CN108245510B - Composition of cannabidiol and acryloyl urea antiepileptic drugs and application thereof - Google Patents

Abstract

The invention discloses a composition of cannabidiol and ethylene propylene ureide antiepileptic drugs and application thereof, the composition comprises cannabidiol and ethylene propylene ureide antiepileptic drugs or pharmaceutically acceptable salts thereof, in particular to a pharmaceutical composition of cannabidiol and phenytoin.

Description

Composition of cannabidiol and acryloyl urea antiepileptic drugs and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a composition of cannabidiol and ethylene propylene ureide antiepileptic drugs, especially phenytoin, and application thereof in treating epilepsy, especially partial epileptic seizure.

Background

Epilepsy (epilepsy) is a chronic brain disease caused by a variety of etiologies and is characterized by repetitive, episodic, and transient central nervous system dysfunction due to excessive firing of brain neurons.

Epilepsy occurs in people of any age, region and race, but occurs at a higher rate in children and adolescents. In recent years, with the aging of the population of China, the incidence rates of cerebrovascular diseases, dementia and nervous system degenerative diseases are increased, and the incidence rate of epilepsy in the elderly population has a rising trend. Epilepsy brings serious negative effects to individuals, families and society, and epileptic seizures cause great physical and psychological pains to patients and seriously affect the quality of life of the patients and families; the long-term taking of antiepileptic drugs and other diagnosis and treatment costs bring heavy economic burden to families.

Partial seizures (also known as focal seizures) are characterized by an initial change in clinical and electroencephalogram that neurons in a certain part of the cerebral hemisphere are first activated, followed by a synchronous rapid discharge that rapidly spreads to the surrounding normal brain area, producing a series of electrophysiological and neurochemical changes until the neurons become depleted in energy and metabolically reduced to automatically terminate the seizures. According to whether the seizure process is accompanied by disturbance of consciousness or not, the seizure process is divided into simple partial seizures (unconsciousness disturbance at the time of seizure) and complex partial seizures (disturbance of consciousness with different degrees). The clinical commonly used drugs include phenytoin sodium, carbamazepine, oxcarbazepine and the like. However, the adverse reactions of these drugs are obvious, such as Phenytoin (PHT) causing gingival hyperplasia, rash, ataxia and chronic toxic encephalopathy, which brings unnecessary pain to patients.

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 through a blood brain barrier after injection, and has remarkable cerebral nerve protection effect. CBD can exert neuroprotective effect through multiple pathways, and has weak toxicity and few side effects. Currently, the FDA has granted cannabidiol-containing drugs three rare diseases (pediatric seizure epilepsy, LGS, Dravet epilepsy syndrome, Neonatal Hypoxic Ischemic Encephalopathy (NHIE)) drug eligibility.

Patent application CN201280004572.6 discloses the use of Cannabidiol (CBD) at doses higher than 300 mg/day in combination with standard antiepileptic drugs acting through sodium or calcium channels for epilepsy and in the examples the combination of CBD with valproate, phenobarbital, which increases the latency of onset of seizures and reduces the percentage of tonic-clonic seizures, but the combination of CBD with phenobarbital has little or no significant synergistic effect, the combination of both being of no interest for the treatment of epilepsy.

The inventor of the invention finds out through experiments that the composition prepared from the ethylene propylene ureide antiepileptic drugs such as phenytoin and CBD is used for treating epilepsy, in particular partial seizure of epilepsy, can obtain unexpected synergistic treatment effect, especially can reduce or eliminate the side effect of single use of cannabidiol or phenytoin, and can greatly improve the compliance of patients.

Disclosure of Invention

The invention provides a pharmaceutical composition, which comprises Cannabidiol (CBD) and an ethylene propylene ureide antiepileptic drug or pharmaceutically acceptable salt thereof.

Preferably, the mass ratio of the CBD to the acryloyl urea antiepileptic drug or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.4-3:1, preferably 1-3:1, and more preferably 3: 1.

Preferably, the ethylene propylene ureide antiepileptic drug is selected from: phenytoin (PHT), phenytoin, ethiytoin, hexamidine.

In a preferred embodiment of the present invention, the said EPT drug is PHT.

