CN114469934B - Composition and pharmaceutical preparation thereof - Google Patents
Composition and pharmaceutical preparation thereof Download PDFInfo
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- CN114469934B CN114469934B CN202210130420.6A CN202210130420A CN114469934B CN 114469934 B CN114469934 B CN 114469934B CN 202210130420 A CN202210130420 A CN 202210130420A CN 114469934 B CN114469934 B CN 114469934B
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Abstract
The invention relates to a composition and a pharmaceutical preparation thereof, which contain ferulic acid and ligustilide in the weight ratio of: ferulic acid: z-ligustilide = 1:4-10, or ferulic acid: z-ligustilide = 1:4, or ferulic acid: z-ligustilide = 1:10, or ferulic acid: z-ligustilide = 1:9.43, said composition further comprises senkyunolide I, (-) -selinic seed lactide, and senkyunolide H, each of the following components in weight percentage: component (A)
Percentage content%
Z-ligustilide
16‑19
Senkyunolide I
1‑3
(-) -celery seed lactide
5‑8
Ferulic acid
1‑3
Senkyunolide H
2‑4。
Description
Technical Field
The invention relates to a composition and a pharmaceutical preparation thereof, in particular to a dripping pill preparation which has the effects of treating headache, dizziness, apoplexy, blurred vision, amnesia and insomnia.
Background
Many traditional Chinese medicines are known to have the effects of regulating qi, activating blood, removing stasis and relieving pain. Such as dripping pills disclosed in national drug standard YBZ00432005-2009Z of the national food and drug administration.
Chinese patent 97105810.5 discloses a dripping pill containing extracts of rhizoma Ligustici Chuanxiong and radix Angelicae sinensis diethyl ether and its preparation method. The embodiment of the invention discloses a preparation process which comprises the following steps: mixing coarse powders of rhizoma Ligustici Chuanxiong and radix Angelicae sinensis with 50% ethanol, soaking the coarse powders in ethanol for 24 hr, slowly percolating until the percolate is almost colorless, collecting the percolate, and recovering ethanol until no ethanol smell; adding diethyl ether at normal temperature into ethanol extract; repeatedly extracting for 3 times, mixing the diethyl ether extracts, and recovering diethyl ether at below 60deg.C under reduced pressure until no diethyl ether smell is present to obtain mixed diethyl ether extract of rhizoma Ligustici Chuanxiong and radix Angelicae sinensis.
Based on the invention, the research shows that the novel composition has no side effect and good curative effect.
The composition of the invention contains Ferulic Acid, the chemical name of which is 4 hydroxy 3 methoxy cinnamic Acid, and the Ferulic Acid is one of derivatives of cinnamic Acid (also called cinnamic Acid, 3 phenyl 2 acrylic Acid, molecular structure). Ferulic acid (sodium ferulate) has effects of resisting platelet aggregation, inhibiting platelet 5-hydroxytryptamine release, inhibiting thromboxane a2 (txa 2) generation, enhancing prostaglandin activity, relieving pain, and relieving vasospasm. Is a basic raw material for producing medicines for treating cardiovascular and cerebrovascular diseases, leucopenia and other symptoms.
The composition also contains ligustilide, ligustilide and alias Dongangelide, which are main active ingredients of the Chinese herbal volatile oil of the Umbelliferae plant. Ligustilide has spasmolytic, antiasthmatic, tranquilizing, microcirculation improving, smooth muscle relaxing, antibacterial, and immunity regulating effects.
The invention researches the characteristics of each of ferulic acid and ligustilide and the combined application, and discovers that the ferulic acid and ligustilide have the effect of dilating blood vessels respectively, and the characteristics of the ferulic acid and ligustilide and the ligustilide are combined to have a synergistic effect, which is not reported in the prior literature.
According to the invention, the curative effect research is carried out by combining ferulic acid and ligustilide, and the unexpected finding that the ferulic acid and the ligustilide have a synergistic effect, so that the pharmaceutical composition containing the ferulic acid and ligustilide combination is provided, and further research shows that other components such as: the invention discovers that the combination of the components has a synergistic effect and also has a novel application, the medicinal preparation removes bitter components, reduces the medicinal dosage, has clear and definite components, has good solubility, good stability and good taste, and is particularly suitable for oral administration and middle-aged and elderly people.
Disclosure of Invention
The invention provides a composition which contains ferulic acid and ligustilide in the following weight ratio: contains ferulic acid and ligustilide in the weight ratio of:
ferulic acid: z-ligustilide = 1:4-10, or ferulic acid: z-ligustilide = 1:4, or ferulic acid: z-ligustilide = 1:10, or ferulic acid: z-ligustilide = 1:9.43.
the composition also contains senkyunolide I, (-) -celery seed lactide and senkyunolide H, and the weight percentages of the components are as follows:
| component (A) | Percentage content% |
| Z-ligustilide | 16-19 |
| Senkyunolide I | 1-3 |
| (-) -celery seed lactide | 5-8 |
| Ferulic acid | 1-3 |
| Senkyunolide H | 2-4 |
The rest is other components.
The composition provided by the invention comprises the following components in percentage by weight:
| component (A) | Percentage content% |
| Z-ligustilide | 17.26 |
| Senkyunolide I | 1.84 |
| (-) -celery seed lactide | 6.49 |
| Ferulic acid | 1.83 |
| Senkyunolide H | 2.61 |
The rest is other components.
