Chondroitin sulfate oligosaccharide composition and application thereof in preparation of Parkinson's disease treatment medicine

Abstract

The invention belongs to the field of biological medicines, and particularly relates to a composition of chondroitin sulfate oligosaccharide and application of the composition in preparation of a Parkinson's disease treatment medicine. The chondroitin sulfate oligosaccharide is chondroitin sulfate octasaccharide from which a 6-site sulfuric acid group is removed and a 4-site sulfuric acid group is specifically retained; the chondroitin sulfate oligosaccharide oral preparation is a composition containing sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate (SNAC) and chondroitin sulfate octasaccharide retaining a 4-position sulfuric acid group. The N-(8-[2-hydroxybenzoyl]-amino) sodium caprylate can effectively promote oral absorption of chondroitin sulfate, and can be used as an oral absorption enhancer; the chondroitin sulfate oligosaccharide has neuroprotective activity and can be used for treating Parkinson's disease.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to a pharmaceutical composition comprising chondroitin sulfate oligosaccharides and its application in the preparation of Parkinson's disease therapeutic drugs. Background Technology

[0002] The information disclosed in this background technology section is only intended to increase the understanding of the overall background of the invention, and is not necessarily regarded as an admission or any form of suggestion that the information constitutes the prior art that has been known to ordinary technicians in the field.

[0003] Parkinson's disease is a neurodegenerative disease that mainly affects middle-aged and elderly people. The main pathological change is the selective degeneration of dopaminergic neurons in the substantia nigra. The incidence of Parkinson's disease is second only to Alzheimer's disease, affecting approximately 2-3% of people aged 65 and above. Clinical manifestations include resting tremor, bradykinesia, muscle rigidity, postural instability, and gait abnormalities. Current treatments mainly focus on symptom relief, and no therapeutic intervention can reverse the progression of Parkinson's disease. Dopamine and levodopa drugs remain the gold standard treatment; however, long-term use can reduce their effectiveness and produce side effects. Therefore, there is an urgent need to develop more effective neuroprotective and disease-modifying treatments.

[0004] In recent years, glycosaminoglycans and their binding proteins have attracted widespread attention from academia and the pharmaceutical industry. Glycosaminoglycans are a class of linear anionic polysaccharides composed of repeating disaccharide units. They are commonly found on the cell surface and in the extracellular matrix and play an important role in regulating biological and physiological processes. Due to their negatively charged nature, glycosaminoglycans can interact with various proteins and exert a wide range of biological activities, including anti-inflammatory, anti-tumor, antiviral and neuroprotective effects. According to the different disaccharide units and the degree of sulfation, glycosaminoglycans can be divided into heparin (HP), heparan sulfate (HS), chondroitin sulfate (CS), etc. Among them, chondroitin sulfate is the most common glycosaminoglycan in the extracellular matrix of the brain, but due to the characteristics of chondroitin sulfate such as large molecular weight, high negative charge, hydrophilicity and instability under acidic conditions, the oral bioavailability of chondroitin sulfate is low and insufficient to provide the expected clinical therapeutic effect. Therefore, it is of great significance to seek an effective strategy to improve the oral bioavailability of chondroitin sulfate. SUMMARY OF THE INVENTION

[0005] In the prior research of the inventors (CN119285810B), a chondroitin sulfate oligosaccharide desulfurized product was provided, which has the activities of promoting the repair of chronic hepatitis and anti-inflammation, can be used for oral treatment of non-alcoholic fatty liver disease, and can significantly improve the oral bioavailability in combination with deoxycholyl ethylamine. The present invention discovers that the above compound not only has anti-inflammatory activity, but also has anti-Parkinson activity. In order to further expand the Parkinson's treatment activity of the above compound and improve the bioavailability of the oral preparation, the present invention combines it with N sodium (8-[2-hydroxybenzoyl]-amino) octanoate (SNAC) for combined application, effectively improving the bioavailability of the oral preparation and the treatment effect for Parkinson's disease. Based on the above technical effects, the present invention provides the following technical solutions: In the first aspect, a pharmaceutical composition is provided. The pharmaceutical composition contains an active dose of the chondroitin sulfate oligosaccharide described in the first aspect. The structure of the chondroitin sulfate oligosaccharide is shown in the following formula (I): Formula (I); In formula (I), R is SO 3 H or H.

