CN113491686A - Anti-stress pharmaceutical composition and application thereof - Google Patents
Anti-stress pharmaceutical composition and application thereof Download PDFInfo
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- CN113491686A CN113491686A CN202010252074.XA CN202010252074A CN113491686A CN 113491686 A CN113491686 A CN 113491686A CN 202010252074 A CN202010252074 A CN 202010252074A CN 113491686 A CN113491686 A CN 113491686A
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- Prior art keywords
- stress
- levocarnitine
- vitamin
- injection
- pharmaceutical composition
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Abstract
The invention discloses an anti-stress pharmaceutical composition and application thereof, the composition consists of one or more of levocarnitine, levocarnitine derivatives, and pharmaceutically acceptable salts and metabolites of levocarnitine or derivatives thereof, phosphate salts, amino acids, minerals, trace elements, vitamins, organic acids, fatty acids, phosphate esters and anti-stress herbs, and has the effects of preventing stress reaction and reducing stress attack injury.
Description
Technical Field
The invention relates to the field of medicines, in particular to an anti-stress medicine composition and application thereof in preparing anti-stress medicines.
Background
Stress refers to the sum of nonspecific reactions of the body caused by external stimuli, and is a combined reaction of hypothalamus-pituitary-adrenal cortex system.
The types of stress can be broadly classified into: physical stresses including noise, vibration, temperature (high and low), moisture, electromagnetic radiation, low oxygen, etc.; chemical stress including toxic substances such as food additives, tobacco, alcohol, toxic gas and exhaust gas, heavy metals, pesticides, and the like; the biological stress mainly refers to biological stressors which can cause infection and allergy, such as pathogenic bacteria, viruses, pollen, moulds and the like; social stress including political economic problems, neighborhood disputes, retirement, unemployment, troubles in work, problems in life such as marriage and funeral marriage, and the like; psychological stress mainly refers to contradiction in work and life and fear, anger, dissatisfaction, uneasiness, hate and sadness caused by interpersonal relationship. In addition, there is also body stress caused by surgery or trauma.
An ideal anti-stress drug should have the effect of preventing stress and reducing stress response. There is currently no such drug.
Disclosure of Invention
The invention aims at providing an anti-stress medicament, aims at providing an anti-stress medicament composition containing the anti-stress medicament, and aims at providing an application of the anti-stress medicament or the anti-stress medicament composition in preparing the anti-stress medicament.
The anti-stress medicament comprises one or more of levocarnitine, levocarnitine derivatives and levocarnitine medicinal salts, wherein the levocarnitine derivatives comprise formyl levocarnitine, acetyl levocarnitine and propionyl levocarnitine; the pharmaceutically acceptable salts of the levocarnitine comprise hydrochloride, hydrobromide, iodohydrorate, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, pantothenate, methanesulfonate and p-toluenesulfonate.
Levocarnitine is an essential natural substance in the body of mammals in energy metabolism, and its main function is to promote lipid metabolism. It can bring long-chain fatty acid into mitochondrial matrix, promote its oxidative decomposition, provide energy for cell, and output short-chain fatty acid produced in mitochondria. The supplement of L-carnitine can relieve fat metabolism disorder and dysfunction of tissues such as skeletal muscle and cardiac muscle caused by carnitine deficiency in vivo. The composition is clinically used for preventing and treating the levocarnitine deficiency, is suitable for a series of complicating symptoms caused by secondary carnitine deficiency, and has clinical manifestations such as cardiomyopathy, skeletal myopathy, arrhythmia, hyperlipidemia, hypotension, muscle spasm in dialysis and the like. In addition, the levocarnitine has an obvious protective effect on ischemia and hypoxia injuries of important tissues such as brain, heart, liver, kidney and the like of a human body, has wide application in the field of treatment of cardiovascular and cerebrovascular diseases, has few adverse reactions and high safety, and has a large number of clinical application reports of treating chronic renal failure, myocarditis, heart failure, angina pectoris, myocardial infarction, fatigue resistance, exercise endurance improvement, oxidation resistance, cancer resistance and the like.
