, biosynthetic products,
It detaches from plant extracts or is prepared using other manner.For example, cannabidiol of the present invention is from plant extract
Object detaches, and the plant extracts is extractable from the outer of the stalk core of hemp Cannabis sativa L., flower, leaf, root or seed
Shell.
Pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier or excipient.
Pharmaceutical composition of the present invention can by any administration route appropriate such as oral, rectum, nose, lung,
In part (including oral cavity and sublingual), transdermal, brain pond, intraperitoneal, vagina and parenteral (including subcutaneous, intramuscular, intrathecal, vein
It is interior and intradermal) approach administration.Preferably, pharmaceutical composition of the present invention is administered by oral route.It should be understood that preferred
Administration route depends on ordinary circumstance, age, gender, weight, the property of disease to be treated, the severity of patient to be treated
With the active constituent of specific choice.
Specific dosage form can be made according to the conventional formulation technologies of this field in pharmaceutical composition of the present invention.
In one embodiment, pharmaceutical composition of the present invention is the dosage form of oral medication.The oral medication
Dosage form can be selected from solid dosage forms and liquid dosage form.Preferably, the solid dosage forms be tablet, powder agent, granule, pill,
Pastille or capsule；The liquid dosage form is solution, emulsion, suspension, syrup or elixir.
In another embodiment, pharmaceutical composition of the present invention is the dosage form of parenteral.The stomach and intestine
The dosage form of external administration can be selected from sterile Injectable solution, dispersion liquid, suspension, lotion and is redissolved in before use sterile
Injectable solution or dispersion liquid injection sterile powder.
In another embodiment, pharmaceutical composition of the present invention is the dosage form of skin or mucosa delivery.It is described
The dosage form of skin or mucosa delivery can be selected from suppository, ointment, cream, gelling agent, aerosol, spray, powder spray, skin
Patch, implant etc..
In one embodiment, the present invention also provides a kind of sides being used to prepare pharmaceutical composition of the present invention
Method, described method includes following steps：1) it is 600 by weight proportion:Active constituents of medicine a) the cannabidiols or its pharmacy of 1-3
Upper acceptable salt and b) tetrahydrocannabinol or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or figuration
Agent is uniformly mixed；2) mixture that step 1) obtains optionally is prepared into any pharmaceutically acceptable dosage form.
In order to prepare described pharmaceutical composition, usually used any pharmaceutically acceptable load in the art may be used
Body, diluent, excipient or other additives.
For example, in order to prepare the solid dosage forms of oral medication, solid carrier known in the art can be used.Solid carrier
Example have lactose, sucrose, cyclodextrin, agar, pectin, Arabic gum, the lower alkyl ether of cellulose, cornstarch, Ma Ling
Sweet potato starch, talcum powder, magnesium stearate, gelatin etc..In addition, any other the purpose of being commonly used in coloring, flavoring, anti-corrosion can be used
Auxiliary material or additive, as long as they are compatible with active constituent or used ingredient.It, can be with using above-mentioned solid carrier
The pharmaceutical composition of the present invention is prepared into the form such as tablet, powder agent, granule, pill, pastille or capsule.
Similarly, in order to prepare the liquid dosage form of oral medication, liquid-carrier known in the art can be used.Liquid carries
The example of body has water, ethyl alcohol, glycerine, propylene glycol, polyethylene glycol, syrup, atoleine, ethyl oleate, isopropyl myristate
And fat oil such as peanut oil, sesame oil, soybean oil, cottonseed oil, olive oil etc..It, can will be of the invention using aforesaid liquid carrier
Pharmaceutical composition be prepared into various preparations, such as solution, emulsion, suspension, syrup or elixir etc..
In order to prepare the dosage form of parenteral, sterile carrier known in the art can be used.The sterile carrier example
Such as water for injection, oil for injection such as vegetable oil such as sesame oil, soybean oil, peanut oil, castor oil, tea oil, other solvent for injection
Such as ethyl alcohol, glycerine, propylene glycol, polyethylene glycol, Ergol, ethyl oleate, dimethylacetylamide.If desired, may be used also
To use various additives such as solubilizer, wetting agent, emulsifier, buffer, suspending agent, antioxidant, bacteriostatic agent, local analgesia
Agent, isotonic regulator etc..For injection sterile powder, filler and protective agent such as lactose, sucrose, malt can also be used
Sugar, mannitol, glycine and human serum albumins etc..
