CN111135304A

CN111135304A - Combined medicine for treating chronic, intractable or primary insomnia and its use

Info

Publication number: CN111135304A
Application number: CN202010067900.3A
Authority: CN
Inventors: 李启芳
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-01-19
Filing date: 2020-01-19
Publication date: 2020-05-12

Abstract

The invention provides a combined medicament for treating chronic, intractable or primary insomnia, which comprises an anticholinergic medicament and a sedative medicament which are used in combination. The invention uses anticholinergic medicine and sedative medicine in the specific proportion, which can effectively enhance the treatment effect and delay the onset of chronic, intractable or primary insomnia patients. The combined medicine has the advantages of small side effect or no side effect and high safety. Meanwhile, the combined medicine can effectively treat chronic, intractable or primary insomnia, and the effect is better than that of the single use of dexmedetomidine, which shows that the medicine has the synergistic effect when used together under the specific proportion of the invention, and the clinical application prospect is good.

Description

Combined medicine for treating chronic, intractable or primary insomnia and its use

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to a combined medicine which comprises an anticholinergic medicine and a sedative medicine and is used for treating chronic, intractable or primary insomnia.

Background

Insomnia is a sleep disorder characterized by frequent and persistent difficulty in falling asleep and/or difficulty in maintaining sleep and resulting in an unsatisfactory sensation of sleep. Insomnia may occur as an independent disease or may be co-morbid with mental disorders, physical disorders or substance abuse and may be accompanied by various functional impairment upon awakening.

The chronic insomnia refers to sleep disorder lasting for at least three months for more than three days per week, and the small-particle-size negative ions have higher activity and can easily penetrate through the human body to exert the recuperative and health-care effects.

The chronic insomnia is classified into primary insomnia and secondary insomnia. Primary insomnia is an unexplained, frequent sleep interruption, long-term or lifetime, short sleep with daytime fatigue, stress, depression and drowsiness. Some patients may have a family history of insomnia, in addition to other factors of intrinsic cause and environmental disturbance. The etiology is unknown but chronic psychomental insomnia is gradually caused at most.

In the classification of insomnia, intractable insomnia is a common disease, and its treatment difficulty is greater than that of secondary insomnia. The intractable insomnia is usually caused by psychological factors, and is clinically mainly manifested by difficulty in falling asleep, difficulty in maintaining sleep and daytime tiredness, the more people want to fall asleep as soon as possible at night, the more difficult it is to fall asleep, the more psychological conflicts are aggravated, tension anxiety, emotional instability and excessive worry are generated, the more subjective pain causes insomnia, and a vicious circle is formed.

Hazards of insomnia:

1. insomnia causes a decrease in body immunity and a decrease in resistance to various diseases.

2. Hypomnesis and headache are caused by insomnia.

3. Insomnia affects work, learning, and life.

4. Insomnia can lead to vegetative nerve disorders.

5. Frequent insomnia can cause senile dementia.

6. Frequent insomnia causes premature aging and shortens the life span.

7. The growth and development of the body can be influenced by the insufficient sleep of the children.

Drug therapy is the most treatment method for many intractable insomnia patients, such as oral hypnotics, but the addiction and dependence of these hypnotics cannot completely help patients to treat insomnia, but the insomnia problem is aggravated because patients cannot fall off the normal sleep of the drugs. Acupuncture treatment may have a certain effect of relieving symptoms in the early stage of insomnia, but the symptoms of intractable insomnia and severe insomnia are aggravated with symptoms and the effect cannot reach the effect of healing.

Therefore, the search for new treatment regimens has been the focus of research on chronic, refractory or primary insomnia.

Disclosure of Invention

In order to solve the problems, the invention provides a combined medicine for treating chronic, intractable or primary insomnia.

It would be desirable to develop a combination comprising an anticholinergic and a sedative drug which can be used for the treatment of chronic, intractable or primary insomnia, which is easy to use, produces no or little side effects and has a high cure rate.

In particular, in a first aspect of the invention, there is provided a combination comprising an anticholinergic agent and a sedative agent for the treatment of chronic, refractory or primary insomnia.