Preferably, the pharmaceutically acceptable salt of phenytoin is selected from the group consisting of: phenytoin sodium, phenytoin calcium, phenytoin sodium;

epilepsy is a disease that sudden abnormal discharge of cerebral neurons causes transient cerebral dysfunction, neuronal cells are damaged, antiepileptic drugs generally control seizures by reducing excitability of cerebral cells, and long-term taking of antiepileptic drugs may cause loss of some nutrients, and preferably, the pharmaceutical composition of the present invention further comprises neurotrophic drugs, particularly neurotrophic drugs for brain, such as neurotrophic factor drugs, B vitamins, such as vitamin B1 and B12, oryzanol, oxiracetam, piracetam, spinosad, ganglioside, sarcosine glycoside, and the like.

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 extract part can be a stalk core, a flower, a leaf, a root or a seed shell of Cannabis sativa l.

Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

The compositions of the present invention may be formulated into specific dosage forms for administration by any suitable route of administration, 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, with the oral route being preferred. It will be appreciated that the preferred route will depend upon the general condition and age of the patient to be treated, the nature of the disease to be treated and the particular active ingredient or ingredients selected.

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 compositions of the invention or produced according to the invention may be administered by any suitable route, and for the preparation of such compositions, methods known in the art may be employed, and any pharmaceutically acceptable carrier, diluent, excipient or other additive conventionally 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, sucrose, cyclodextrin, agar, pectin, acacia, lower alkyl ethers of cellulose, corn starch, potato starch, talc, magnesium stearate, gelatin 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.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the step of uniformly mixing the acryloyl urea antiepileptic drug or the pharmaceutically acceptable salt thereof and cannabidiol in proportion to obtain the composition.

The invention also provides an application of the CBD in preparing a medicament for preventing and/or treating epilepsy, wherein the CBD is combined with an EPT (ethylene propylene ureide) antiepileptic medicament or a pharmaceutically acceptable salt thereof.

The invention also provides application of the pharmaceutical composition in preparing a medicament for preventing and/or treating epilepsy.

Preferably, the epilepsy type is partial seizure, including simple partial seizure (local seizure), complex partial seizure, more preferably local seizure;

preferably, the application is to reduce or eliminate side effects caused by the single use of the ethylene propylene ureide antiepileptic drug or cannabidiol, such as cognitive impairment, ataxia, lethargy, headache, gingival hyperplasia, hirsutism and the like caused by the single use of the ethylene propylene ureide antiepileptic drug.

The present invention also provides a method of preventing and/or treating epilepsy, particularly partial seizures, which comprises administering to a patient in need thereof a therapeutically effective amount of a combination of cannabidiol and an epichlorurium antiepileptic drug, particularly phenytoin or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the present invention may be administered simultaneously or sequentially. The term "simultaneous administration" as used herein means that the cannabidiol and the acrylurea antiepileptic drug, such as phenytoin, are administered no more than 15 minutes apart, such as up to 10 minutes, such as up to 5 minutes, or such as up to 2 minutes apart. Cannabidiol and an epicyclylurea antiepileptic drug such as phenytoin may also be included in the "same unit dosage form" or in a "separate dosage form". The term "same unit dosage form" as used herein refers to a dosage form that contains both cannabidiol and an epichloruride antiepileptic drug such as phenytoin. The term "isolated dosage form" as used herein means that cannabidiol is contained in one dosage form and an anti-epileptic drug of the acrylurea type, such as phenytoin, is contained in another dosage form. These compositions are administered to a patient in an amount and in a dosing regimen effective to treat epilepsy, particularly partial seizures.

The pharmaceutical composition provided by the invention comprises Cannabidiol (CBD) and ethylene propylene ureide antiepileptic drugs or pharmaceutically acceptable salts thereof, in particular to the pharmaceutical composition of cannabidiol and phenytoin.

Detailed Description

The compounds used in the present invention are commercially available or can be prepared according to the disclosed preparation methods, which do not limit the therapeutic scope of the present invention.

EXAMPLE 1 Effect of combination of CBD and Epipuride antiepileptic drugs on the therapeutic Effect of epilepsy

Experimental Material

Experimental animals: healthy male Wistar rats weighing 75-110 g. Before the experiment, the animals are adapted to the experimental environment, mouse cage, injection scheme and operation. Animals were exposed to 21 ℃, 50% humidity and 12 hours of light, and were free to eat and drink.

