CN118976016A - Application of 10-hydroxydecenoic acid in the preparation of drugs for the treatment of Parkinson's disease - Google Patents
Application of 10-hydroxydecenoic acid in the preparation of drugs for the treatment of Parkinson's disease Download PDFInfo
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- CN118976016A CN118976016A CN202311074095.7A CN202311074095A CN118976016A CN 118976016 A CN118976016 A CN 118976016A CN 202311074095 A CN202311074095 A CN 202311074095A CN 118976016 A CN118976016 A CN 118976016A
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- China
- Prior art keywords
- hydroxydecenoic acid
- hydroxydecenoic
- acid
- meglumine
- oral
- Prior art date
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Classifications
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- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses application of 10-hydroxydecenoic acid and an oral preparation thereof in preparing medicines for treating parkinsonism. Experiments prove that the PD symptoms can be obviously improved after 10-hydroxydecenoic acid is continuously administrated for 7 days in an oral mode, and whether an oral solution or a solid tablet is taken, the meglumine is added to be beneficial to enhancing the drug effect or increasing the dissolution of the meglumine, so that the 10-hydroxydecenoic acid and the oral preparation thereof can be used for rapidly and efficiently exerting the anti-PD drug effect. The 10-hydroxydecenoic acid is derived from the popular high-grade health-care product royal jelly, and has the characteristics of convenience and safety for oral administration and small side effect, so that the invention provides a powerful support for the research and development of PD-resistant medicaments and has great significance.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of 10-hydroxydecenoic acid in preparation of a medicine for treating parkinsonism.
Background
10-Hydroxydecenoic acid is also called royal jelly acid, and is derived from one of royal jelly, which is a food supplied to larvae of queen bee to be fed to the head gland of the queen bee, and is a food for the life of queen bee, unlike bee venom and propolis, which are used and characterized by containing ingredients. The royal jelly contains 62.5% -70% of water, and the rest of proteins, saccharides, fatty acids and the like, wherein the main active substances in the royal jelly are proteins and fatty acids. For a long time, royal jelly has been widely used as a health product worldwide, and has been reported to have antihyperlipidemic, antioxidant, antiproliferative, antimicrobial, neuroprotective, antiinflammatory, immunomodulating and antiaging activities.
10-Hydroxydecenoic acid (10-HDA, C 10H18O3) is a natural unsaturated fatty acid, which is unique to royal jelly in nature and has been used as an important index for measuring the quality and distinguishing the authenticity of the royal jelly. 10-hydroxydecenoic acid accounts for 50% of total fatty acids of Lac Regis Apis, and accounts for about 1.8% of dry weight of Lac Regis Apis. The 10-hydroxydecenoic acid is white crystal at normal temperature, has stable property, is insoluble in water and is easy to dissolve in methanol, ethanol and chloroform, is slightly soluble in acetone, and has a melting point of 64 ℃. In general, 10-hydroxydecenoic acid can be isolated from royal jelly or can be artificially synthesized.
Parkinson's Disease (PD) is a common degenerative Disease of the central nervous system, which was systematically described by the earliest uk doctor james Parkinson. PD affects mainly the motor nervous system, and clinical symptoms mainly include motor symptoms (resting tremor, stiffness, gait abnormalities, etc.) and non-motor symptoms (sleep disorders, cognitive disorders, anxiety, depression, etc.). The main pathological features of PD include: the striatal dopamine (dopamine, DA) content was significantly reduced, the degeneration of the mesocephalic nigral dopaminergic neurons (dopaminergic neuron, SN) died, and eosinophilic inclusion bodies consisting of alpha-synuclein (alpha-synuclein, a-Syn) were present in the substantia nigra, i.e. lewy bodies (Lewybody). In addition, PD can also affect other brain regions including cholinergic neurons of the mernert basal nuclei (cholinergic neuron, CN), noradrenergic neurons of the blue spots (noradrenergic neuron, NN), the dorsal motor nuclei of the vagus nerve, the midbrain nuclei of the brain stem, the cerebral cortex, and the hypothalamus. The above pathological changes together affect the motor symptoms and the non-motor symptoms of PD. Wherein the significant reduction of striatal DA content is closely related to the symptoms of PD movement, whereas the changes of the mesencephalon-limbic system and the mesencephalon-cortical system are