Pharmaceutical composition and application thereof

Abstract

The invention discloses a pharmaceutical composition and application thereof. The pharmaceutical composition provided by the invention comprises the following active components in percentage by weight: 10-50% of geniposide, 10-50% of a surfactant, and 10-50% of a 10% to 50% of geniposide; 10% to 50% of genipin gentiobioside; 10 to 50 percent of crocin I and 10 to 50 percent of ursolic acid. The composition can effectively inhibit paralysis of tremor, improve the balancing capacity and grasping capacity of mice, reduce the content of interleukin-1beta and tumor necrosis factor-alpha, promote secretion of dopamine, reduce the content of malondialdehyde and improve the total antioxidant capacity in brain tissue. The compound has a good treatment effect on a Parkinson's disease model, so that the effect of treating the Parkinson's disease is expected to be greatly improved, and adverse reactions are reduced.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition and application thereof. Background Art

[0002] Parkinson's disease (PD) is a chronic, progressive neurological disorder characterized by symptoms such as muscle stiffness, tremors, slowed movements, and unsteady movements. Due to the complexity of PD's pathogenesis, the mechanisms underlying its development and progression remain largely unknown. While there is currently no cure for Parkinson's disease, medication, surgery, and rehabilitation can alleviate symptoms and improve quality of life. Commonly used medications include dopamine-containing drugs and anticholinergics.

[0003] Gardenia jasminoides (Gardenia jasminoides J.Ellis), a shrub of the Rubiaceae family, is native to China and is now distributed in Shandong, Jiangsu, Anhui, Zhejiang, and other places in China. The traditional pharmacological effects of Gardenia jasminoides include purging heat and relieving restlessness, clearing heat and promoting diuresis, cooling blood and detoxifying. The active terpenoid components of Gardenia jasminoides mainly include iridoids, monoterpenoid glycosides, diterpenes, and triterpenes, which have anti-diabetic, anti-inflammatory, antidepressant, antioxidant, liver-protecting and choleretic, soothing and sedative effects, improving sleep, and treating sprains and contusions. Currently, the most studied are gardeniaside, geniposide, geniposide, crocin I, and ursolic acid, among which gardeniaside, an iridoid terpenoid, has the highest activity.

[0004] Although modern research shows that Gardenia has certain effects in treating neurodegenerative diseases, its therapeutic effect is limited and requires a larger dose to show therapeutic effects. However, some studies have shown that large doses of Gardenia have certain liver and kidney toxicity, which leads to certain difficulties in using the terpenoid compounds in Gardenia to treat Parkinson's disease. Summary of the Invention

[0005] The present invention aims to overcome the shortcomings of terpenoids from Gardenia jasminoides in the treatment of Parkinson's disease, such as limited efficacy and insignificant results, by providing a pharmaceutical composition and its use. Specifically, the present composition can reduce parkinsonism, reduce the release of inflammatory factors, lower malondialdehyde levels, increase dopamine secretion, and enhance antioxidant capacity.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] One object of the present invention is to provide a pharmaceutical composition comprising the following active ingredients in weight fractions: 10-50% of geniposide; 10-50% of geniposide; 10-50% of geniposide; 10-50% of crocin I and 10-50% of ursolic acid.

[0008] In the composition, geniposide, geniposide, geniposide, crocin I and ursolic acid can be active substances chemically synthesized or extracted and separated from Gardenia jasminoides.

[0009] In the composition, the weight fraction of the geniposide may be 20-40%, for example, 20%, 30% or 40%.

[0010] In the composition, the weight fraction of geniposide may be 10-20%, for example, 10% or 20%.

[0011] In the composition, the weight fraction of the genipin gentiobioside may be 10-20%, for example, 10% or 20%.

[0012] In the composition, the weight fraction of crocin I may be 10-20%, for example, 10% or 20%.

[0013] In the composition, the weight fraction of ursolic acid may be 20-40%, for example, 20%, 30% or 40%.

[0014] The pharmaceutical composition comprises the following active ingredients: gardeniaside, geniposide, geniposide-gentiobioside, crocin I and ursolic acid.

[0015] The pharmaceutical composition comprises the following active components in weight fractions: 30-50% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 30-50% of ursolic acid.