Experimental methods

Establishing a rat partial epileptic seizure model: penicillin was used to induce the rat partial seizure model (bosanci and Bagirici, 2006).

Experimental animals were randomly grouped into 20 animals each. Vehicle control or test samples are administered to the test animals by intraperitoneal injection. One week prior to this, cannulae have been surgically implanted into the right ventricle of the animal under anesthesia. 1 hour after administration, penicillin (1000IU/kg) was injected into the lateral ventricle of the animal over 1 minute and 2 hour onset behavior was recorded.

The rating scale for penicillin-induced partial seizures is shown in table 1.

Human Equivalent Dose (HED) can be evaluated using the following formula:

HED-animal dose (mg/kg) multiplied by animal Km/human Km

Km for rat is 6 and Km for human is 37.

Thus, for a 60kg human, a dose of 100mg/kg in rats is equivalent to a dose for a human of about 1000 mg/day, all of which are calculated as corresponding human doses from experimental animals below to avoid confusion.

TABLE 1 penicillin induced partial seizure scores and Experimental animal Performance

Scoring	Performance of experimental animals
		0	Without convulsion, normal behavior
1	Crazy running/jumping
		2	Myoclonus stage
3	Unilateral forelimb clonus
		4	Bilateral forelimb clonus
5	Tonic-clonus firing with postural control preservationMaking
		6	Tonic-clonic seizures without postural control

The duration of seizures was calculated by recording the time from the start of penicillin injection to the appearance of the action grade 1 in table 1, as the start time (latency), recording the time from the first partial seizure to the last seizure disorder or death of the animal.

The number of deaths of the experimental animals was recorded, the mortality was calculated and most animals paying attention to the formation of tonic-clonic seizures were therefore usually dead. The number of non-outbreaks of the animals was recorded.

The dosing regimen and the results of the experiments are shown in tables 2-4.

TABLE 2 combination dosing regimen of CBD and phenytoin and experimental results

TABLE 3 combination dosing regimen of CBD and Methylytoin and results of the experiment

TABLE 4 combination dosing regimen of CBD and hexamidine and experimental results

As shown in the results of tables 2-4, the combination of CBD and EP-acrylurea antiepileptic drugs has therapeutic effect on epilepsy animal models, but when the combination ratio of CBD to EP-acrylurea antiepileptic drugs is 0.4-3:1, the combination has better therapeutic effect compared with the combination with other ratio ranges, such as the combination can increase the latency period of onset of epileptic seizure, reduce the duration time of epileptic seizure, reduce the death rate and increase the percentage of non-seizures.

Example 2 animal experiments on the Effect of combinations of CBD and Epimetrylurea antiepileptic drugs on the side effects of drugs

Experimental animals: healthy male SD rats, 250-300 g. Feeding conditions are as follows: the room temperature is 22 +/-1 ℃, the humidity is 50 +/-10 percent, and the drinking water can be freely taken under natural illumination. 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. Experimental animals were randomly divided into 10 groups of 6 animals each.

Normal control group: normal experimental animals, equal amount of vehicle is given;

CBD and phenytoin combination group 1: the animal model of epilepsy ignited by hydrargyrum acid is administered with 200mg phenytoin +60mg CBD/day;

CBD and phenytoin combination group 2: the animal model of epilepsy ignited by hydrargyrum acid is administered with 200mg phenytoin +800mg CBD/day;

CBD and phenytoin combination group 3: a pimaric acid-ignited animal model of epilepsy, 200mg phenytoin +600mg CBD/day is administered.

CBD and phenytoin combination group 1: an animal model of epilepsy ignited by hydrargyrum acid, 100mg of methyl-tolin +30mg of CBD is administered per day;

CBD and phenytoin combination group 2: the animal model of epilepsy ignited by hydrargyrum acid is administered with 100mg of methyl-tolin +400mg of CBD/day;

CBD and phenytoin combination group 3: an animal model of epilepsy ignited by hydrargyrum acid, 100mg of methyloin +300mg of CBD per day.

CBD and hexamidine combination group 1: the animal model of epilepsy ignited by the hydrargyrum acid is administrated with 50mg of hexamidine and 15mg of CBD per day;

CBD and hexamidine combination group 2: the animal model of epilepsy ignited by the hydrargyrum acid is administrated with 50mg of hexamidine and 200mg of CBD per day;

CBD and hexamidine combination group 3: the animal model of epilepsy ignited by hydrargyrum acid is administered with 50mg of hexamidine and 150mg of CBD per day.