The composition disclosed by the invention comprises the following components in percentage by weight:
| component (A) | Percentage content% |
| Z-ligustilide | 16-19 |
| Senkyunolide I | 1-3 |
| (-) -celery seed lactide | 5-8 |
| Ferulic acid | 1-3 |
| Senkyunolide H | 2-4 |
| Butylphthalide | 0.5-0.9 |
| Linoleic acid | 16-19 |
| Oleic acid | 3-5 |
| Stearic acid | 4-7 |
| Palmitic acid | 0.5-1 |
| Eicosanoids | 0.1-0.2 |
The rest is medicinal auxiliary materials.
The composition disclosed by the invention comprises the following components in percentage by weight:
| component (A) | Percentage content% |
| Z-ligustilide | 17.26 |
| Senkyunolide I | 1.84 |
| (-) -celery seed lactide | 6.49 |
| Ferulic acid | 1.83 |
| Senkyunolide H | 2.61 |
| Butylphthalide | 0.71 |
| Linoleic acid | 17.65 |
| Oleic acid | 3.80 |
| Stearic acid | 5.27 |
| Palmitic acid | 0.74 |
| Eicosanoids | 0.12 |
The rest is medicinal adjuvants such as sugar powder or polyethylene glycol.
The structural formula of each component of the composition is as follows:
the composition of the invention, wherein the pharmaceutical auxiliary material is sugar powder or polyethylene glycol, and is used for bearing related pharmaceutical active ingredients, so that the sum of the proportions of the components of the obtained composition is 100%. Wherein the sugar powder is sucrose powder or lactose powder, mannose powder, maltose powder, xylitol powder, etc. Wherein the polyethylene glycol can be polyethylene glycol 1000-10000, preferably polyethylene glycol 4000, polyethylene glycol 6000.
The invention further provides a pharmaceutical preparation containing the composition of the invention, which is prepared by using the composition of the invention as a pharmaceutical active ingredient.
The pharmaceutical preparation provided by the invention is an oral pharmaceutical preparation. The oral pharmaceutical preparation is selected from tablets, capsules, granules, oral liquid, pills and dripping pills. Wherein, the most preferable oral pharmaceutical preparation is dripping pill. The dripping pill is a small pill preparation prepared by heating, melting and mixing solid or liquid medicine and proper substances (generally called matrixes), dripping into immiscible condensate, and shrinking and condensing, and is mainly used for oral administration.
The dripping pill of the invention has the following characteristics:
1. the equipment is simple, the operation is convenient, the labor protection is facilitated, the process period is short, and the production rate is high;
2. the process conditions are easy to control, the quality is stable, the dosage is accurate, the heating time is short, and the stability of the medicine which is easy to oxidize and has volatility can be improved after the medicine is dissolved in the matrix;
3. the matrix contains a large amount of liquid medicine, so that the liquid medicine can be solidified;
4. the dripping pill prepared by solid dispersion technology has the characteristics of rapid absorption and high bioavailability.
The dripping pill of the present invention may be further divided into quick acting dripping pill, slow releasing and controlled releasing dripping pill, solution dripping pill, suppository dripping pill, hard capsule dripping pill, coated dripping pill, liposome dripping pill, enteric coated dripping pill, dry pressure coated dripping pill, etc.
The common carrier of the dripping pill is water-soluble and non-water-soluble, and the common carrier of the dripping pill is polyethylene glycol (PEG), preferably PEG4000 or PEG 6000, which has low melting point (55-60 ℃) and toxicity and stable chemical property (which can be decomposed at more than 100 ℃), can be compatible with most medicines, has good water solubility, can be dissolved in various organic solvents, and can ensure that the insoluble medicines are dispersed in the carrier in a molecular state. The viscosity gradually increases during the evaporation of the solvent, which prevents aggregation of the drug molecules. The water insoluble carrier is commonly used with stearic acid, glyceryl monostearate and the like, which can lead the medicine to be released slowly, and can also be used in the water soluble carrier to regulate the melting point. The dripping pill of the invention can be prepared according to the following method: 100g of polyethylene glycol (PEG 4000) is placed in a thermostat melting tank, a thermostat heating switch and a thermostat pump switch are turned on, and after the temperature in a heat-preserving liquid storage tank is heated to about 70 ℃, the polyethylene glycol begins to melt. And after the liquid medicine is completely melted, the liquid medicine is ready for use. Closing a centrifugal pump outlet regulating valve and a discharge valve of the pill dropping machine, opening a flow regulating valve after the centrifugal pump is started to introduce liquid paraffin (pill condensate) into the glass pill dropping machine, regulating the liquid flow to 250l/h when overflow occurs, opening the feed valve to enable the opening degree to be about 75%, keeping the liquid level in the pill dropping machine stable all the time in an experiment, pouring melted polyethylene glycol into a heat-insulating liquid storage tank, and dripping liquid by gravity through a dripping head to form pills after the condensate is cooled in the pill dropping machine. Separating the dripping pill from the condensate on the receiving screen to finish the dripping process of the dripping pill, wiping the condensate on the dripping pill by using paper towel, and weighing the total weight of the dripping pill.
The composition disclosed by the invention has the following effects through research: can be used for treating headache, dizziness, apoplexy, blurred vision, amnesia, insomnia, NK- κB expression inhibition, calcium ion antagonism, antioxidation, antiinflammatory, senile dementia cerebral ischemia apoplexy, cerebral neuroprotection, and myocardial hypertrophy due to hypertension, and can be used for treating hypertension complicated with myocardial hypertrophy.