[0016] The pharmaceutical composition comprises the following active components in weight fractions: 20-40% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 20-40% of ursolic acid.

[0017] The pharmaceutical composition comprises the following active components in weight fractions: 30-40% of geniposide; 10% of geniposide; 10% of geniposide; 10% of crocin I and 30-40% of ursolic acid.

[0018] The pharmaceutical composition consists of the following active ingredients in weight fractions: 10-50% of geniposide; 10-50% of geniposide; 10-50% of geniposide; 10-50% of crocin I and 10-50% of ursolic acid.

[0019] The pharmaceutical composition consists of the following active ingredients in weight fractions: 30-50% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 30-50% of ursolic acid.

[0020] The pharmaceutical composition consists of the following active ingredients in weight fractions: 20-40% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 20-40% of ursolic acid.

[0021] The pharmaceutical composition consists of the following active ingredients in weight fractions: 30-40% of geniposide; 10% of geniposide; 10% of geniposide; 10% of crocin I and 30-40% of ursolic acid.

[0022] The pharmaceutical composition can also be in the form of a liquid preparation or a solid preparation.

[0023] The present invention also provides a use of the above composition in preparing a drug for treating or improving neurodegenerative diseases.

[0024] The neurodegenerative disease may be one, two, three, four, five or six selected from the group consisting of interleukin-1β-mediated diseases, tumor necrosis factor-α-mediated diseases, dopaminergic neuron loss-mediated diseases, malondialdehyde-mediated diseases or diseases mediated by decreased total antioxidant capacity in brain tissue.

[0025] The neurodegenerative disease may be Parkinson's disease.

[0026] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0027] The reagents and raw materials used in the present invention are commercially available.

[0028] The positive and progressive effects of the present invention are: the pharmaceutical composition of the present invention can effectively inhibit tremor paralysis, improve the balance and grasping ability of mice, reduce the levels of interleukin-1β and tumor necrosis factor-α, promote dopamine secretion, reduce the content of malondialdehyde and enhance the total antioxidant capacity; it has a good therapeutic effect on Parkinson's models, and is expected to significantly improve the effect of treating Parkinson's disease and reduce the occurrence of adverse reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Effects of different drug combinations on parkinsonism in mice

[0030] Figure 2 Effects of different drug combinations on the narrow strip passing time of mice

[0031] Figure 3 Effects of different drug combinations on the balance ability of mice

[0032] Figure 4 Effects of different drug combinations on the grip strength of mice

[0033] Figure 5 Effects of different drug combinations on the inflammatory factor interleukin-1β

[0034] Figure 6 Effects of different drug combinations on the inflammatory factor tumor necrosis factor-α

[0035] Figure 7 Effects of different drug combinations on dopamine

[0036] Figure 8 Effects of different drug combinations on malondialdehyde

[0037] Figure 9 Effects of different drug combinations on total antioxidant capacity DETAILED DESCRIPTION

[0038] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0039] Example 1 Effect of the pharmaceutical composition on the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinson's disease model in C57 / BL mice

[0040] 1. Five-week-old C57 / BL male mice weighing 23-27 g were housed in a SPF environment with free access to water and food. The room temperature was controlled at 22 ± 2°C, with a 12-h light-dark cycle and humidity maintained at 40-60%.

[0041] 2. After one week of adaptive feeding, the rats were randomly divided into groups of 8;

[0042] 3. Dissolve MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in normal saline and inject it intraperitoneally into the experimental group mice at a dose of 20 mg / kg for 7 consecutive days.

[0043] 4. The drug was administered on the second day after modeling. The drug was dissolved in 5‰ carboxymethyl cellulose (CMC-Na). The dosage of each administration group is shown in Table 1 below. The drug was administered once a day. The model group was given an equal amount of CMC-Na for 14 consecutive days. The dosage was 20 mg / kg and was administered by gavage.