The anti-stress medicine composition comprises the anti-stress medicine and one or more of metabolism, phosphate, amino acids, minerals, trace elements, vitamins, organic acids, fatty acids, phosphate and anti-stress herbs.
The metabolic drugs comprise trimetazidine, trimetazidine dihydrochloride, vinpocetine, creatinine glucose, coenzyme A, an energy mixture and fructose diphosphate sodium; the phosphate substances comprise adenosine monophosphate, adenosine diphosphate and adenosine triphosphate; the amino acids comprise leucine, isoleucine, valine, leucine, methionine, lysine, phenylalanine, tryptophan, threonine and histidine; the minerals comprise calcium, potassium, iron, zinc and magnesium; the vitamins comprise vitamin A, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin B13, vitamin B15, choline and inositol; the microelements comprise iron, zinc, selenium and iodine; the organic acids include creatine; the phospholipids include phosphatidylserine; the fatty acids comprise long chain fatty acids, medium chain triglycerides; the anti-stress herbs include herba Hyperici perforati, herba Passiflorae Caeruleae, rhizoma et radix Valerianae, folium Ginkgo, Ginseng radix, and radix Acanthopanacis Senticosi.
The invention also provides application of the anti-stress medicament or the anti-stress medicament composition in preparing a medicament for resisting stress fluctuation.
The stress comprises physical stress caused by noise, vibration, temperature (high and low temperature), humidity, electromagnetic radiation, hypoxia and the like; chemical stress caused by toxic substances such as food additives, tobacco, alcohol, toxic gas and waste gas, heavy metals and pesticides; biological stress caused by biological stressors which can cause infection and allergy, such as pathogenic bacteria, viruses, pollen, molds and the like; social stress caused by political economic problems, household neighborhood disputes, retirement, unemployment, troubles in work, problems in marriage and funeral marriage and the like in life and the like; psychological stress caused by contradiction in work and life and fear, anger, dissatisfaction, uneasiness, hate, sadness and the like caused by interpersonal relationship; and physical stress caused by surgery or trauma.
The pharmaceutical composition is administered in an oral administration form, an injection administration form or a topical administration form. The oral administration forms comprise tablets, granules, capsules, oral solutions, syrups, inhalants and sprays; the injection administration forms comprise freeze-dried powder injection, suspension for injection, emulsion for injection and solution injection; the topical administration forms comprise aerosol, ointment, lotion, suppository, patch, liniment, eye drop, and vaginal effervescent tablet.
The dosage of each drug component in the drug composition refers to the dosage recorded in the drug use instruction of the single preparation products on the market, and the preferable weight ratio range or specific ratio of each drug component can be screened out through limited scientific experiments.
The specific implementation mode is as follows:
the following examples may assist those skilled in the art in a more complete understanding of the present invention, but are not intended to limit the invention in any way.
Example 1: effect on hypoxic stress at Low pressure
SD rats, 40, were randomly divided into plateau control group, levocarnitine group (levocarnitine 400 mg/kg), levoqu group (levocarnitine 400mg/kg + trimetazidine hydrochloride group 5 mg/kg), levogardine group (levocarnitine 400mg/kg + adenosine disodium triphosphate 20 mg/kg), and 10 rats each. The drug intervention groups respectively administer corresponding drugs by intragastric administration, the plateau control group administers normal saline with intragastric volume of 5 ml/kg, and the administration is carried out 2 times per day for 7 days continuously.