The anticholinergic medicine in the combined medicine of the invention particularly relates to scopolamine, anisodamine and atropine, and the sedative medicine in the combined medicine particularly relates to diazepam, propofol and dexmedetomidine.

The combination of the invention may exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and this application includes all variant forms of the combination.

The combination drug comprises at least one of anticholinergic agents such as scopolamine, derivatives of scopolamine, salts of scopolamine, anisodamine, derivatives of anisodamine, salts of anisodamine, atropine, derivatives of atropine and salts of atropine, and at least one of sedative drugs such as diazepam, derivatives of imidazole, salts of imidazole, propofol, derivatives of propofol, salts of propofol, dexmedetomidine, derivatives of dexmedetomidine and salts of dexmedetomidine, and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is a conventional drug carrier in the pharmaceutical field, and comprises: diluents, excipients, and water, etc.; fillers such as starch, sucrose, lactose, microcrystalline cellulose, and the like; binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone, and the like; humectants such as glycerol; disintegrating agents such as agar, calcium carbonate, sodium bicarbonate, etc.; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol and the like; adsorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, polyethylene glycol, etc., and other adjuvants such as flavoring agents, sweetening agents, etc. may also be added to the composition.

The combination drug is any one of the dosage forms in pharmaceutics, including tablets, capsules, soft capsules, gels, oral agents, suspensions, medicinal granules, patches, ointments, pills, powder, injections, infusion solutions, freeze-dried injections, intravenous emulsions, liposome injections, suppositories, sustained-release preparations or controlled-release preparations. Preferably an injection.

Various dosage forms of the combination drug can be prepared according to the conventional production method in the pharmaceutical field and then prepared into the required dosage form. Furthermore, the combination drug is prepared into an injection administration form.

The combined medicine is applied to treating chronic, intractable or primary insomnia.

Further, the sedative drug is at least one of diazepam, propofol and dexmedetomidine, the dosage of the diazepam, the diazepam and the propofol is 0.01-0.05mg/h, 0.01-0.05mg/h and 4-10mg/h per kilogram of body weight respectively, and the administration lasts for 2-6 h; the dosage of the dexmedetomidine is 0.5-1 ug/h per kilogram of body weight, and the drug is administered for 2-12 h, preferably 4 h.

Further, the application method of the combination drug comprises the following steps: continuously using the sedative drug for 0.5 to 2 hours before the patient revives, and using the anticholine drug after the patient enters the sleep state for 5 to 30 minutes.

Furthermore, the sedative drug comprises at least one of diazepam, diazepam and propofol, and the dosage of the diazepam, the diazepam and the propofol is 0.01-0.05mg/h, 0.01-0.05mg/h and 4-10mg/h per kilogram of body weight respectively, and the sedative drug is administrated for 5 min-30 min; the dosage of the dexmedetomidine is 0.5-1 ug/h per kilogram of body weight, and the drug is administered for 2-12 h, preferably 4 h.

Further, at least one of diazepam, diazepam and propofol is administered to the patient before the patient enters sleep for 5-30 min, and at this time, the administration of at least one of diazepam, diazepam and propofol is stopped and dexmedetomidine and anticholinergic agents are administered simultaneously.

Further, the anticholinergic drug is at least one selected from scopolamine and anisodamine, the dosage of the anticholinergic drug is 0.01-0.03 ug per kilogram of body weight, and the administration is completed within 1-3 h.

Furthermore, the anticholinergic drug and the sedative drug are both administered by intravenous injection.

The actual dosage level in the combination of the invention may be varied to obtain an actual dosage which is effective for the particular patient and which achieves a certain therapeutic response. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. One skilled in the art can start with a lower dose than is required to achieve the desired therapeutic effect and then gradually increase the dose until the desired therapeutic effect is achieved.

The combination of the invention may be used in the treatment of chronic, refractory or primary insomnia, and the term "treatment" includes treatment to ameliorate one or more symptoms of chronic, refractory or primary insomnia, or to delay the progression of such a condition, for example to delay the onset of a patient suffering from chronic, refractory or primary insomnia; it also includes treatments to cure such diseases, to bring the patient into a normal functional state and/or to maintain the patient in a normal functional state or to prolong the time to relapse.