The composition is prepared by mixing pure compound monomers of all components, can also be obtained by mixing all traditional Chinese medicine extracts rich in the components, or can be obtained by extracting one, two, three, four or more traditional Chinese medicines rich in the components.
For example, the Chinese herbal extract rich in ferulic acid is prepared from the following Chinese herbal materials: the present invention provides ferulic acid which is obtained by extracting plants of the family Umbelliferae, the family Ligusticum wallichii Ligusticum chuanxiong Hort, the rhizome, the family Pinaceae, the family Selaginella, lycopodium selago L, the whole herb, the family Equisetaceae, equisetum hiemale L, the whole herb, the family Ranunculaceae, cimicifuga foetida L, the rhizome, the family Gramineae, oryza sativa L, the seed coat, the family Liliaceae, the onion Allium cepa L, the root, the bulb, the leaf, the radish plant of the family Brassicaceae, the plant Raphanus sativus L, the root, the plant of the family Bignoniaceae, the bark of Catalpa ovata G.don, the plant of the family Compositae, the plant of the chamomile, the plant of the family Matricaceae, the plant of the Mirabilis, the plant of the family Mirabilis, and the like.
For example, the Chinese medicinal extract rich in Z-ligustilide is prepared from the following Chinese medicinal plants: the Chinese medicinal herbs of Umbelliferae plant radix Angelicae sinensis, rhizoma Ligustici Chuanxiong Ligusticum chuanxiong, donggui Angelica acutiloba, liaogong Ligusticum jeholense, ou Dang Gui Levisticum officinale, medicinal cnidium Cnidium officinale, etc., therefore, the Z-ligustilide of the invention can be obtained by extracting the Chinese medicinal herbs.
The composition of the invention can be obtained by mixing the Chinese medicinal extract rich in ferulic acid and the Chinese medicinal extract rich in Z-ligustilide according to the proportion of the invention, the composition of the invention containing the rest components can also be prepared by similar or identical methods, for example, the compositions can be obtained by taking the monomers of the compositions or the extracts of the compositions according to the determined proportion of the invention, the mixing methods are all physical mixing, and the active substances are the medicinal active substances after mixing, namely, the composition of the invention, and the composition of the invention is used as the medicinal active substances to prepare medicinal preparations suitable for taking, such as dripping pills, and can also be directly used for oral administration.
The principal ingredients of the composition of the present invention were studied, wherein Ferulic Acid (FA) in the composition had a vasodilatory effect on norepinephrine-induced vasoconstriction, which is associated with extra-vascular calcium influx on vascular smooth muscle cells. Ferulic acid also reduces shrinkage caused by NE in calcium-free high potassium K-H solution, and is associated with calcium release from sarcoplasmic reticulum storage. Wherein Z-Ligustilide (LG) in the composition has a vasodilatory effect on vasoconstriction by norepinephrine, which is associated with the NO signaling pathway and with the cGMP-L-NAME pathway. The invention researches the combined use of Ferulic Acid (FA) and Z-Ligustilide (LG), in the combined use process, when the concentration of Ferulic Acid (FA) is 44 mu M, 88 mu M and 132 mu M, the concentration of Ligustilide (LG) is 70 mu M, 140 mu M and 210 mu M, the inhibition effect of ferulic acid and Z-Ligustilide (LG) on vascular contraction caused by norepinephrine is 44 mu M-70 mu M, 88 mu M-140 mu M and 132M-210 mu M, and the maximum contraction rate caused by NE is 100%.
And calculating the combined effect by using a probability sum method (Q value method), and calculating the obtained data by using the following formula to obtain a Q value, wherein Q >1.15 indicates that the two are compatible and have a synergistic effect, Q <0.85 indicates that the two are antagonistic, and the two are compatible and added.
Wherein EA and EB respectively represent the effect of drug single, E (A+B) represents the actual effect after the combination of the two, and EA+EB-EA×EB represents the effect which should be obtained theoretically by the combination of the two.
Through the calculation of the Q value,
the Q values of the combined FA-LG (44 mu M-70 mu M, 88 mu M-140 mu M and 132 mu M-210 mu M) are sequentially 2.94, 1.74 and 2.61, which are all more than 1.15, which indicates that the ferulic acid and the Z-ligustilide have good synergistic effect.
The vasodilation effect of FA in combination with LG is concentration dependent and is related to the release of calcium in the sarcoplasmic reticulum and the influx of extracellular calcium.
Research shows that Ferulic Acid (FA) and Z-Ligustilide (LG) have strong effects of dilating thoracic aortic vessels. Its diastolic effect can be inhibited by heme oxygenase-1 (HO-1) inhibitor ZnPP, and its diastolic effect is related to CO signal molecule. The regulation effect on blood pressure is expressed as follows: after FA administration, SHR rats had reached minimal blood pressure at 1 h; FA. LT and FA-LT both have minimal hypotensive effect with 1h, and the hypotensive effect of FA-LT is greater than that of FA and LT. Blood pressure in SHR rats was reduced at both 1h and 4h, with 4h reaching a minimum. The results of the echocardiographic experiments show that the FA, the LT and the combination thereof can inhibit the myocardial hypertrophy of SHR and protect the heart. The invention further uses the dripping pill to study, and discovers that compared with the administration of ferulic acid monomer, the dripping pill avoids the liver and intestine circulation of ferulic acid after the administration, improves the effective concentration of the ferulic acid, and further improves the bioavailability of the ferulic acid.