closely related to the symptoms of PD non-movement such as cognitive decline, mood disorder, etc. However, to date, surgical treatments and existing drugs (e.g., levodopa, amantadine, selegiline, etc.) have had low efficacy and poor efficacy, however, to date, surgical treatments and existing drugs have had limited efficacy and poor efficacy. At present, the main surgical therapy of PD is deep brain electrical stimulation (deep brain stimulation, DBS) therapy, but the main surgical therapy has the problems of psychological disorder of patients, high treatment cost, strict technical conditions and the like, and is not suitable for most PD patients. Clinically major anti-PD drugs include: anticholinergic agents such as benzomarix (susceptible to side effects such as unresponsiveness, mental disorders, and cognitive decline); amantadine (may appear as reticulate blue spots of the lower limb skin and edema of the lower leg after long-term administration); DA supplements such as L-dopa (poor efficacy against tremors, induced catabolism, high doses are prone to gastrointestinal reactions such as nausea, vomiting, etc.); DA receptor agonists such as pramipexole (prone to orthostatic hypotension, gastrointestinal reactions and psychotic symptoms); monoamine oxidase inhibitors of type B such as selegiline (leading to insomnia, gastrointestinal reactions, etc.); catechol-O-methyltransferase inhibitors such as tolcapone (side reactions including insomnia, dyskinesia, etc.). In conclusion, most of the drug treatments only can relieve the illness state, the effect is not satisfactory, and the side effect is obvious. The medicine has the advantages of high pertinence, high efficiency, good effect and less side effects. There is a great need for new and highly effective anti-PD agents.
Disclosure of Invention
The invention aims at providing an application of 10-hydroxydecenoic acid in preparing medicines for treating parkinsonism.
Further, the therapeutic drug is an oral preparation, an injection, a suppository or a transdermal preparation.
The second object of the invention is to provide the application of the 10-hydroxydecenoic acid oral preparation in preparing the medicines for treating the parkinsonism.
Further, the oral preparation is selected from oral solutions, granules, capsules, common tablets, dripping pills, micropills, oral patch films, dispersible tablets, effervescent tablets and sustained release tablets.
Still further, the oral formulation contains meglumine.
The research of the invention discovers that the meglumine is adopted to solubilize the 10-hydroxydecenoic acid to form a completely dissolved true solution agent, thus obtaining unexpected effect of treating the parkinsonism. Meanwhile, the method of adding meglumine into auxiliary materials is adopted to prepare the 10-hydroxydecenoic acid solid preparation, such as a tablet, so that the 10-hydroxydecenoic acid is promoted to be dissolved out of the tablet more quickly, and the 10-hydroxydecenoic acid is beneficial to exerting better anti-parkinsonism treatment effect.
The beneficial effects are that: experiments prove that the PD symptoms can be obviously improved after the continuous administration of the 10-hydroxydecenoic acid for 7 days. The 10-hydroxydecenoic acid is shown to be a rapid and efficient PD-resistant medicament. The 10-hydroxydecenoic acid is derived from the popular high-grade health-care product royal jelly, and has the characteristics of convenience and safety for oral administration and small side effect, so that the invention provides a powerful support for the research and development of PD-resistant medicaments and has great significance.
Drawings
FIG. 1 shows the result of the anti-PD effect of the lavage administration of 10-hydroxydecenoic acid solution in test example 1 on MPTP model mice. A is the design of experimental schemes such as modeling, drug administration, PD index test and the like; B-C is the result of open field test determination 7 days after administration; d is the measurement result of a rotating rod test after 8 days of administration; e is the Y maze test measurement after 10 days of administration. Using one-wayANOVA analysis, p <0.05, p <0.01, p <0.001.
FIG. 2 is a graph showing the results of exposure levels in rats following parenteral administration of 10-hydroxydecenoic acid solution in test example 2. A is the exposure level of 10-hydroxydecenoic acid in plasma; b is the level of 10-hydroxydecenoic acid exposure in the hippocampus; c is the exposure level of 10-hydroxydecenoic acid in the striatum. Using one-wayANOVA analysis, p <0.05, p <0.01, p <0.001.
FIG. 3 shows the dissolution results of the tablet of 10-hydroxydecenoic acid in test example 3. A is the dissolution rate of artificial gastric juice; b is the dissolution rate in artificial intestinal juice.