For example, the sterile Injectable solution of parenteral can be prepared as follows：By one or more active constituents and
Possible additive is dissolved in a part of Injectable sterile liquid-carrier (preferably sterile water), adjustment solution to required volume,
It by solution sterilization and is filled into ampoule or bottle appropriate, to obtain sterile Injectable solution.
Preparation for the dosage form of skin or mucosa delivery may be used known in the art for skin or mucosa delivery
Carrier.The carrier for skin or mucosa delivery can be selected from for example cocoa butter, fatty glyceride, polyethylene glycol,
Poloxamer, paraffin, vaseline, dimethicone, lanolin, beeswax, carbomer, cellulose derivative, polyvinyl alcohol, poly- second
Alkene pyrrolidone, dichlorodifluoromethan hydrocarbon, compressed gas, reservoir material etc..It is used for skin or mucosa delivery using above-mentioned
Carrier, can by the present invention pharmaceutical composition be prepared into such as suppository, ointment, cream, gelling agent, aerosol, spray
The forms such as mist agent, powder spray, dermal patch or implant.For example, suppository can be prepared as follows：By suppository base such as cocoa butter
Heating fusing is added drug and is simultaneously uniformly mixed, then by the mixture of gained inject in mold and it is cooling to get.
The preparation of the pharmaceutical composition of invention described above can easily be made according to the standardization program of pharmaceutical formulation
At unit dosage forms.The amount of reactive compound in per unit dosage form may according to the various pharmaceutical activity in pharmaceutical composition at
Point property, the property of the pharmaceutical composition, the property of disease to be treated and the situation of patient and change.With regard to the medicine of the present invention
For the application of compositions, it should provide a effective amount of active constituents of medicine, and generate expected technique effect.Preferably,
The pharmaceutical composition include 300mg to the cannabidiol of 1200mg or its pharmaceutically acceptable salt and 0.5mg extremely
The tetrahydrocannabinol of 6mg or its pharmaceutically acceptable salt.Certainly, generate useful effect needed for active constituents of medicine most
Whole dosage can change and finally be determined by medical worker.
The present invention also provides a kind of pharmaceutical compositions of the present invention to prepare the drug for preventing and/or treating epilepsy
In purposes.
Preferably, the types of epilepsy is partial seizures.In one embodiment, the partial seizures are single
Pure partial seizures (limitation breaking-out) or complex partial seizures, more preferably simple partial seizure (limitation breaking-out).
The present invention also provides a kind of prevention and/or the method for the treatment of epilepsy, especially partial seizures, this method
It include the pharmaceutical composition of the present invention that therapeutically effective amount is given to patient in need.
Cannabidiol (CBD) of the present invention containing special ratios or its pharmaceutically acceptable salt and tetrahydrochysene are secondary big
The pharmaceutical composition of numb phenol (THCV) or its pharmaceutically acceptable salt is sent out suitable for treatment epilepsy, especially partial epilepsy
Make.Present inventor with specified weight in the pharmaceutical composition it was unexpectedly observed that match existing cannabidiol and tetrahydrochysene
Secondary cannabinol can especially generate unexpected synergy in epilepsy in the therapeutic process of partial seizures,
At the same time it can also mitigate side effect when two kinds of active components are used alone, improve the compliance of patient.
For example, when using medicine composite for curing epileptic attack of the present invention, can be mitigated or eliminated individually makes
The side effect caused by cannabidiol or tetrahydrocannabinol, it is the drowsiness, diarrhea generated when being used alone such as cannabidiol, tired
Labor, convulsions, vomiting, loss of appetite and weight loss.
In order to which the essence and spirit that make the present invention are further understood, with reference to specific embodiment to the excellent of the present invention
Embodiment and its effect is selected to be described.It is understood, however, that these descriptions are only intended to the spy further illustrated the present invention
It seeks peace advantage, and any restrictions is constituted to the claim of the present invention absolutely not.
Specific implementation mode
The source of all raw materials used in the preparation of described pharmaceutical composition is not particularly limited in the present invention, in city
It is being bought on field or according to conventional method well known to those skilled in the art preparation.
Prepare embodiment 1
Pharmaceutical composition 1
The tetrahydrocannabinol for weighing the cannabidiol and 1mg micronizings of 600mg micronizings, is sufficiently mixed in mortar
The pharmaceutical composition 1 of the even present invention to get powder agent (powder) form.