The study further shows that ferulic acid, Z-ligustilide, (-) -selinic acid lactide, senkyunolide I and senkyunolide H are main substances which exert the drug effect of the dripping pill.
The dripping pill has multiple purposes, including the function of dilating blood vessels, anti-inflammatory function and the function of treating chronic cerebral ischemia. The dripping pill has calcium ion antagonism; has effects in improving nerve and lowering blood pressure.
The dripping pill has a certain inhibition effect on myocardial hypertrophy caused by hypertension, can be used as a potential medicament for treating hypertension with myocardial hypertrophy diseases, has good cardiovascular and cerebral nerve protection effects, and can be used for treating patients with cardiovascular and cerebral nerve injury.
By comparing the BPI graph of the administered blood sample with the BPI graph of a blank brain tissue sample and the BPI graph of the dripping pill extracting solution, the blood sample detection of the rat after the dripping pill is subjected to gastric administration shows that ferulic acid, senkyunolide I/H, senkyunolide A and Z-ligustilide are blood components after the dripping pill is administered. The components are the effective components of the dripping pill for playing the drug effect,
after the dripping pill is subjected to gastric lavage and drug administration, rat brain tissue detection is carried out, and the BPI diagram of a brain tissue sample is compared with the BPI diagram of a blank brain tissue sample and the BPI diagram of the dripping pill extracting solution to obtain that the brain-entering components of the dripping pill are mainly senkyunolide I/H and Z-ligustilide, and the two components are phthalides components with more content in the dripping pill, so that the two components can permeate a blood brain barrier.
The invention discovers that 3 effective components with Ca2+ antagonistic activity in the dripping pill comprise ferulic acid, senkyunolide I/H and Z-ligustilide.
The invention discovers that the dripping pill has 3 active ingredients with ATP regulating function, including ferulic acid, senkyunolide I/H and Z-ligustilide.
The invention discovers that the components with antioxidation in the dripping pill, ferulic acid and Z-ligustilide can obviously reduce MDA content and increase the activities of NO, NOS and SOD in a dose-dependent way.
The invention discovers that the dripping pill can regulate 47 biological targets, and the names of the targets are as follows: PTGS2, PRKACA, PTGS1, CDK2, CCNA2, ESR2, ESR1, CA1, HBA2, CA2, OPRM1, OPRK1, PDE4D, OPRD1, SCN5A, PGR, HSD17B1, AR, GLTP, LCN2, ACHE, NR3C2, ADRB2, ADRB1, PRSS1, POLK, ADRA2A, HTR2A, DRD2, DRD1, NCOA1, CHRM1, NOS2, PLA2G1B, ADRA1A, PDE4B, CA4, NOS3, IFNG, GABBR1, ABCC8, GABRA1, GABRA5, HRH1, ADRA2B, DHFRP1, TUBA1A.
The beneficial effects of the present invention are further illustrated by the following test data, tables, and drawings.
The inventor takes the dripping pill of the embodiment 13 of the invention as a research medicament, and carries out pharmacodynamics research, and the related research results are as follows:
test 1. In vitro vasomotor action study of the dripping pill of the invention
The dripping pill (dripping pill of the embodiment 13) is provided by a sixth traditional Chinese medicine factory of New pharmaceutical industry Co., ltd.
Laboratory animals, sprague-Dawley rats, males, weighing 200+ -20 g, provided by the laboratory animal center of the national academy of military medical science; license number: SCXK-2007-004, experimental rats were subjected to an experiment after being subjected to an adaptive breeding for one week at 25 ℃.
Preparation of test drug: grinding the dripping pill in a mortar, accurately weighing 4.0g in a 10mL volumetric flask, adding deionized water to a certain volume, carrying out ultrasonic treatment for 10min, and then, cooling to room temperature and preserving at 4 ℃ for later use.
Statistical analysis was performed using two software, the biofunction experimental system and SPSS20. The former is mainly to collect image data and record the change of blood vessel tension; the latter was used for data analysis, and the mean between groups was statistically significant using independent sample t-test, with P < 0.05.
Fig. 11 effects of different concentrations of the inventive dripping pill on norepinephrine pre-contracted vascular ring (endothelial intact e+, endothelial E-) (p <0.05 p <0.01 compared to endothelial) (n=5).
In conclusion, the experimental method for relaxing blood vessels in vitro is used for research, and the result shows that: the dripping pill can cause the vasodilation of the thoracic aorta.
Experiment 2. Research on the acute hypotensive effect of the dripping pill of the present invention
The dripping pill (dripping pill of the embodiment 13) is provided by a sixth traditional Chinese medicine factory of New pharmaceutical industry Co., ltd.
According to the clinical administration dosage, SHR rats and Wistar rats are orally administrated with the dripping pill (5.25 g/kg), and the acute antihypertensive effect for 6 hours is measured, and the result is as follows:
FIG. 12 changes over time in blood pressure of spontaneously hypertensive rats after oral administration of the dripping pill of the present invention.
FIG. 13 shows systolic blood pressure change in spontaneous hypertensive rats within 6h of oral administration of the dripping pill of the invention.