Therefore, the anticholinergic, the sedative and the related compounds can be developed into the medicine for preventing or treating chronic, intractable or primary insomnia by combined administration, and has good application prospect.

Detailed Description

The "ranges" disclosed herein are in the form of lower and upper limits. There may be one or more lower limits, and one or more upper limits, respectively. The given range is defined by the selection of a lower limit and an upper limit. The selected lower and upper limits define the boundaries of the particular range. All ranges that can be defined in this manner are inclusive and combinable, i.e., any lower limit can be combined with any upper limit to form a range. For example, ranges of 60-120 and 80-110 are listed for particular parameters, with the understanding that ranges of 60-110 and 80-120 are also contemplated. Furthermore, if the minimum range values 1 and 2 are listed, and if the maximum range values 3, 4, and 5 are listed, the following ranges are all contemplated: 1-3, 1-4, 1-5, 2-3, 2-4 and 2-5.

In the present invention, all embodiments and preferred embodiments mentioned herein may be combined with each other to form a new technical solution, if not specifically stated. In the present invention, all the technical features mentioned herein and preferred features may be combined with each other to form a new technical solution, if not specifically stated.

The invention provides a combined medicament for treating chronic, intractable or primary insomnia, which comprises an anticholinergic medicament and a sedative medicament which are used in combination. Wherein the anticholinergic agent is at least one selected from scopolamine, anisodamine and atropine; the sedative drug is at least one selected from diazepam, propofol and dexmedetomidine. It will be appreciated that the at least one anticholinergic agent may be used in combination with the at least one sedative agent in a variety of combinations, for example, the combination may comprise scopolamine and propofol in combination, or scopolamine, propofol and dexmedetomidine in combination, or scopolamine, propofol, diazepam, dexmedetomidine and imidazofin in combination, without limitation.

The pharmacology of the combination drug for treating chronic, refractory or primary insomnia according to the present protocol is detailed below:

the anticholinergic drug in the sleep therapy combination can improve human microcirculation and mainly has the following aspects: 1 regulating micro-vasomotor and correcting blood flow pathological distribution, the anticholinergic drug can relieve arteriole and micro-vasospasm, open the front and back gates of occluded microcirculation, and slightly contract relaxed venules, so that blood deposited on the microcirculation is prevented from flowing back again to enter circulation, and the blood flow pathological distribution is improved. Patients suffering from long-term insomnia mostly have poor microcirculation in vivo, long-term metabolite deposition, tissues are in a chronic anoxic state for a long time, and particularly, the microcirculation metabolite in the center is accumulated for a long time to stimulate cerebral cortex, so that the cerebral cortex is excited, and therefore sleep disorder is caused. The sedative drugs such as dexmedetomidine and the like are mainly used for resisting the side effects of the anticholinergic drugs, such as fast heart rate, dry mouth, delirium and the like, and in addition, the sedative drugs have certain treatment effect on insomnia.

The sedative drug is selected from diazepam, imidazole diazepam, propofol or/and dexmedetomidine, wherein the diazepam, imidazole diazepam and propofol after intravenous injection are rapidly distributed in the whole body, can generate a sleep state within 40 seconds, and can be rapidly and stably calmed, and also has a new pharmacological effect of improving microcirculation; dexmedetomidine has no respiratory depression, can regulate sympathetic nerve activity, is complementary to the parasympathetic regulation of scopolamine/anisodamine, and has synergistic effect. Preferably, the sedative drug simultaneously selects at least one of diazepam, imidazole diazepam and propofol and dexmedetomidine, the use of diazepam, imidazole diazepam and propofol has the defect of respiratory depression, the use of dexmedetomidine alone has the defect of slow effect, generally at least 1h of effect is needed to enable a patient to enter a deep sleep state, however, the combined use of the diazepam and the imidazole diazepam can not inhibit the respiratory of the patient and has quick effect.

Further, the sedative drug includes at least one of diazepam, diazepam and propofol and includes dexmedetomidine.