Prepare embodiment 2
Pharmaceutical composition 2
The tetrahydrocannabinol for weighing the cannabidiol and 2mg micronizings of 600mg micronizings, is sufficiently mixed in mortar
The pharmaceutical composition 2 of the even present invention to get powder agent (powder) form.
Prepare embodiment 3
Pharmaceutical composition 3
The tetrahydrocannabinol for weighing the cannabidiol and 3mg micronizings of 600mg micronizings, is sufficiently mixed in mortar
The pharmaceutical composition 3 of the even present invention to get powder agent (powder) form.
The combination of 1 cannabidiol of experimental example and tetrahydrocannabinol is in penicillin-induced rat portions epileptic attack model
In antiepileptic activity
Experimental animal：Healthy male Wistar rat, weight 75-110g.By animal 21 DEG C, 50% humidity and 12 hours
It is adapted to three days under illumination condition, animal can ad lib and drinking-water.
Experimental method
Rat portions epileptic attack model foundation：Using penicillin-induced rat portions epileptic attack model
(Bostanci and Bagirici, 2006).
Experimental animal is grouped at random, every group 20.Vehicle controls or given the test agent give experimental animal peritoneal injection
Medicine.Herein before one week, by performing the operation the ventriculus dexter cerebri of intubation implantation animal under anaesthesia.After administration 1 hour, at 1 minute
It is interior that penicillin (1000IU/kg) is injected into animal ventriculus dexter cerebri, and record breaking-out behavior in 2 hours.
The grading system of partial seizures for penicillin induction is as shown in table 1.
Following formula can be used to evaluate for human body equivalent dose (HED)：
HED=animals dosage (mg/kg) is multiplied by animal Km/ people Km
The Km of rat is 6, and the Km of people is 37.
Therefore, for the people of 60kg, the dosage of 100mg/kg is equal to the dosage of about 1000mg/ days people in rat, is
It avoids confusion, dosage as described below is the dosage that corresponding people is calculated as according to experimental animal.
Partial seizure scoring and the experimental animal of 1 penicillin of table induction show
| Scoring | Experimental animal shows |
| 0 | Without twitch, behavior is normal |
| 1 | Madness runs/jumps |
| 2 | The myoclonia stage |
| 3 | Unilateral forelimb clonic spasm |
| 4 | Bilateral forelimb clonic spasm |
| 5 | Retain the tonic-clonic seizures of ability of posture control |
| 6 | Tonic-clonic seizures without ability of posture control |
Animal is recorded since injecting penicillin to there is 1 grade of actuation time in table 1, is calculated as the time started (incubation period),
It records from animal and first appears the time that seizure disorder or death once occur to the end in partial seizures, calculate insane
Epilepsy is broken out the duration.
Recording laboratory animal The dead quantity calculates the death rate, pays attention to forming the most of dynamic of tonic-clonic seizures
Object is often therefore dead.The quantity that record animal does not break out.
Dosage regimen and experimental result (assessment result of epileptic attack is indicated with the mean+SD of measurement result)
As shown in table 2.
The dosage regimen and experimental result of 2 pharmaceutical composition of the present invention of table
As shown in Table 2, for cannabidiol and tetrahydrocannabinol, no matter it is single use or combines
It uses, certain therapeutic effect is all had for animal epileptic model.But applicants have unexpectedly found that, when by cannabidiol
With tetrahydrocannabinol with 600:When the specific weight proportion of 1-3 is applied in combination, with positive control phenytoinum naticum and individually make
Cannabidiol, tetrahydrocannabinol and with other ratios combine cannabidiol compared with tetrahydrocannabinol, have
Notable better synergistic therapeutic effect, such as the incubation period that epileptic attack starts can be dramatically increased, when reduction epileptic attack continues
Between, the death rate is reduced, the percentage not broken out is improved.
The combination of 2 cannabidiol of experimental example and tetrahydrocannabinol is lived in the anti-epileptic of maximal electroshock seizure model
Property
Experimental animal：This experiment uses 5-7 week old male ICR mouses.By animal feeding temperature be 25 ± 2 DEG C, humidity
It is 60 ± 10%, striation part is 7AM to 7PM photoperiods, under conditions of 7PM to the 7AM dark periods.Mouse can arbitrarily feed feed and
Drinking public water supply.
Experimental method and experimental result：
Used test compound be positive control phenytoinum naticum and experiment object cannabidiol, tetrahydrocannabinol and
The combination of the two in varing proportions.All test compounds are intraperitoneally given, and administered dose is to be scaled corresponding people's
Dosage indicates.