It was concluded that there was no significant change in systolic blood pressure in Wistar rats within 6 hours after administration of the dripping pill of the present invention, blood pressure in SHR rats was reduced both at 1 hour and at 4 hours, and the minimum was reached at 4 hours. The dripping pill has a certain influence on the blood pressure of SHR.
Test 3. Determination of NOS content in serum after administration of the dripping pill of the present invention:
the dripping pill (dripping pill of the embodiment 13) is provided by a sixth traditional Chinese medicine factory of New pharmaceutical industry Co., ltd.
Grouping: the dripping pill group, the model group M and the blank control group WKY group of the invention
8 weeks after administration, 5% sodium ubarbitus (0.6 g/kg) was anesthetized after the last administration and blood pressure was measured, and the femoral artery was bled to sacrifice the animals. Taking more than 4ml of blood, centrifuging for 30min by a low-temperature centrifuge at 3000rpm, separating serum, and freezing at-80 ℃ before serum detection to prepare for measuring the NO, NOS and CO contents of the serum.
FIG. 14 NOS content in serum of SHR rats of the dripping pill group of the invention.
FIG. 15 CO content in serum of SHR rats of the dripping pill group of the invention.
FIG. 16 lung index of SHR rats of the dripping pill group of the invention
In conclusion, after the dripping pill is given, the content of monooxo NOS is obviously higher than that of a model group (p <0.05 compared with M), and the same trend is shown as that of a blank control group WKY group (p <0.01 compared with M), so that the dripping pill achieves the effect of dilating blood vessels and further has the effect of reducing blood pressure by increasing the content of NOS.
Experiment 4 research on the therapeutic action of the dripping pill on Alzheimer's disease
The dripping pill (dripping pill of the embodiment 13) is provided by a sixth traditional Chinese medicine factory of New pharmaceutical industry Co., ltd.
FIG. 17 incubation period of AD rats after oral administration of the dripping pill of the present invention
FIG. 18 number of passes through the platform of AD rats after oral administration of the drop pills of the present invention
FIG. 19 effect of the dripping pill of the present invention on SOD content in plasma of D-gal-induced cognitive impairment rats.
In conclusion, in the space exploration experiments, the latency of the blank group, the brain rehabilitation administration group, the low-dose group and the high-dose group is smaller than that of the model group, and the blank group, the low-dose group and the high-dose group have significant differences (P <0.05, P <0.01 and P < 0.01). The number of times of the blank group, the cerebral rehabilitation administration group, the low-dose group and the high-dose group passing through the platform is larger than that of the model group, and the blank group and the low-dose group have significant differences (P < 0.05) compared with the model group. The dripping pill can reduce the incubation period of the D-galactose molding rat and improve the cognition level of the D-galactose molding rat. By measuring the SOD content in the serum of the D-galactose-induced aging rat, the SOD content in the serum of the low-dose group and the high-dose group is obviously higher than that in the model group, which indicates that the dripping pill can resist the aging damage caused by the D-galactose through the antioxidation stress effect.
Morphological observation of the hippocampal region
The CA1 region of the rat hippocampus has normal structure, compact and orderly arrangement of nerve carpets, clear level, 4-6 layers of cells, round cell nucleus and clear nucleolus. The model group rat hippocampus CA1 region has serious pathological changes, scattered and loose neuron arrangement, incomplete cone cell bands, obvious reduction of cell quantity, obvious nuclear shrinkage, obvious improvement of the pathological changes of the hippocampus CAl region compared with the model group, clear structure, tidy cell arrangement and insignificant nuclear shrinkage, and the pathological changes of the model rat brain tissues are obviously reduced compared with the model group and almost have no difference from blank control, so that the dripping pill can obviously improve the pathological changes of the model rat brain tissues.
In another AD animal test, the following open field test was performed,
table 1 mouse open field (means+ -SE, n=10)
Note that: # representation of comparison of p with control group<0.05； * Representation comparison of p with model control group<0.05。
Compared with the control group, the total movement distance and the erection times of the mice in the model control group are obviously reduced (p < 0.05), the total movement distance reflects the autonomous movement ability of the mice, the erection times reflect the exploration ability of the mice to the novel environment, the mice in the model control group are reduced in autonomous movement ability and exploration ability, and symptoms similar to depression are presented. The positive control medicine donepezil and the dripping pill of the invention can increase the total distance of the activity and the erection times of the mice in different degrees, which indicates that the dripping pill of the invention can improve the symptom of the AD model animal depression.
Experiment 5 research on the therapeutic action of the dripping pill on cerebral ischemia apoplexy
Experimental medicine
The dripping pill (dripping pill of the embodiment 13) is provided by a sixth traditional Chinese medicine factory of New pharmaceutical industry Co., ltd.
The preparation of the test medicine is to grind the dripping pill, weigh the powder and dissolve the powder with 5 percent CMC-Na to a certain concentration.
Grouping and administration, wherein 0.3mL (1 mL/kg) of 1% phenobarbital sodium is used for abdominal anesthesia, a prone position is adopted for fixing a rat on a constant temperature operating table, a notch at the top of a sterile head is adopted, a first cervical vertebra transverse process wing small hole is exposed, an electric burning needle is inserted into the wing small hole, and bilateral vertebral arteries are cauterized to permanently block the vertebral arteries, and wounds are sutured for normal feeding. After 24h, the rat is in supine position, the shallow hemp rat is fixed on a constant temperature operating table, a 3cm median incision is made between the larynx and the sternum under aseptic condition, the bilateral common carotid artery is separated, a surgical suture is used for tying the slipknot to block blood of the bilateral common carotid artery, so that cerebral ischemia is caused for 10min, and the slipknot is loosened to cause the whole cerebral ischemia reperfusion model of the rat.