In this example, the combination is prepared as an injectable dosage form and administered by intravenous injection. In the case of intravenous administration, when the anticholinergic agent is at least one selected from scopolamine and anisodamine, the dosage of the anticholinergic agent is 0.01-0.03 ug per kg body weight, and the administration is completed within 1-3 h; when the sedative drug is at least one of diazepam, propofol and dexmedetomidine, the dosage of diazepam, diazepam and propofol is 0.01-0.05mg/h, 0.01-0.05mg/h and 4-10mg/h per kilogram of body weight respectively, and the administration lasts for 2-6 h; the dosage of dexmedetomidine is 0.5 ug/h-1 ug/h per kilogram of body weight, and the drug is administered for 2 h-12 h, preferably 4 h; when the sedative drug comprises at least one of diazepam, diazepam and propofol and comprises dexmedetomidine, the dosage of the at least one of diazepam, diazepam and propofol is 0.01-0.05mg/h, 0.01-0.05mg/h and 4-10mg/h per kilogram of body weight respectively, and the drug is administrated for 5-30 min; the dosage of the dexmedetomidine is 0.5-1 ug/h per kilogram of body weight, and the drug is administered for 2-12 h, preferably 4 h.

It is understood that the combination can be prepared into other dosage forms, such as tablets, and when the combination is prepared into other dosage forms, the dosage of the combination is adjusted according to the using effect.

Some specific examples are listed below, but it should be noted that the following examples are not exhaustive of all possible dosing scenarios. The components can be added or subtracted arbitrarily or selected in different amounts according to the actual disease condition and the drug resistance degree of the patient, so as to obtain the following embodiments which are not listed.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

The experimental subjects were: the patients are treated conventionally before admission according to the 'Chinese insomnia definition, diagnosis and drug therapy consensus', the treatment drugs are more than two types, the treatment time is 3 months, and the treatment effect is poor or ineffective. The Pittsburgh sleep quality index score before admission is more than 9 points, patients with chronic intractable primary insomnia are diagnosed, the age of the patients is 18-60 years old, the gender is unlimited, and the diagnosis standard and the elimination standard of the chronic intractable primary insomnia related to mental disorder diagnosis and statistical manual (DSM-IV) formulated by the American psychiatric society are met. A total of 60 patients, not stratified by design, were randomized and evenly divided into multiple treatment groups and control groups as follows. Specifically, a third party employs a telephone or network for randomization grouping and an interactive voice response system for randomization. The recruited patients were from the department of neurology of the medical institute of Shanghai university of transportation, Rekin Hospital department of neurology, Luwan division of Rekin Hospital, and the encephalopathy center.

The place of administration was in the Shanghai university of transportation medical school affiliated with Renjin Hospital and Luwan division.

Experimental materials: propofol (from asikang); scopolamine (Shanghai Hefeng pharmaceuticals, Inc.); dexmedetomidine (Chenxin pharmaceutical Co., Ltd.); benzodiazepines. Wherein the propofol, scopolamine and dexmedetomidine are in the form of injection, and can be used in a diluted way or not, and when not diluted, a micro pump or an infusion pump is preferably used so as to control the infusion rate; for example, when the scopolamine is diluted in 500 ml of ringer's lactate solution, intravenous drip is completed within 1-3 h, and optimally, drip is completed within 2h, the diluent should be prepared aseptically and prepared before administration. It is to be noted that all amounts mentioned in the present invention are amounts when undiluted.

Patients in the treatment group are scheduled to a designated hospital to handle admission procedures, diet prohibition is given 8 hours before treatment, the patients enter an operating room for electrocardiographic monitoring and blood pressure monitoring, and peripheral veins are opened.

The administration of each treatment group and control group is shown in the following table, wherein the unit ug/kg/h represents the amount of drug (ug) required to be injected per kilogram of body weight per hour; the unit mg/kg represents the total amount of drug (mg) required to be injected per kilogram of body weight of the patient.