[0006] The chondroitin sulfate oligosaccharide shown in formula (I) is a linear polysaccharide formed by connecting repeating disaccharide units of uronic acid and N N-acetylgalactosamine, with a degree of polymerization of 8. This octasaccharide specifically removes the 6-position sulfate group of N N-acetylgalactosamine, and only retains the 4-position sulfate group, named CS-dp8-de6S. Its preparation method includes the following steps: (1) Enzymatically hydrolyze chondroitin sulfate into low-molecular-weight chondroitin sulfate; (2) Chromatographically separate the low-molecular-weight chondroitin sulfate prepared in step (1) to obtain chondroitin sulfate octasaccharide; (3) Pass the chondroitin sulfate octasaccharide prepared in step (2) through an H + ion exchange column, add pyridine to the product passing through the column to obtain chondroitin sulfate octasaccharide pyridinium salt, and react it with N N-methyl- N N-trimethylsilyltrifluoroacetamide (MSTFA) at 90 - 110 °C with stirring for 10 - 14 h to obtain the above CS-dp8-de6S.

[0007] The specific operation of step (1) is as follows: Dissolve chondroitin sulfate in part of the enzymatic hydrolysis buffer, add chondroitin ABC enzyme, incubate at 35 - 39 °C for 7 - 9 h for enzymatic hydrolysis, inactivate the reaction system at high temperature after completion, and centrifuge to retain the supernatant to obtain low-molecular-weight chondroitin sulfate.

[0008] Furthermore, the partial enzymatic hydrolysis buffer is a mixture of sodium acetate and calcium acetate, wherein the molar ratio of sodium acetate to calcium acetate is 1.8-2.2:0.02-0.04.

[0009] Furthermore, the dosage ratio of the chondroitin sulfate, partial enzymatic hydrolysis buffer, and chondroitin sulfate ABC enzyme is 1:28~32 mL:0.7~0.8 IU.

[0010] Furthermore, the purpose of the high temperature inactivation is to inactivate the chondroitin sulfate ABC enzyme in the reaction system, and the method usually adopted is high temperature heating, such as heating by water bath or microwave.

[0011] Furthermore, the centrifugal parameters are as follows: high-speed centrifugation at 12000-16000 rpm for 12-17 min.

[0012] In step (2), the mobile phase of the chromatographic separation is 0.2 M ammonium bicarbonate aqueous solution, the chromatographic column is P10, and the retention time of the chromatographic separation of the chondroitin sulfate octasaccharide is 380-425 min.

[0013] The specific operation of step (3) is as follows: dissolve the above chondroitin sulfate octasaccharide in water to a concentration of 0.2-0.3 g / mL, and pass through H + Ion exchange column, add pyridine to the eluate received by the column until the pH of the eluate is 7, stir thoroughly and concentrate to dry to obtain chondroitin sulfate octasaccharide pyridinium salt, add pyridine to dissolve again, stir with N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) at 90~110℃ for 11~13 h to obtain the above CS-dp8-de6S.

[0014] Furthermore, the H + The eluent of the ion exchange column is water.

[0015] Furthermore, the dosage ratio of the chondroitin sulfate octasaccharide pyridinium salt to MSTFA is 1g:0.8~1.2mL.

[0016] Furthermore, the separation method of CS-dp8-de6S is as follows: the solution system after the reaction of chondroitin sulfate octasaccharide pyridinium salt and MSTFA is dialyzed against water for 22-26 hours, and the components in the dialysis bag are freeze-dried.

[0017] The "active dose" referred to in the first aspect, according to the general understanding in the field, can be the drug dose for the purpose of prevention, improvement, treatment or auxiliary treatment. After clarifying the therapeutic activity of the above-mentioned ingredients, the dose belongs to the technical content that can be routinely inferred based on the general technology mastered by those skilled in the art.

[0018] ​In addition to the CS-dp8-de6S described in the first aspect, the above composition also includes other auxiliary ingredients, and the feasible types of the other auxiliary ingredients are absorption enhancers, carriers, diluents, adhesives, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, antibacterial agents or buffers, any one or a combination of at least two. In one embodiment verified by the present invention, the other auxiliary ingredients are absorption enhancers, and the specific ingredients are N -(8-[2-hydroxybenzoyl]-amino) sodium caprylate (SNAC), in this embodiment, the mass ratio of CS-dp8-de6S to SNAC is 2-4:1.