The rats were divided into 6 groups, namely, a sham operation group, a model group, a high-dose group of the dripping pill of the invention (BFMH, 30 times of 1 day and 2 times), a dose group of the dripping pill of the invention (BFMM, 15 times of adult dose), a low-dose group of the dripping pill of the invention (BFML, 5 times of adult dose) and a positive drug group (nimodipine dose is a clinical effective dose (2 mg/100g weight) after conversion, and the administration is performed by stomach irrigation after dilution and is performed for 7 days continuously (nimodipine dose is also 1.2mg/100g weight after conversion in the experiment).
Sample collection
72h after administration, 5% sodium ubarbitus (0.6 g/kg) was anesthetized after the last administration and blood pressure was measured, and the femoral artery was bled to kill the animal. Taking more than 4mL of blood, centrifuging for 30min by a low-temperature centrifuge at 3000rpm, separating serum, and freezing at-80 ℃ before serum detection to prepare for measuring the contents of NO, NOS, SOD and H2S in the serum. Brain is preserved in neutral formalin for pathological section, and Hippocampus and cortex liquid nitrogen are preserved for biochemical index detection.
Observation index and method
Behavioural assay
The rats were scored neurological after surgery and before sacrifice. The rat tail was grabbed 30 cm from the table top and the extension and degree of body rotation of the rat forelimbs were observed. Scoring criteria: 0 point: normal, without any neurological deficit; 1, the method comprises the following steps: the forelimb on the contralateral side of the operation is slightly bent towards the operation side; 2, the method comprises the following steps: the forelimb on the opposite side of the operation is completely bent towards the side of the operation; 3, the method comprises the following steps: the body rotates slightly to the normal side; 4, the following steps: the body is rotated to the normal side completely; 5, the method comprises the following steps: is completely motionless.
Brain Ma Xingtai observation and detection method
After HE staining, brain hippocampus CA1 area was observed for pathological changes in tissue morphology.
Detection of serum GSH, GPx, SOD, MDA and CAT
Both serum GSH, GPx, SOD, MDA and CAT detection were performed strictly as described in the kit. Statistical treatment, using SPSS20.0 statistical analysis software to perform statistical analysis on the measured parameters, comparing experimental data using double-sided t-test, and P <0.05 indicates significant difference.
Fig. 20 neuro-functional scores of rats of each group (< 0.05 p, comparison prior to drawing and prior to molding)
Mortality of rats administered to each group of FIG. 21 (10 rats per group)
In conclusion, in the research of cerebral ischemia resistance of the dripping pill, a chronic cerebral ischemia stroke model is established by adopting a carotid artery ligation method, a Longa/Bederson5 division method is utilized for carrying out nerve function scoring, and a kit is used for measuring oxidative stress indexes, so that the result proves that the dripping pill has a certain treatment effect on cerebral ischemia injury.
TABLE 2 Chinese and English and abbreviation comparison tables in the inventive test
| Chinese name | English name | Abbreviations (abbreviations) |
| Ferulic acid | Ferulic acid | FA |
| Z-ligustilide | Ligustilide | LG |
| The drop pill of the invention | Benfaming pill | BFM |
| Valsartan (Valsartan) | Valsartan | VAL |
| Nimodipine | Nimodipine | NMDP |
| Spontaneous hypertension rat | Spontaneously Hypertensive Rat | SHR |
| Kyoto Wirst rat | Wistar-Koyto rats | WKY |
| Wistar rat | Wistar rat | Wistar |
| Nitric Oxide (NO) | Nitric oxide | NO |
| Nitric oxide synthase | Nitric oxide synthase | NOS |
| Carbon monoxide | Carbon monoxide | CO |
| Hydrogen sulfide | Sulfuretted hydrogen | H2S |
| Superoxide dismutase | Superoxide dismutase | SOD |
| Glutathione | Glutathione | GSH |
| Catalase enzyme | Catalase | CAT |
| Glutathione peroxidase | Glutathione peroxidase | GPx |
Description of the drawings:
FIG. 1, effect of FA (1-44. Mu.M, 2-88. Mu.M, 3-132. Mu.M), LG (1-70. Mu.M, 2-140. Mu.M, 3-210. Mu.M) and FA-LG (1-44. Mu.M-70. Mu.M, 2-88. Mu.M-140. Mu.M, 3-132. Mu.M-210. Mu.M) on norepinephrine pre-contracted vascular ring (endothelial intact E+, endothelial E-) (p <0.05 p <0.01 compared to endothelial) (n=5).
Fig. 2, effect of low, medium, high concentration ferulic acid, Z-ligustilide, ferulic acid-Z-ligustilide on the potassium chloride-depleted pre-constriction of the vascular ring (endothelial intact e+, endothelial depleted E-) (p <0.05 p <0.01 compared to endothelial depleted) (n=5).
Fig. 3, effect of different concentrations of ferulic acid-Z-ligustilide in combination on norepinephrine pre-contracted vascular ring (endothelial intact e+, endothelial removed E-) (p <0.05 p <0.01 compared to endothelial removed) (n=5).