FIG. 4 is a graph showing the effect of 10-hydroxydecenoic acid on dopamine in the main brain tissue of test example 4. A is hippocampal dopamine level; b is striatal dopamine level; c is cortical dopamine level. Using one-wayANOVA analysis, p <0.05.
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the present invention and are not intended to limit the invention to the embodiments described.
EXAMPLE 110 liquid formulation of hydroxydecenoic acid solubilization prescription study
The 10-hydroxydecenoic acid is insoluble in water, and a solubilizing means such as a cosolvent is added by a pharmaceutical method to examine the dissolution state and stability. The formulation was prepared by dispensing the solutions in EP tubes at about 1.5 ml each, and cooling at room temperature and 4 ℃. The solution state was observed. Both prescriptions 2,3 were found to be cloudy or to have little precipitate undissolved and did not change significantly after standing at room temperature or after refrigeration at 4 ℃. After formulation 1, 4 and 5, the compositions were stable, clear and transparent after storage at room temperature for 3 days and after storage at 4℃for three days (Table 1).
Table 110-hydroxydecenoic acid liquid formulation solubilization prescription study
EXAMPLE 2 preparation of oral true solution of 10-hydroxydecenoic acid
Based on the results of the prescription study of prescription 5 in example 1, 10-hydroxydecenoic acid oral solutions were prepared with meglumine as a co-solvent, with the objective of dissolving 10-hydroxydecenoic acid to form a stable true solution, and purified water as a dispersion medium, with specifications ①-② at 90 and 180mg/5mL, respectively. The prescription is as follows:
The preparation process comprises the following steps: weighing meglumine 6.0 g, adding into 50mL of purified water for dissolution, respectively weighing 1.8g/3.6g of 10-hydroxydecenoic acid, respectively dissolving in the above solutions, adding purified water to 100mL, shaking for uniform mixing, filtering with a 0.8 micrometer microporous filter membrane, and packaging to obtain 5mL of unit preparation containing 90mg or 180mg of 10-hydroxydecenoic acid respectively.
Example 3 preparation of 10-hydroxydecenoic acid oral suspension
Based on the results of the prescription study of prescription 5 in example 1, 10-hydroxydecenoic acid suspension was prepared without the goal of dissolving 10-hydroxydecenoic acid, with specifications ①-② being 90 and 180mg/5mL, respectively. The prescription is as follows:
10-hydroxydecenoic acid 1.8g/3.6g
Sodium carboxymethylcellulose 0.5g
Distilled water was added to 100mL
The preparation process comprises the following steps: weighing 1.8g/3.6g of 10-hydroxydecenoic acid respectively, and sieving with a 60-mesh sieve; 0.5g of sodium carboxymethylcellulose (CMC-Na) is taken and sieved by a 80-mesh sieve. Sodium carboxymethyl cellulose is dispersed and dissolved in 100mL of distilled water, 10-hydroxydecenoic acid is dispersed and suspended in 0.5% sodium carboxymethyl cellulose water solution, and the suspension is uniformly vibrated, wherein each preparation contains 90mg or 180mg of 10-hydroxydecenoic acid in 5 mL.
Example 4 preparation of 10-hydroxydecenoic acid tablet
10-Hydroxydecenoic acid tablet formulations were prepared, with a size ①-② of 90 and 180 mg/tablet, respectively. The prescription is as follows:
The preparation process comprises the following steps: weighing 10-hydroxydecenoic acid, compressible starch and sodium carboxymethyl starch according to the prescription, sieving with 80 mesh sieve respectively, and mixing uniformly; taking 5g of povidone, dissolving in about 9 ml of 30% ethanol solution, preparing soft material by a conventional method, sieving with a 20-mesh sieve, granulating, flow-drying at 60 ℃ for 2 hours, adding superfine silica powder (sieving with a 120-mesh sieve), mixing well, and tabletting. Prepared into 100 tablets, each tablet contains about 0.44 or 0.53g of 10-hydroxydecenoic acid 90mg or 180mg.