For treatment groups 1-3, propofol is continuously pumped into the vein until the patient is awake for 1h, scopolamine is continuously pumped into the vein after the patient falls asleep for 30min, the fluctuation of heart rate and blood pressure is kept within 20%, the vital signs of the patient are continuously monitored, and BIS monitors a shallow-sedation sleep state until the patient is completely awake. For treatment groups 4-6, dexmedetomidine was continuously pumped intravenously until 1h before waking up, scopolamine was continuously pumped intravenously after the patient fell asleep for 30min, heart rate and blood pressure fluctuation were maintained within 20%, vital signs of the patient were continuously monitored, and BIS monitored shallow sedation sleep until the patient was fully awake. For the treatment groups 7-9, propofol is continuously pumped into the vein until the patient falls asleep for about 30min, the time is about 25-35 min, and then scopolamine and dexmedetomidine are pumped into the vein simultaneously, so that the fluctuation of the heart rate and the blood pressure is kept within 20%, the vital signs of the patient are continuously monitored, and the BIS monitors the shallow-sedation sleep state until the patient is completely awake.

The treatment group and the control group treated patients with chronic, refractory or primary insomnia for 7 days, wherein 7 days are one treatment course, and Pittsburgh sleep index (PSQI) and excessive arousal scale (HAS) scores are carried out at 1 week (T1), 2 weeks (T2), 1 month (T3), 3 months (T4) and 6 months (T5).

The experimental results are as follows: the total PSQI index of the treatment group is greatly reduced, and the differences have statistical significance P less than 0.05. HAS index decreased in each group, P was < 0.05. The decrease of the HAS index is not obvious in the PSQI index of the control group, and the index HAS no statistical significance.

Therefore, the combined medicine for treating chronic, intractable or primary insomnia has obviously better treatment effect on the chronic, intractable or primary insomnia than the prior art.

Compared with the prior art, the combined medicine for treating chronic, intractable or primary insomnia disclosed by the invention has the advantages of high cure rate, convenience in application, no side effect or small side effect and the like when being applied to treating chronic, intractable or primary insomnia.

The above embodiments are merely examples of the invention and are not intended to limit the scope of the invention, which is defined by the claims and their equivalents, and all changes and modifications that are equivalent to the contents of the claims are intended to be included in the scope of the invention.

Claims

1. A combined medicine for treating chronic, intractable or primary insomnia is characterized by comprising an anticholinergic medicine and a sedative medicine which are used in combination.

2. The combination of claim 1, wherein the anticholinergic is selected from at least one of scopolamine, anisodamine or atropine.

3. The combination of claim 1, wherein the sedative drug is selected from at least one of diazepam, propofol and dexmedetomidine.

4. The combination of claim 1, wherein the combination is formulated for administration by injection.

5. Use of a combination according to claim 1 for the treatment of chronic, refractory or primary insomnia.

6. The combination according to claim 5, wherein the sedative drug is selected from at least one of diazepam, propofol and dexmedetomidine, and wherein the respective amounts of diazepam, diazepam and propofol are 0.01-0.05mg/h, 0.01-0.05mg/h and 4-10mg/h per kg body weight, for 2-6 h; the dosage of the dexmedetomidine is 0.5-1 ug/h per kilogram of body weight, and the drug is administered for 2-12 h, preferably 4 h.

7. The use of a combination as claimed in claim 6, wherein the method of use of the combination is: continuously using the sedative drug for 0.5 to 2 hours before the patient revives, and using the anticholine drug after the patient enters the sleep state for 5 to 30 minutes.

8. The use of a combination according to claim 5, wherein the sedative drug comprises at least one of diazepam, diazepam and propofol, and comprises dexmedetomidine, and wherein the amounts of diazepam, diazepam and propofol are 0.01-0.05mg/h, 0.01-0.05mg/h and 4-10mg/h, respectively, per kg body weight for 5-30 min; the dosage of the dexmedetomidine is 0.5-1 ug/h per kilogram of body weight, and the drug is administered for 2-12 h, preferably 4 h.

9. The use of a combination as claimed in claim 8, wherein the administration of at least one of diazepam, midazolam and propofol is commenced after the patient has entered sleep for a period of 5 to 30 minutes, whereupon the administration of at least one of diazepam, midazolam and propofol is discontinued in conjunction with the administration of dexmedetomidine and the anticholinergic agent.

10. The use of a combination according to claim 5, wherein the anticholinergic is selected from at least one of scopolamine, anisodamine and atropine, the amount of anticholinergic is 0.01 ug-0.03 ug per kg body weight, and administration is completed within 1 h-3 h.

11. The combination according to claim 5, wherein the anticholinergic agent and the sedative agent are administered intravenously.