Fig. 4, effects of various concentrations of ferulic acid-Z-ligustilide on norepinephrine pre-contracted vascular ring (endothelial intact e+, endothelial removed E-) (p <0.05 p <0.01 compared to endothelial removed) (n=5) FA, combined with LG, vasodilation was not endothelial dependent.
Fig. 5, effect of PAG 10-4M, L-NAME 10-4M, ODQ 10-6M, znPP 10-5M on endothelial complete vasodilation effect caused by ferulic acid-Z-ligustilide (a) at 44 μm-70 μm concentration and ferulic acid-Z-ligustilide (b) at 88 μm-140 μm concentration (p <0.05 p <0.01 compared to blank) (n=5).
Fig. 6, effect of potassium channel inhibitors on endothelial complete vasodilation effect (p <0.05 x p <0.01 compared to blank) caused by ferulic acid-Z-ligustilide (a) at 44 μm-70 μm concentration and ferulic acid-Z-ligustilide (b) at 88 μm-140 μm concentration (n=5).
Fig. 7, effect of varying concentrations of ferulic acid-Z-ligustilide on norepinephrine pre-contracted vascular ring (endothelial intact e+, endothelial removed E-) (p <0.05 p <0.01 compared to endothelial removed) (n=5).
Fig. 8, effect of ferulic acid-Z-ligustilide on CaCl 2-induced dose-dependent contraction profile of endothelial-vascular ring removal (p <0.05 p <0.01 compared to blank) (n=5).
Fig. 9, TNF- α induced model group (M) showed significantly reduced inhibition of NF- κb (# # P < 0.001) compared to blank group (C), positive drug (Dex) group showed significantly inhibited expression level of NF- κb· (P < 0.001) compared to model group, and the inventive pellet administration group showed significantly inhibited expression of NF- κb (P <0.001, # P < 0.01) and exhibited concentration dependence compared to model group.
Fig. 10, ionomycin and 12-myristate-13-acetate induced model group (M) showed significantly increased expression of calcium ion-related factor (# # P < 0.001) compared to blank group (C), indicating successful modeling, content of ca2+ expression (x P < 0.01) was significantly inhibited in positive drug (Nimodipine) group compared to model group, ca2+ expression was significantly inhibited (x P < 0.005) and concentration dependence was exhibited in the inventive drop pill administration group compared to model group.
FIG. 11 effects of different concentrations of the dripping pills of the present invention on the norepinephrine pre-constriction of the vascular ring.
FIG. 12 shows the change of blood pressure with time in spontaneously hypertensive rats after oral administration of the dripping pill of the present invention.
FIG. 13 shows systolic blood pressure change in spontaneous hypertensive rats within 6h of oral administration of the dripping pill of the invention.
FIG. 14, NOS content in serum of SHR rats of the dripping pill group of the invention.
FIG. 15, CO content in serum of SHR rats of the dripping pill group of the invention.
FIG. 16, SHR rat lung index of the dripping pill group of the invention.
Fig. 17, latency of AD rats after oral administration of the drop pills of the invention.
Figure 18, number of passes across the platform for AD rats after oral administration of the drop pills of the invention.
FIG. 19 shows the effect of the dripping pill of the present invention on SOD content in plasma of rats with D-gal induced cognitive impairment.
Fig. 20, neuro-functional scores for rats of each group.
Figure 21 mortality rate of rats dosed in each group (10 rats per group).
The specific embodiment is as follows:
the invention is further illustrated by the following examples, which are not intended to be limiting.
Example 1
The composition contains ferulic acid and Z-ligustilide in the weight ratio:
ferulic acid: z-ligustilide = 1:4.
the composition is obtained by mixing ferulic acid and Z-ligustilide, or by mixing ferulic acid-containing Chinese medicinal extract and Z-ligustilide-containing Chinese medicinal extract, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 2
The composition contains ferulic acid and Z-ligustilide in the weight ratio:
ferulic acid: z-ligustilide = 1:5
The composition is obtained by mixing ferulic acid and Z-ligustilide, or by mixing ferulic acid-containing Chinese medicinal extract and Z-ligustilide-containing Chinese medicinal extract, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 3
The composition contains ferulic acid and Z-ligustilide in the weight ratio:
ferulic acid: z-ligustilide = 1:6
The composition is obtained by mixing ferulic acid and Z-ligustilide, or by mixing ferulic acid-containing Chinese medicinal extract and Z-ligustilide-containing Chinese medicinal extract, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 4
The composition contains ferulic acid and Z-ligustilide in the weight ratio:
ferulic acid: z-ligustilide = 1:7
The composition is obtained by mixing ferulic acid and Z-ligustilide, or by mixing ferulic acid-containing Chinese medicinal extract and Z-ligustilide-containing Chinese medicinal extract, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 5
The composition contains ferulic acid and Z-ligustilide in the weight ratio:
ferulic acid: z-ligustilide = 1:8
The composition is obtained by mixing ferulic acid and Z-ligustilide, or by mixing ferulic acid-containing Chinese medicinal extract and Z-ligustilide-containing Chinese medicinal extract, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 6
The composition contains ferulic acid and Z-ligustilide in the weight ratio:
ferulic acid: ligustilide = 1:9.43
The composition is obtained by mixing ferulic acid and Z-ligustilide, or by mixing ferulic acid-containing Chinese medicinal extract and Z-ligustilide-containing Chinese medicinal extract, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 7
The composition contains ferulic acid and Z-ligustilide in the weight ratio:
ferulic acid: ligustilide = 1:10
The composition is obtained by mixing ferulic acid and Z-ligustilide, or by mixing ferulic acid-containing Chinese medicinal extract and Z-ligustilide-containing Chinese medicinal extract, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 8
The composition comprises the following components in percentage by weight:
| component (A) | Percentage content% |
| Z-ligustilide | 17.26 |
| Senkyunolide I | 1.84 |
| (-) -celery seed lactide | 6.49 |
| Ferulic acid | 1.83 |
| Senkyunolide H | 2.61 |
The rest is other components.