The previous day is tested, mouse is weighed and is assigned randomly to several groups, every group 20.Experimental day morning is again
It weighs, to calculate the dosage of every animal.According to dosage shown in the following table 3, it is (insane that mouse physiological saline is given in peritonaeum
Epilepsy model group), phenytoinum naticum, cannabidiol, the combination of tetrahydrocannabinol and the two in varing proportions, give electricity after 30 minutes
Stimulation.It gives 100Hz pulse frequencies using the electric current of 30mA by ear-lobe electrode and reaches 200mse, by stimulant (UGOBASILE
ECT UNIT 7801, Italia) inducing mouse maximal electroshock seizure (MES) c.Observation mouse 10 seconds and record it is tetanic after
The incidence of limb elongation.
Dosage regimen and experimental result are as shown in table 3.
The dosage regimen and experimental result of the pharmaceutical composition of 3 present invention of table
By the result in table 3 as it can be seen that nearly all animal in epilepsy model group all show by electro photoluminescence (30mA,
Hind leg elongation 200msec) induced.For cannabidiol and tetrahydrocannabinol, no matter it is single use or combines
It uses, certain inhibiting effect is all had for the hind leg elongation induced by electro photoluminescence (30mA, 200msec), but in degree still
Slightly it is weaker than positive control phenytoinum naticum.But applicants have unexpectedly found that, when by cannabidiol and tetrahydrocannabinol with 600:1-
When 3 specific weight proportion is applied in combination, with positive control phenytoinum naticum and the cannabidiol of exclusive use, tetrahydrochysene time hemp
Phenol and the cannabidiol combined with other ratios are compared with tetrahydrocannabinol, are had significantly preferably for by electro photoluminescence
The inhibiting effect of the hind leg elongation of (30mA, 200msec) induction.
The clinical trial that the combination of 3 cannabidiol of experimental example and tetrahydrocannabinol influences drug side-effect
Experimental subjects：90 people of partial seizures volunteer, men and women is unlimited, and stochastic averagina is divided into 6 groups, every group of 15 people,
Respectively control group 1-3 and experimental group 1-3.
Control group 1：400mg phenytoinum naticums/day；
Control group 2：600mg cannabidiols/day；
Control group 3：600mg cannabidiols+0.5mg tetrahydrocannabinol/day；
Control group 4：600mg cannabidiols+4mg tetrahydrocannabinol/day；
Experimental group 1：600mg cannabidiols+1mg tetrahydrocannabinol/day；
Experimental group 2：600mg cannabidiols+2mg tetrahydrocannabinol/day；
Experimental group 3：600mg cannabidiols+3mg tetrahydrocannabinol/day.
Experimental method：Experimental subjects is administered according to above-mentioned dosage regimen, once a day, successive administration 12 months；Observation
Seizure frequency, side effect during recording the 2nd, 4,6,8,10,12 month, are compareed based on treating preceding 2 months seizure frequencies.
Side effect：Chemical examination blood routine, electrolyte simultaneously monitor blood concentration, record what each point of observation was occurred in 2 months
Side effect；The side effect includes drowsiness, diarrhea, fatigue, convulsions, vomiting, loss of appetite and weight loss etc..
Experimental result is as shown in table 3.
3 side effect of table and recurrence rate experimental result
As seen from the results in Table 3, when by cannabidiol and tetrahydrocannabinol with 600:The specific weight proportion of 1-3 combines
In use, the side effect main suit incidence of patient can be substantially reduced simultaneously and the later six months incidence again that is discontinued, to significantly improve
The compliance of patient reaches better therapeutic effect.
The above is only a preferred embodiment of the present invention.It should be pointed out that for the ordinary skill people of the art
For member, under the premise of not departing from spirit and principles of the present invention, several improvement, modification and equivalent replacement can also be made
Deng, these improve, modification and equivalent replacement after technical solution also should be regarded as falling within the scope and spirit of the invention.
Claims (11)
1. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes active constituents of medicine and pharmaceutically acceptable
Carrier or excipient, wherein the active constituents of medicine is：A) cannabidiol or its pharmaceutically acceptable salt and b) tetrahydrochysene
Secondary cannabinol or its pharmaceutically acceptable salt, two of which active constituents of medicine a) and b) between weight proportion be 600:1-
3。
2. pharmaceutical composition as described in any of claims 1, which is characterized in that the pharmaceutical composition be take orally to
The dosage form of the dosage form of medicine, the dosage form of parenteral, skin or mucosa delivery.