The experimental method comprises the following steps: after administration for 90 days, Morris water maze experiments are carried out for 5 days, each group of experimental animals are taken during the experiments, the animals are placed in a pool facing the pool wall every day, the time for finding the platform within 2min (namely the escape latency) is recorded, and the average value is taken as the learning achievement in four quadrants. The rats did not find the platform within 2min, were introduced to the platform by the experimenter and stayed for 30s, and were returned to the cage to observe surrounding markers for cognitive purposes.

The Morris water maze experiment is a space learning and memory model which is directly related to the function of the hippocampus and can accurately reflect the space learning and memory ability of animals, and the experimental results are shown in tables 5 to 7.

TABLE 5 comparison of spatial learning and memory ability search time of rats in each group 90 days after administration of CBD and phenytoin

TABLE 6 comparison of spatial learning and memory ability search time of rats in each group 90 days after administration of CBD and phenytoin

TABLE 7 comparison of spatial learning and memory ability search time of rats in each group 90 days after administration of CBD and hexamidine

The results in tables 5-7 show that the combined administration of CBD and acryloyl urea antiepileptic drugs can improve the learning and memory abilities of rats, namely the combination of CBD and acryloyl urea antiepileptic drugs improves the cognitive ability while inhibiting epileptic seizures, and the best effect is achieved when the combined administration dosage of CBD and acryloyl urea antiepileptic drugs is 3: 1.

Example 3 clinical trials of the Effect of the combination of CBD and PHT on the side effects of drugs

Subject: the partial epileptic seizure volunteers were 60 persons, male and female were not limited, and were randomly and equally divided into 2 groups of 20 persons each, which were a control group and an experimental group, respectively.

Experimental groups: 200mgPHT +600 mgCBD/day;

control group: PHT administration dose is 200 mg/day;

the experimental method comprises the following steps: the drug is administered to the experimental subject once a day for 12 months according to the above administration scheme; the frequency of attacks, side effects during months 2, 4, 6, 8, 10, 12 were recorded and observed, based on the frequency of attacks 2 months prior to treatment.

Side effects: testing blood routine, electrolyte and monitoring blood concentration, and recording side effects generated within 2 months of each observation point; the side effects include ataxia, lethargy, headache, involuntary movements such as dystonia (common acute adverse effects of phenytoin); gingival hyperplasia, hirsutism, facial roughness, acne and the like (common chronic adverse reactions of phenytoin); rash, etc. (phenytoin-specific adverse reactions).

The results of the experiment are shown in Table 8.

TABLE 8 Experimental results of side effects and recurrence rate

As can be seen from the results in Table 8, the combination of CBD and PHT can significantly reduce the side effects and recurrence rate of both, improve the therapeutic effect, and improve the compliance of patients.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and the like that are within the spirit and principle of the present invention are included in the present invention.

Claims (5)

1. Use of a pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of epilepsy and for the reduction or elimination of side effects associated with the use of an epicyclylurea antiepileptic drug or cannabidiol alone;

the pharmaceutical composition comprises cannabidiol, ethylene propylene ureide antiepileptic drugs or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients;

the mass ratio of cannabidiol to the acryloyl urea antiepileptic drug or pharmaceutically acceptable salt thereof in the pharmaceutical composition is 3: 1;

the ethylene propylene ureide antiepileptic medicine is selected from: phenytoin, ethotoin, hexamidine;

the epilepsy is partial seizure;

the side effect is cognitive impairment.

2. The use of claim 1, wherein the pharmaceutical composition comprises cannabidiol and phenytoin or a pharmaceutically acceptable salt thereof.

3. The use of claim 1, wherein said pharmaceutical composition further comprises a neurotrophic agent.

4. The use of any one of claims 1 to 3, wherein the pharmaceutical composition is selected from the group consisting of: capsules, tablets, pills, lozenges, granules, emulsions, suspensions, syrups, sterile injectable solutions, sterile powders, suppositories, sprays, ointments, gels, inhalants, dermal patches and implants.

5. The use of any one of claims 1 to 3, wherein the partial seizures comprise simple partial seizures, complex partial seizures.