Feeding rat in normal plain environment, 1 hr after the last administration, placing rat in low-pressure and low-oxygen animal experiment cabin at 6 m.s-1Reducing pressure, increasing to simulated altitude of 7000m, intracapsule intragastric administration for 1d, reducing simulated altitude to 5000m during administration, in cabin, stopping water and fasting for 12h, keeping simulated altitude of 5000m 2h after last administration, performing anesthesia by intraperitoneal injection of 10% urethane at 1.5g/kg, collecting brain tissue and arterial blood, and detecting Reactive Oxygen Species (ROS), superoxide dismutase (SOD), Malondialdehyde (MDA), lactic acid (Lactate), corticosterone, Norepinephrine (NE), interleukin-10 (IL-10), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta).
The results show that:
the low-pressure hypoxia induces the hypoxia stress reaction of rats, and the drug intervention group can obviously reduce the content of cortisol and norepinephrine in the serum of the rats. The compound of the levocarnitine, the levocarnitine and the trimetazidine hydrochloride and the compound of the levocarnitine and the adenosine triphosphate can reduce the stress reaction of organisms.
Compared with a plateau control group, the drug intervention group can obviously reduce the content of ROS and MDA in the brain tissue of the rat. Suggesting that the L-carnitine, the acetyl L-carnitine and the propionyl L-carnitine have the function of resisting oxidative stress.
Compared with the plateau control group, the drug intervention group has obviously reduced IL-1 beta, IL-6 and IL-10. The suggestion is that the compound of the L-carnitine, the L-carnitine and the trimetazidine hydrochloride, the compound of the L-carnitine and the adenosine triphosphate can obviously reduce the inflammatory reaction of the brain tissue of rats simulating the acute hypoxia at the altitude of 7000m for 24 hours.
TABLE 1 Effect on serum hormone levels and lactate in rats with hypoxia 24 hours simulated altitude 7000m
| Group of | Corticosterone (ug/ml) | NE（ng/L） | Lactate(ug/L) |
| Plateau control group | 82.58±13.69 | 119.18±22.59 | 56.11±9.95 |
| Sinistraside group | 70.60±12.18△ | 120.09±14.59 | 47.20±9.70*△ |
| Left bend group | 59. 69±12.27△△ | 113.97±26.26 | 49.90±8.06 |
| Left card set | 45.86±7.03△△ | 89.73±15.11**△△ | 47.07±9.83*△ |
△ P<0.05，△△ P<0.01 vs plateau control group
TABLE 2 Effect on the lipid peroxidation index of rat brain tissue at simulated altitude 7000m hypoxia 24 h
△ P<0.05，△△ P<0.01 vs plateau control group
TABLE 3 Effect on simulating the medium of brain tissue inflammation in rats with 7000m altitude hypoxia for 24 hours
| Group of | IL-1β(ng/L) | IL-6（pg/ml） | IL-10（ng/L） |
| Plateau control group | 9.39±3.31 | 20.1±1.25** | 16.2±2.63 |
| Sinistraside group | 6.79±1.36△ | 14.9±3.31△△ | 13.0±1.66△△ |
| Left bend group | 6.23±1.20△△ | 13.9±2.70△△ | 11.1±1.58**△△ |
| Left card set | 6.15±1.40△△ | 15.3±4.27△△ | 13.5±3.41△ |
△ P<0.05，△△ P<0.01 vs plateau control group
Example 2: prevention effect on posttraumatic stress disorder of rats
After one week of adaptive feeding, the rats were randomly divided into 5 groups, namely a normal group, a model group, a left-muscle group (acetyl-L-carnitine 400mg/kg + creatine 200 mg/kg), a left-silk group (acetyl-L-carnitine 400mg/kg + phosphatidylserine 200 mg/kg), and 10 rats in each group.
The preparation is administered by intragastric administration at a weight of 1 ml/100 g per day, and the normal group and the model group are administered with physiological saline for intragastric administration, and the drug intervention group is administered with corresponding drug for 2 times per day for 2 weeks.