[0019] In the second aspect, the use of the chondroitin sulfate oligosaccharide and the pharmaceutical composition described in the first aspect in the preparation of a drug for treating Parkinson's disease is provided.

[0020] Existing studies have shown that low molecular weight chondroitin sulfate can play a protective role on dopaminergic neurons in the PD disease model induced by the neurotoxin MPTP. It is well known in the art that low molecular weight chondroitin sulfate is a type of polysaccharide mixture with a very complex structure. The present invention provides a chondroitin sulfate oligosaccharide with a specific structure. From the perspective of drug preparation development, the research results of the present invention are more conducive to achieving drug quality control. Those skilled in the art can obtain the corresponding compounds based on the above-mentioned preparation method provided by the present invention, or prepare them by chemical synthesis and other methods.

[0021] On the other hand, Parkinson's disease is a chronic disease that requires long-term medication, so oral preparations are more suitable for patients. However, since chondroitin sulfate is a macromolecular substance with low bioavailability, in order to improve the oral bioavailability of the above compound, the present invention designs and selects ingredients that can promote the absorption of CS-dp8-de6S for combined administration. According to the research results of the present invention, the drug combination of CS-dp8-de6S and SNAC can effectively increase the expression level of tyrosine hydroxylase in the brain tissue of Parkinson's disease model mice through oral intake, thereby increasing the brain dopamine content and improving Parkinson's symptoms.

[0022] Depending on the form in which the drug is applied to the affected area, the dosage form of the Parkinson's disease treatment drug includes but is not limited to intramuscular injection, subcutaneous injection, intravenous injection, oral preparation or interventional preparation taken by surgical means, etc. In one embodiment verified by the present invention, the above-mentioned pharmaceutical composition is in an oral form, specifically, an oral tablet.

[0023] Compared with the prior art, the beneficial effects of the present invention are: 1. The pharmaceutical composition of SNAC and CS-dp8-de6S provided by the present invention effectively promotes the oral absorption of chondroitin sulfate octasaccharide and greatly improves the oral bioavailability of chondroitin sulfate octasaccharide.

[0024] 2. The pharmaceutical composition provided by the present invention has good neuroprotective activity and can be used for oral treatment of Parkinson's disease. Brief Description of the Figures

[0025] The drawings constituting part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0026] Figure 1 is the P10 chromatogram of the chondroitin sulfate octasaccharide prepared in Example 1; Figure 2 HSQC NMR spectrum of chondroitin sulfate octasaccharide prepared in Example 1; Figure 3 HSQC NMR spectrum of CS-dp8-de6S prepared in Example 1; Figure 4 The blood drug concentration curves of subcutaneous injection of CS-dp8-de6S and oral administration of the composition in Example 5; Figure 5 is the immunohistochemical staining diagram of tyrosine hydroxylase in Example 5; Among them, Figure 5 A is the immunohistochemical staining result of substantia nigra section of brain tissue of normal mice; Figure 5 B is the immunohistochemical staining result of substantia nigra sections of brain tissue of mice in the model group; Figure 6 C is the immunohistochemical staining result of substantia nigra sections of brain tissue of mice in the drug-treated group; Figure 1 This is a statistical analysis chart of the average optical density of Example 5. Specific implementation method

[0027] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by ordinary technicians in the technical field to which the present invention belongs.

[0028] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or their combinations.

[0029] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0030] Example 1 In this embodiment, a chondroitin sulfate oligosaccharide is provided, named CS-dp8-de6S, and its structure is shown in the following formula: Formula (I); In formula (I), R is SO 3 H or H.

[0031] In this embodiment, a method for preparing the above CS-dp8-de6S is also provided, comprising the following steps: 1. Preparation of low molecular weight chondroitin sulfate by enzymatic hydrolysis Weigh 1 g of chondroitin sulfate, dissolve it in 30 mL of partial enzymatic buffer, add 0.75 IU of chondroitin sulfate ABC enzyme, and incubate at 37°C for 8 h. After the enzymatic hydrolysis is completed, boil it in a 100°C water bath to inactivate the chondroitin sulfate ABC enzyme, and centrifuge it at 14,000 rpm for 15 min, take the supernatant, and freeze-dry it to obtain low molecular weight chondroitin sulfate.