[0044] Table 1:

[0045]

[0046] 5. At the end of the experiment, Parkinson's disease scoring and behavioral testing were performed, including a narrow bar passage test and a grip strength test;

[0047] The test indicators are as follows:

[0048] (1) Parkinson's disease scoring criteria:

[0049] 0 points: the same as the blank group mice

[0050] 1 point - intermittent fine tremor, free movement

[0051] 2 points - frequent tremors, stiffness of hind limbs, and tail trembling

[0052] 3 points - continuous tremor, limb stiffness, limited movement

[0053] 4 points - death due to total paralysis

[0054] (2) Mouse grip strength test:

[0055] 1 minute - 1-10 seconds

[0056] 2 points - 11-25s

[0057] 3 points - 26-60s

[0058] 4 points - 61-90s

[0059] 5 points——>90s

[0060] (3) Gait scoring of mice through narrow bar experiment:

[0061] 0 points - normal gait, no slips or falls.

[0062] 1 point - Mild gait abnormality, occasional slipping, but no falls.

[0063] 2 points - obvious gait abnormality, multiple slips, and possible a few falls.

[0064] 3 points - severe gait abnormalities, frequent slips and falls.

[0065] Note: The narrow stripe passing experiment in this invention is finally presented as a comprehensive score, which is the total passing time (s) + gait score.

[0066] The results of Parkinson's disease scoring are as follows (eg Figure 1 ):

[0067] Table 2

[0068] Group score Group score Blank group 0.00±0.00 Treatment group 4 2.25±0.43 Model Group 2.63±0.48 Treatment group 5 2.38±0.70 Treatment group 1 2.38±0.48 Treatment group 6 2.25±0.66 Treatment group 2 2.25±0.66 Treatment group 7 1.38±0.48 Treatment group 3 2.38±0.70 Treatment group 8 1.50±0.50

[0069] The narrow strips were scored comprehensively through the experiment as follows (e.g. Figure 2 、 3 ):

[0070] Table 3

[0071] Group score Group score Blank group 4.44±0.72 Treatment group 4 10.35±0.81 Model Group 10.99±0.92 Treatment group 5 9.8±0.72 Treatment group 1 10.66±1.03 Treatment group 6 9.18±1.31 Treatment group 2 9.98±0.67 Treatment group 7 6.79±0.70 Treatment group 3 10.08±0.98 Treatment group 8 6.66±1.20

[0072] The grip strength test is scored as follows (eg Figure 4 ):

[0073] Table 4

[0074] Group score Group score Blank group 4.75±0.43 Treatment group 4 2.25±0.66 Model Group 1.63±0.48 Treatment group 5 2.38±0.86 Treatment group 1 1.88±0.60 Treatment group 6 2.75±0.43 Treatment group 2 2.75±0.66 Treatment group 7 4.00±0.71 Treatment group 3 2.75±0.43 Treatment group 8 3.88±0.60

[0075] 6. Blood was collected from the eyeballs until the mice died, and the blood was centrifuged to obtain serum for the detection of inflammatory factors (interleukin-1β and tumor necrosis factor-α);

[0076] Interleukin-1β test results (pg / mL) are as follows (e.g. Figure 5 ):

[0077] Table 5

[0078] Group score Group score Blank group 548.20±49.69 Treatment group 4 1156.84±96.39 Model Group 1499.85±98.87 Treatment group 5 1199.08±82.89 Treatment group 1 1021.36±66.12 Treatment group 6 1057.08±111.95 Treatment group 2 1234.79±69.31 Treatment group 7 784.00±52.47 Treatment group 3 1242.26±110.10 Treatment group 8 765.61±41.18

[0079] The tumor necrosis factor-α test results (pg / mL) are as follows (e.g. Figure 6 ):

[0080] Table 6

[0081] Group score Group score Blank group 798.19±26.28 Treatment group 4 1200.69±108.86 Model Group 1373.04±103.38 Treatment group 5 1328.60±71.08 Treatment group 1 1049.53±89.22 Treatment group 6 1038.45±83.76 Treatment group 2 1329.11±56.62 Treatment group 7 862.44±66.18 Treatment group 3 1301.70±75.68 Treatment group 8 964.00±51.04

[0082] 7. Dissect the mice and take brain tissue for detection of brain dopamine content, malondialdehyde (MDA) and total antioxidant capacity (T-AOC).