A PTSD rat model is constructed by an SPS method according to a literature method, namely, firstly, the rat is tightly bound for 2 hours, secondly, the rat is placed in a water tank (the water depth is 45cm and the water temperature is 25 ℃) and is forcedly swim for 20 minutes, thirdly, after the swimming is finished for 15 minutes, the rat is placed in a closed container for ether anesthesia, and after the anesthesia, the rat is placed in a ventilation position, and fourthly, the rat is placed back to the rat cage after the rat is awakened. And (3) finishing the model building after 7 days, performing an open field experiment, placing the rat in the center of the bottom surface in the open field box, and performing camera shooting observation by using an automatic observation and analysis system. Laboratory staff keeps away from spacious field case among the process of making a video recording, avoids causing the interference. And stopping shooting after 5 min. After each experiment, the inside of the open-field box is cleaned by alcohol so as to avoid interference on the next test. And analyzing the camera shooting result by adopting computer software, and measuring the single maximum movement distance, the total movement distance and the grid penetrating times of each group of rats within 5 min. On the end of the experiment, the rats are anesthetized by intraperitoneal injection with 0.03 ml/kg of 10% chloral hydrate, blood is taken from the abdominal aorta, serum is taken by centrifugation, and the content of the serum corticosterone is detected by an ELISA method.
The results show that: the drug intervention group can remarkably increase the total movement distance and the lattice penetration times of a PTSD model rat, reduce the serum corticosterone level of the PTSD rat, and prompt that the compound of acetyl levocarnitine, acetyl levocarnitine and creatine and the compound of acetyl levocarnitine and phosphatidylserine can effectively prevent the anxiety behavior of the PTSD rat and enhance the adaptability of the rat to stress.
TABLE 4 Effect on the results of the rat open field experiments
| Group of | Total distance of movement (cm) | Single maximum movement distance (cm) | Number of passes (times) |
| Normal group | 2165.52±912.47 | 11.06±1.83 | 81.6±36.12 |
| Model set | 1184.03±531.86 | 7.98±1.25 | 40.3±26.54 |
| Left thread group | 1772.87±111.54* | 8.05±1.61 | 65.23±38.78* |
| Left muscle group | 1866.41±218.60* | 9.36±1.37* | 67.76±28.41* |
| Left card set | 1908.43±216.53* | 8.61±1.44* | 69.24±27.80* |
P < 0.05 in comparison with model group
TABLE 5 Effect on rat serum corticosterone
| Group of | Corticosterone (μ g/ml) |
| Normal group | 88.13±11.22 |
| Model set | 118.96±31.56 |
| Left thread group | 76.12±11.43* |
| Left muscle group | 75.41±18.60* |
| Left card set | 69.73±16.32* |
P < 0.05 in comparison with model group
Example 3: propionyl levocarnitine injection
Prescription: propionyl levocarnitine 500g
0.5g disodium edetate
Appropriate amount of hydrochloric acid
Adding water for injection to 1000ml
The process comprises the following steps: adding 80% of injection water according to the prescription amount into a preparation container, adding propionyl levocarnitine for dissolving, adding prepared edetate disodium and hydrochloric acid solution, stirring uniformly, adjusting the pH value of the liquid medicine to 6.5, adding the injection water to the full amount, adding 0.1% of activated carbon for decoloring, filtering by using a sintered glass filter and a membrane filter, filling and sealing under nitrogen gas flow, and finally sterilizing by circulating steam at 100 ℃ for 15 min.
Example 4: compound tablet (acetyl levocarnitine + phosphatidic acid serine)
Prescription: acetyl L-carnitine 1000g
Phosphatidic acid serine 500g
Lactose 1000g
Microcrystalline cellulose 500g
Hydroxypropyl cellulose 100g
Croscarmellose sodium 50g
Proper amount of magnesium stearate
Making into 5000 pieces
The process comprises the following steps: sieving acetyl levocarnitine and phosphatidic acid serine with a 80-mesh sieve, mixing with microcrystalline cellulose and lactose, adding hydroxypropyl cellulose to obtain soft material, granulating with a 14-mesh sieve, drying in a 70 deg.C air-blast drying oven for 4 hr, grading with a 20-mesh sieve, adding croscarmellose sodium and magnesium stearate, mixing, and tabletting.