3. pharmaceutical composition as claimed in claim 2, which is characterized in that the dosage form of the oral medication be solid dosage forms or
Liquid dosage form.
4. pharmaceutical composition as claimed in claim 3, which is characterized in that the solid dosage forms is tablet, powder agent, particle
Agent, pill, pastille or capsule；The liquid dosage form is solution, emulsion, suspension, syrup or elixir.
5. pharmaceutical composition as claimed in claim 2, which is characterized in that the dosage form of the parenteral is sterile notes
Penetrate solution, dispersion liquid, suspension, lotion or the injection that sterile Injectable solution or dispersion liquid are redissolved in before use
Aseptic powdery.
6. pharmaceutical composition as claimed in claim 2, which is characterized in that the dosage form of the skin or mucosa delivery be suppository,
Ointment, cream, gelling agent, aerosol, spray, powder spray, dermal patch or implant.
7. pharmaceutical composition as described in any of claims 1, which is characterized in that the pharmaceutical composition includes
300mg to the cannabidiol of 1200mg or its pharmaceutically acceptable salt and 0.5mg to the tetrahydrocannabinol of 6mg or its
Pharmaceutically acceptable salt.
8. the pharmaceutical composition described in any one of claim 1-7 is being prepared for preventing and/or treating in the drug of epilepsy
Purposes.
9. purposes as claimed in claim 8, which is characterized in that the type of the epilepsy is partial seizures.
10. purposes as claimed in claim 9, which is characterized in that the partial seizures are simple partial seizure or complexity
Partial seizures.
11. a kind of method being used to prepare the pharmaceutical composition described in any one of claim 1-7, which is characterized in that described
Method includes the following steps：1) it is 600 by weight proportion:Active constituents of medicine a) the cannabidiols of 1-3 or its can pharmaceutically connect
The salt received and b) tetrahydrocannabinol or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient mixing
Uniformly；2) mixture that step 1) obtains optionally is prepared into any pharmaceutically acceptable dosage form.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109700853A (en) * | 2019-03-13 | 2019-05-03 | 昆明龙津药业股份有限公司 | A kind of composition and its application in the drug of preparation prevention and treatment epilepsy |
| CN110101804A (en) * | 2019-05-30 | 2019-08-09 | 厦门梓素生物科技有限公司 | A kind of epilepsy drugs combination of the extract containing cannabidiol and preparation method thereof |
| WO2021070120A1 (en) * | 2019-10-11 | 2021-04-15 | Pike Therapeutics, Inc., 1219014 B.C. Ltd. | Transdermal compositions comprising cannabidiol (cbd) for use in the treatment of seizure disorders |
| WO2021135665A1 (en) * | 2019-12-31 | 2021-07-08 | 汉义生物科技（北京）有限公司 | Application of tetrahydrocannabivarin in prevention and/or treatment of pulmonary arterial hypertension |
| CN113874344A (en) * | 2019-03-08 | 2021-12-31 | 加利福尼亚大学董事会 | Use of 8, 9-dihydrocannabidiol compounds |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113874344A (en) * | 2019-03-08 | 2021-12-31 | 加利福尼亚大学董事会 | Use of 8, 9-dihydrocannabidiol compounds |
| EP3935037A4 (en) * | 2019-03-08 | 2023-03-22 | The Regents Of The University Of California | Use of 8,9-dihydrocannabidiol compounds |
| CN109700853A (en) * | 2019-03-13 | 2019-05-03 | 昆明龙津药业股份有限公司 | A kind of composition and its application in the drug of preparation prevention and treatment epilepsy |
| CN110101804A (en) * | 2019-05-30 | 2019-08-09 | 厦门梓素生物科技有限公司 | A kind of epilepsy drugs combination of the extract containing cannabidiol and preparation method thereof |
| WO2021070120A1 (en) * | 2019-10-11 | 2021-04-15 | Pike Therapeutics, Inc., 1219014 B.C. Ltd. | Transdermal compositions comprising cannabidiol (cbd) for use in the treatment of seizure disorders |
| WO2021135665A1 (en) * | 2019-12-31 | 2021-07-08 | 汉义生物科技（北京）有限公司 | Application of tetrahydrocannabivarin in prevention and/or treatment of pulmonary arterial hypertension |
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