[0032] The above-mentioned partial enzymatic buffer was prepared by mixing 0.1 mol / L sodium acetate (adjusting pH to 7.0 with acetic acid) and 0.01 mol / L calcium acetate in a volume ratio of 20:3. Among them, 0.1 mol / L sodium acetate was prepared as follows: weigh 0.2461 g sodium acetate and dissolve it in 30 mL water, and adjust pH to 7.0 with acetic acid; 0.01 mol / L calcium acetate was prepared as follows: weigh 26.43 mg calcium acetate and dissolve it in 15 mL water.

[0033] 2. Chromatographic separation to obtain chondroitin sulfate octasaccharide Mobile phase: 0.2 M ammonium bicarbonate aqueous solution, ultrasonic dissolution, filtration to remove impurities, ultrasonic removal of bubbles.

[0034] Chromatographic column: P10; filling method is as follows: add filler to a beaker, soak it with 20% ethanol, then replace 20% ethanol with high-purity water, filter the filler to remove bubbles, and pour it into the column. First compact the filler with water, then compact the filler with 0.2 M ammonium bicarbonate mobile phase, and then load the sample.

[0035] Chromatographic separation: 300 mg of the obtained low molecular weight chondroitin sulfate was dissolved in water and separated by high performance liquid chromatography to obtain chondroitin sulfate octasaccharide. The results were characterized as follows Figure 2 、 Figure 3 As shown.

[0036] 3. Directed desulfation of the sulfate group to prepare CS-dp8-de6S Weigh 5 g of the above chondroitin sulfate octasaccharide and dissolve it in 20 mL of deionized water. + Ion exchange column. Pyridine was added to the eluate received after the column until the pH of the solution was 7. After stirring at room temperature for 1 h, vacuum concentration was performed and freeze-dried to obtain chondroitin sulfate octasaccharide pyridinium salt. Weigh 1 g of chondroitin sulfate octasaccharide pyridinium salt and dissolve it in 6 mL of anhydrous pyridine, and 1 mL of MSTFA was added. After stirring at 100 ° C for 12 h, the solution was diluted with 5 mL of pure water. The solution was dialyzed in water for 24 h and freeze-dried to obtain the desulfurization product of chondroitin sulfate octasaccharide, namely CS-dp8-de6S.

[0037] Characterization: Weigh 15 mg of the above CS-dp8-de6S, dissolve in deuterium oxide, and lyophilize three times to replace the exchangeable protons. The lyophilized sample was dissolved in 200 µL deuterium oxide, vortexed, centrifuged, and the supernatant was analyzed using NMR HSQC spectra. The results are shown in Figure 4 As shown.

[0038] Example 2 In this embodiment, another method for preparing CS-dp8-de6S is provided, which is different from that in Example 1 in that: 1. Preparation of low molecular weight chondroitin sulfate by enzymatic hydrolysis Weigh 1 g of chondroitin sulfate, dissolve it in 28 mL of partial enzymatic buffer, add 0.7 IU of chondroitin sulfate ABC enzyme, and incubate at 35℃ for 9 h. After the enzymatic hydrolysis is completed, boil it in a 100℃ water bath to inactivate the chondroitin sulfate ABC enzyme, and centrifuge it at 12000 rpm for 17 min, take the supernatant, and freeze-dry it to obtain low molecular weight chondroitin sulfate.

[0039] The above partial enzymatic hydrolysis buffer was prepared by mixing 0.1 mol / L sodium acetate (adjusted to pH 7.0 with acetic acid) and 0.01 mol / L calcium acetate in a volume ratio of 18:2.

[0040] 2. Chromatographic separation to obtain chondroitin sulfate octasaccharide​ Same as Example 1.

[0041] 3. Directed desulfation of the sulfate group to prepare CS-dp8-de6S Weigh 4 g of the above chondroitin sulfate octasaccharide and dissolve it in 20 mL of deionized water. + Ion exchange column. Pyridine was added to the eluate received after the column until the pH of the solution was 7. After stirring at room temperature for 1 h, vacuum concentration was performed and freeze-dried to obtain chondroitin sulfate octasaccharide pyridinium salt. Weigh 1 g of chondroitin sulfate octasaccharide pyridinium salt and dissolve it in 6 mL of anhydrous pyridine, and add 0.8 mL of MSTFA. After stirring at 90°C for 13 h, the solution was diluted with 5 mL of pure water. The solution was dialyzed in water for 24 h and freeze-dried to obtain the desulfurization product of chondroitin sulfate octasaccharide, namely CS-dp8-de6S.