The composition is obtained by mixing the above components, or by mixing the above Chinese medicinal extracts, or by extracting radix Angelicae sinensis and rhizoma Ligustici Chuanxiong together.
Example 9
The composition comprises the following components in percentage by weight:
the balance of sugar powder.
The composition is obtained by mixing the components.
Example 10
The composition comprises the following components in percentage by weight:
| component (A) | Percentage content% |
| Z-ligustilide | 17.26 |
| Senkyunolide I | 1.84 |
| (-) -celery seed lactide | 6.49 |
| Ferulic acid | 1.83 |
| Senkyunolide H | 2.61 |
| Butylphthalide | 0.71 |
| Linoleic acid | 17.65 |
| Oleic acid | 3.80 |
| Stearic acid | 5.27 |
| Palmitic acid | 0.74 |
| Eicosanoids | 0.12 |
The balance of polyethylene glycol 6000.
The composition is obtained by mixing the components.
Example 11
The composition comprises the following components in percentage by weight:
| component (A) | Percentage content% |
| Z-ligustilide | 16 |
| Senkyunolide I | 1 |
| (-) -celery seed lactide | 5 |
| Ferulic acid | 1 |
| Senkyunolide H | 2 |
| Butylphthalide | 0.5 |
| Linoleic acid | 16 |
| Oleic acid | 3 |
| Stearic acid | 4 |
| Palmitic acid | 0.5 |
| Eicosanoids | 0.1 |
The balance of polyethylene glycol 6000.
The composition is obtained by mixing traditional Chinese medicine extracts containing the components or by jointly extracting angelica and ligusticum wallichii.
Example 12
The composition comprises the following components in percentage by weight:
the balance of sugar powder.
The composition is obtained by mixing traditional Chinese medicine extracts containing the components or by jointly extracting angelica and ligusticum wallichii.
Example 13
The dripping pill preparation prepared by taking any one of the compositions of the examples 9-12 as a raw material is prepared by taking any one of the compositions of the examples 9-12 as a medicinal active substance through a conventional technical means of pharmaceutics,
if the medicine active substance is added into melted dripping pill matrix polyethylene glycol 6000, dripping into cold liquid paraffin to obtain dripping pill.
The weight of each drop pill is 20mg, wherein each drop pill contains the composition of any one of examples 9-12, preferably the composition of example 10, in an amount of 5mg.
Example 14
The tablet prepared by using the composition of example 11 as a raw material is prepared by using the composition of example 11 as a pharmaceutically active substance and adopting conventional technical means of pharmaceutics, such as adding starch and ethanol as a wetting agent, granulating, tabletting and coating.
Example 15
The capsule prepared by taking the composition of the example 11 as a raw material is prepared by taking the composition of the example 11 as a medicinal active substance through the conventional technical means of pharmaceutics, such as adding starch and ethanol as a wetting agent, granulating and encapsulating.
Example 16
The granule prepared by taking the composition of the example 11 as a raw material is prepared by taking the composition of the example 11 as a medicinal active substance through the conventional technical means of pharmaceutics, such as adding powdered sugar and ethanol as a wetting agent, granulating and packaging.
Example 17
The dripping pill preparation prepared by taking the composition of the example 9 as a raw material is prepared by taking the composition of the example 9 as a medicinal active substance through the conventional technical means of pharmacy, such as adding the medicinal active substance into melted dripping pill matrix polyethylene glycol 6000, and dripping the medicinal active substance into cold liquid methyl silicone oil to obtain the dripping pill. The weight of each drop pill was 50mg, and the weight of the composition of example 9 contained in each drop pill was 25mg.
Example 18
The dripping pill preparation prepared by taking the composition of the example 10 as a raw material is prepared by taking the composition of the example 10 as a pharmaceutically active substance through the conventional technical means of pharmacy, such as adding the pharmaceutically active substance into melted dripping pill matrix polyethylene glycol 6000, and dripping the mixture into cold liquid methyl silicone oil to obtain the dripping pill. The weight of each drop pill was 40mg, and the weight of the composition of example 10 was 20mg.
Example 19
The dripping pill preparation prepared by taking any one of the compositions in the examples 1-7 as a raw material is prepared by taking any one of the compositions in the examples 1-7 as a pharmaceutically active substance through a conventional technical means of pharmaceutics, such as adding the pharmaceutically active substance into melted dripping pill matrix polyethylene glycol 6000 and obtaining the dripping pill by dripping into cold liquid methyl silicone oil. The weight of each drop pill was 30mg, and the weight of each drop pill containing any one of the compositions of examples 1 to 7 was 10mg.
Claims (3)
1. The composition is characterized by comprising the following components in percentage by weight:
the rest is medicinal auxiliary materials; the medicinal auxiliary material is polyethylene glycol 6000.
2. A pharmaceutical formulation prepared from the composition of claim 1.
3. The pharmaceutical formulation according to claim 2, characterized in that it is a drop pill.
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