Example 5: compound tablet (levocarnitine and trimetazidine dihydrochloride)
Prescription: 1000g of L-carnitine
Trimetazidine hydrochloride 5g
Lactose 200g
Starch 100g
10% starch slurry 100g
Crosslinked Povidone 20g
Magnesium stearate 15g
Making into 2000 pieces
The process comprises the following steps: sieving levocarnitine and trimetazidine hydrochloride with a 80-mesh sieve, mixing with starch and lactose, adding starch slurry to prepare a soft material, granulating with a 14-mesh sieve, drying at 70-80 ℃, grading with a 12-mesh sieve, adding crospovidone and magnesium stearate, mixing uniformly, and tabletting to obtain the compound preparation.
Example 6: compound oral liquid (acetyl levocarnitine, creatine and ginseng extract)
Prescription: acetyl L-carnitine 100g
Creatine 50g
Ginseng radix extract 50g
Lactose 150g
Sucralose 10g
Beta Cyclodextrin 50g
Arabic gum 50g
Made into 1000ml
The process comprises the following steps: dissolving beta-cyclodextrin and Arabic gum in water, adding acetyl levocarnitine, creatine, Ginseng radix extract, lactose and sucralose, stirring to dissolve, and adding water to 1000 ml.
Claims (7)
1. An anti-stress drug, which is characterized by comprising one or more of levocarnitine, levocarnitine derivatives, levocarnitine or pharmaceutically acceptable salts of the derivatives of the levocarnitine.
2. The anti-stress agent of claim 1, wherein the levocarnitine derivative comprises acetyl levocarnitine, propionyl levocarnitine, butyryl levocarnitine; the pharmaceutically acceptable salts of the levocarnitine comprise hydrochloride, hydrobromide, iodohydrorate, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, pantothenate, methanesulfonate and p-toluenesulfonate.
3. An anti-stress pharmaceutical composition, characterized in that the anti-stress pharmaceutical composition comprises the anti-stress drug of any one of claims 1-2 and one or more of metabolic, phosphate, amino acids, minerals, trace elements, vitamins, organic acids, fatty acids, phosphate esters and anti-stress herbs.
4. The anti-stress pharmaceutical composition according to claim 3, wherein the metabolic drug comprises trimetazidine, trimetazidine dihydrochloride, vinpocetine, creatinine glucose, coenzyme A, an energy mixture, and fructose diphosphate sodium; the phosphate substances comprise adenosine monophosphate, adenosine diphosphate and adenosine triphosphate; the amino acids comprise leucine, isoleucine, valine, leucine, methionine, lysine, phenylalanine, tryptophan, threonine and histidine; the minerals comprise calcium, potassium, iron, zinc and magnesium; the vitamins comprise vitamin A, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin B13, vitamin B15, choline and inositol; the microelements comprise iron, zinc, selenium and iodine; the organic acids include creatine; the phospholipids include phosphatidylserine; the fatty acids comprise long chain fatty acids, medium chain triglycerides; the anti-stress herbs include herba Hyperici perforati, herba Passiflorae Caeruleae, rhizoma et radix Valerianae, folium Ginkgo, Ginseng radix, and radix Acanthopanacis Senticosi.
5. Use of the anti-stress agent of any one of claims 1 to 2 or the anti-stress pharmaceutical composition of any one of claims 2 to 4 for the manufacture of an anti-stress medicament.
6. Use according to claim 5, wherein the pharmaceutical composition is administered orally, by injection or topically.
7. The oral administration forms comprise tablets, granules, capsules, oral solutions, syrups, inhalants and sprays; the injection administration forms comprise freeze-dried powder injection, suspension for injection, emulsion for injection and solution injection; the topical administration forms comprise aerosol, ointment, lotion, suppository, patch, liniment, eye drop, and vaginal effervescent tablet.
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