[0042] Example 3 In this embodiment, another method for preparing CS-dp8-de6S is provided, which is different from that in Example 1 in that: 1. Preparation of low molecular weight chondroitin sulfate by enzymatic hydrolysis Weigh 1 g of chondroitin sulfate, dissolve it in 32 mL of partial enzymatic buffer, add 0.8 IU of chondroitin sulfate ABC enzyme, and incubate at 39°C for 7 h. After the enzymatic hydrolysis is completed, boil it in a 100°C water bath to inactivate the chondroitin sulfate ABC enzyme, and centrifuge it at 16,000 rpm for 12 min, take the supernatant, and freeze-dry it to obtain low molecular weight chondroitin sulfate.

[0043] The above partial enzymatic hydrolysis buffer was prepared by mixing 0.1 mol / L sodium acetate (adjusted to pH 7.0 with acetic acid) and 0.01 mol / L calcium acetate in a volume ratio of 22:4.

[0044] 2. Chromatographic separation to obtain chondroitin sulfate octasaccharide Same as Example 1.

[0045] 3. Directed desulfation of the sulfate group to prepare CS-dp8-de6S Weigh 6 g of the above chondroitin sulfate octasaccharide and dissolve it in 20 mL of deionized water. + Ion exchange column. Pyridine was added to the eluate received after the column until the pH of the solution was 7. After stirring at room temperature for 1 h, vacuum concentration was performed and freeze-dried to obtain chondroitin sulfate octasaccharide pyridinium salt. Weigh 1 g of chondroitin sulfate octasaccharide pyridinium salt and dissolve it in 6 mL of anhydrous pyridine, and 1.2 mL of MSTFA was added. After stirring at 110°C for 11 h, the solution was diluted with 5 mL of pure water. The solution was dialyzed in water for 24 h and freeze-dried to obtain the desulfurization product of chondroitin sulfate octasaccharide, namely CS-dp8-de6S.

[0046] Example 4​​ In this embodiment, a composition comprising the above CS-dp8-de6S is provided, wherein the composition comprises the CS-dp8-de6S prepared in any one of Examples 1-3, and further comprises an absorption enhancer SNAC, wherein the mass ratio of the two is 1:3, and the preparation method of the composition is as follows: Weigh 300 mg CS-dp8-de6S and 100 mg SNAC, and ultrasonicate for 40 min until the mixture is uniformly mixed to obtain the above composition.

[0047] Example 5 In this embodiment, an oral tablet is provided, and the preparation method is as follows: The composition in Example 4 was crushed to a particle size of 20 mesh and fully dried, and the dried powder was placed in a tablet press to prepare tablets.

[0048] Biological Validation 1. Bioavailability Verification 1. Experimental materials: C57BL / 6J mice, 8 weeks old.

[0049] 2. Experimental methods 18 mice were injected subcutaneously into the CS-dp8-de6S group in Example 1 and 18 mice were injected orally into the composition group in Example 4. The drugs were administered at a dose of 10 mg / kg for subcutaneous injection and 100 mg / kg for oral administration. Blood was collected from the inner canthus at 5 min, 10 min, 20 min, 30 min, 60 min and 120 min after administration. The whole blood was centrifuged at 3000 rpm for 15 min at 4°C, and the supernatant was the plasma. The plasma was mixed with methanol in a volume ratio of 1:9, and the solution was allowed to stand for 10 min at room temperature for alcohol precipitation. The solution was centrifuged at 1000 g for 10 min, and the supernatant was discarded. The precipitate was enzymatically hydrolyzed with pronase E at 55°C for 24 h. After the enzymatic hydrolysis, it was boiled at 100°C for 10 min to inactivate the protease. The supernatant was obtained by centrifugation at 14000 rpm for 10 min. It was then purified by an anion exchange column, and impurities were further washed to obtain a relatively pure CS-dp8-de6S. The eluted sugars were desalted using an ultrafiltration tube with a molecular weight cutoff of 2 kDa and freeze-dried. The desalted CS-dp8-de6S was completely hydrolyzed into disaccharides using CS ABC enzyme. After AMAC labeling, the disaccharides were quantitatively analyzed by LC-MS / MS-MRM using the Nexera LC-20A UPLC liquid phase system and the SCIEX Triple Quad™5500+ mass spectrometry system.