[0083] Dopamine test results (μg / g) are as follows (eg Figure 7 ):

[0084] Table 7

[0085] Group score Group score Blank group 14.50±1.40 Treatment group 4 10.31±1.20 Model Group 9.01±0.88 Treatment group 5 7.84±0.62 Treatment group 1 10.24±0.95 Treatment group 6 9.85±1.11 Treatment group 2 8.54±0.73 Treatment group 7 11.49±1.29 Treatment group 3 8.61±0.65 Treatment group 8 11.30±1.12

[0086] Malondialdehyde test results (mmol / mg) are as follows (e.g. Figure 8 ):

[0087] Table 8

[0088] Group score Group score Blank group 196.56±5.98 Treatment group 4 322.56±11.09 Model Group 339.01±23.96 Treatment group 5 333.59±14.02 Treatment group 1 289.14±15.42 Treatment group 6 309.23±13.08 Treatment group 2 330.51±10.66 Treatment group 7 233.53±18.29 Treatment group 3 316.99±29.90 Treatment group 8 228.85±15.07

[0089] The results of total antioxidant capacity test (U / mg) are as follows ( Figure 9 ):

[0090] Table 9

[0091] Group score Group score Blank group 6.51±0.43 Treatment group 4 4.74±0.56 Model Group 4.75±0.41 Treatment group 5 4.57±0.24 Treatment group 1 5.22±0.66 Treatment group 6 5.15±0.50 Treatment group 2 4.70±0.49 Treatment group 7 6.12±0.67 Treatment group 3 4.97±0.29 Treatment group 8 5.95±0.30

Claims

1. A pharmaceutical composition, characterized in that The invention comprises the following active components in weight fractions: 10-50% of geniposide; 10-50% of geniposide; 10-50% of geniposide; 10-50% of crocin I and 10-50% of ursolic acid.

2. The pharmaceutical composition according to claim 1, wherein Gardeniaside, geniposide, geniposide, crocin I and ursolic acid are independently active substances chemically synthesized or extracted and separated from Gardenia jasminoides.

3. The pharmaceutical composition according to claim 1, wherein The weight fraction of the geniposide is 20-40%, for example, 20%, 30% or 40%; And / or, the weight fraction of the geniposide is 10-20%, for example 10% or 20%; And / or, the weight fraction of the genipin gentiobioside is 10-20%, for example 10% or 20%; And / or, the weight fraction of crocin I is 10-20%, for example 10% or 20%; And / or, the weight fraction of ursolic acid is 20-40%, such as 20%, 30% or 40%.

4. The pharmaceutical composition according to claim 1, wherein The active components consist of geniposide, geniposide, geniposide-gentiobioside, crocin I and ursolic acid.

5. The pharmaceutical composition according to claim 1, wherein The invention comprises the following active components in weight fractions: 30-50% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 30-50% of ursolic acid; Or, it contains the following active ingredients in weight fractions: 20-40% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 20-40% of ursolic acid; Alternatively, it comprises the following active ingredients in weight fractions: 30-40% of geniposide; 10% of geniposide; 10% of geniposide; 10% of crocin I and 30-40% of ursolic acid.

6. The pharmaceutical composition according to any one of claims 1-2 and 4-5, characterized in that The invention is composed of the following active components in weight fractions: 10-50% of geniposide; 10-50% of geniposide; 10-50% of geniposide; 10-50% of crocin I and 10-50% of ursolic acid; Or, it is composed of the following active ingredients in weight fractions: 30-50% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 30-50% of ursolic acid; Or, it is composed of the following active ingredients in weight fractions: 20-40% of geniposide; 10-20% of geniposide; 10-20% of geniposide; 10-20% of crocin I and 20-40% of ursolic acid; Alternatively, it is composed of the following active ingredients in weight fractions: 30-40% of geniposide; 10% of geniposide; 10% of geniposide; 10% of crocin I and 30-40% of ursolic acid.

7. The pharmaceutical composition according to any one of claims 1-2 and 4-5, characterized in that The dosage form of the pharmaceutical composition is a liquid preparation or a solid preparation.

8. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating or ameliorating neurodegenerative diseases.

9. The use according to claim 8, characterized in that The neurodegenerative disease is selected from 1, 2, 3, 4, 5 or 6 of the diseases mediated by interleukin-1β, tumor necrosis factor-α, dopaminergic neuron loss, malondialdehyde elevation or total antioxidant capacity reduction in brain tissue.

10. The use according to claim 8 or 9, characterized in that The neurodegenerative disease is Parkinson's disease.

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