[0050] 3. Experimental results Figure 5 ​​Table 1 is the blood drug concentration curve of the subcutaneous injection and oral composition, and Table 2 is the relevant parameters and bioavailability of the subcutaneous injection and oral composition.

[0051] Table 1 Related parameters and bioavailability of subcutaneous injection and oral compositions From the quantitative results, it can be seen that the bioavailability of the subcutaneous injection group (control group) is 90.56%, and the bioavailability of the oral composition group is 8.19%. Generally speaking, the oral absorption rate of chondroitin sulfate drugs does not exceed 1%. And the actual drug concentration absorbed into the blood (i.e., AUC value) is the effective concentration for the actual efficacy, so the AUC value can be increased by increasing the oral dose. In this study, an oral dose 10 times the injection dose was used. At this dose, the drug concentration of the composition group was 204.7, which can reach about 90% of the drug concentration of the subcutaneous injection group, indicating that the prepared composition has a good oral absorption effect after administration, effectively improving the oral absorption rate of CS, and has great therapeutic potential.

[0052] 2. Verification of the effect of Parkinson's treatment 1. Experimental materials: C57BL / 6J mice, 8 weeks old.

[0053] 2. Experimental methods 2.1 Experimental Grouping The mice were randomly divided into 3 groups: (A) normal group, (B) model group, and (C) drug-treated group. The drug was the composition in Example 4.

[0054] 2.2 Modeling Methods Groups B and C were subcutaneously injected with MPTP 20 mg / kg / day for 5 consecutive days to establish Parkinson's disease models; Group A was intraperitoneally injected with an equal amount of normal saline as a control.

[0055] 2.3 Method of administration After successful modeling, drug treatment was started. Group C was gavaged with the composition of Example 4 for 7 consecutive days, and Groups A and B were gavaged with an equal amount of saline as a control. The drug administration method for Group C was: CS-dp8-de6S administration dose of 300 mg / kg / day, SNAC administration dose of 100 mg / kg / day.

[0056] 3. Experimental results After the model was established, tyrosine hydroxylase (TH) immunohistochemical staining was performed on the substantia nigra sections of the brain tissue, and the results were quantified using the average optical density (AOD). The results are shown in Figure 6 、 ​ ​​​​​. According to the results of statistical analysis, after treatment with the neurotoxin MTPT, the number of TH-positive cells in the model group was significantly lower than that in the normal group, and the average optical density value was statistically significantly different ( P <0.05, indicating that the Parkinson's model was successfully established. After the administration of the composition in Example 4, the number of TH positive cells increased significantly compared with the model group ( P <0.001), indicating that CS-dp8-de6S has good neuroprotective activity and can be used to treat Parkinson's disease.

[0057] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition contains an active dose of chondroitin sulfate oligosaccharide; the structure of the chondroitin sulfate oligosaccharide is shown in the following formula (I): Formula (I); In formula (I), R is SO3H or H, and is named CS-dp8-de6S.

2. The pharmaceutical composition according to claim 1, characterized in that In addition to chondroitin sulfate oligosaccharides, the pharmaceutical composition also includes any one or a combination of at least two of an absorption promoter, a carrier, a diluent, a binder, a wetting agent, a disintegrant, an emulsifier, a solubilizer, a solubilizing agent, an osmotic pressure regulator, a surfactant, a coating material, a colorant, a pH regulator, an antioxidant, an antibacterial agent or a buffer.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition is composed of chondroitin sulfate oligosaccharides and an absorption enhancer, wherein the absorption enhancer is N -(8-[2-hydroxybenzoyl]-amino)caprylic acid sodium.

4. The pharmaceutical composition according to claim 3, characterized in that The chondroitin sulfate oligosaccharide and N The mass ratio of sodium -(8-[2-hydroxybenzoyl]-amino) caprylate is 2~4:

1.

5. The pharmaceutical composition according to claim 4, characterized in that The chondroitin sulfate oligosaccharide and N The mass ratio of sodium -(8-[2-hydroxybenzoyl]-amino)caprylate is 3:

1.

6. Use of the chondroitin sulfate oligosaccharide represented by formula (I) and the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a drug for treating Parkinson's disease, characterized in that: The dosage form of the Parkinson's disease treatment drug is selected from intramuscular injection, subcutaneous injection, intravenous injection, oral preparation or interventional preparation taken by surgical means.

7. The use according to claim 6, characterized in that The Parkinson's disease treatment drug is an oral preparation.

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