EXAMPLE 5 preparation of meglumine-containing 10-hydroxydecenoic acid tablets
Meglumine-containing tablets of 10-hydroxydecenoic acid were prepared in sizes ①-② of 90 and 180 mg/tablet, respectively. The prescription is as follows:
The preparation process comprises the following steps: weighing 10-hydroxydecenoic acid, compressible starch, sodium carboxymethyl starch and meglumine according to the prescription, sieving with 80 mesh sieve respectively, and mixing uniformly; preparing soft material from 30% ethanol solution, sieving with 20 mesh sieve, granulating, flow-drying at 60deg.C for 2 hr, adding micropowder silica gel (sieving with 120 mesh sieve), mixing, and tabletting. Prepared into 100 tablets, each tablet contains about 0.54 or 0.78g, and 90mg or 180mg of 10-hydroxydecenoic acid.
EXAMPLE 6 preparation of 10-hydroxydecenoic acid capsules
10-Hydroxydecenoic acid capsules were prepared with specifications ①-② of 90 and 180 mg/capsule, respectively. The prescription is as follows:
The preparation process comprises the following steps: weighing 10-hydroxydecenoic acid, microcrystalline cellulose and lactose according to the prescription, sieving with 60 mesh sieve, and mixing; adding appropriate amount of 0.5% sodium carboxymethylcellulose to make into soft mass, granulating with 15 mesh sieve, flow-drying at 60deg.C for 2 hr, oven drying, grading, and respectively filling into No. 1 and No. 0 common capsules, wherein each preparation contains granule 0.19 or 0.28g, and 10-hydroxydecenoic acid 90 and 180mg respectively.
Example 7 preparation of 10-hydroxydecenoic acid effervescent tablet
The 10-hydroxydecenoic acid effervescent tablet is prepared, and the specification ①-② is 90 mg/tablet and 180 mg/tablet respectively. The prescription is as follows:
The preparation process comprises the following steps: respectively weighing 10-hydroxydecenoic acid according to the prescription, and dissolving in 30 ml of medicinal ethanol to obtain a component A for later use; taking compressible starch, sodium carboxymethyl starch, sodium bicarbonate, meglumine and citric acid, fully drying, weighing according to the prescription, respectively sieving with a 80-mesh sieve, uniformly mixing, adding the component A-10-hydroxydecenoic acid ethanol solution, and uniformly mixing to obtain a component B for later use; and 3g of povidone is dissolved in about 12 ml of polyethylene glycol 400 solution, added into the component B, made into soft materials by a conventional method, sieved by a 15-mesh sieve, granulated, flow-through dried for 3 hours at 60 ℃, added with micro silica gel (sieved by a 120-mesh sieve), uniformly mixed and tabletted. Prepared into 100 tablets, each tablet contains about 1.29 or 1.65g of 10-hydroxydecenoic acid 180mg or 360mg.
Test example 1 anti-PD effect of 10-hydroxydecenoic acid on MPTP model mice
Animal species selection: c57BL/6J mice (male, 7-8 weeks, purchased from Experimental animal technologies Co., ltd., beijing, vitolith weight 21.+ -.3 g) were adapted to feed for one week under standard feeding conditions (free diet with drinking water, alternating day and night, 12 hours each).
Building an animal model: seven days after C57BL/6J mice were adaptively cultured, a PD mouse model was established by intraperitoneal injection of the molding compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine, MPTP) at a dose of 20mg/kg for 14 consecutive days. MPTP is able to cross the blood brain barrier and convert the metabolite 1-methyl-4-phenylpyridine ion (MPP +) in astrocytes, thereby causing ATP production disorders with elevated intracellular Ca 2+ levels, and the generated reactive oxygen and nitrogen cause apoptosis of dopaminergic neurons. The mice were randomly grouped on the fourth day of modeling: experiments were performed in model, true solution, and suspension groups (a in fig. 1).
The administration mode is as follows: PD model mice were given a 180mg/kg dose of 10-hydroxydecenoic acid (true solution and suspension) by gavage as in example 2 and example 3, respectively, and an equal volume of 0.5% CMC-Na solution was administered to the control and model groups.
Effects on motor behavior of mice: social behavior evaluation was performed 7 days after continuous administration. Mice were placed in the behavioural test room to accommodate light and temperature for more than 30 minutes prior to the experiment. The C57BL/6J mice are placed in a 50X 50cm open field, a single experimental animal is placed in the center of the open field, free movement is carried out for 5min, the movement condition of the C57BL/6J mice in 300s is recorded, and the mice are removed after the completion. After the test, alcohol was sprayed to remove the taste, and the next animal experiment was performed. The activity distance and time of the experimental animal in the central area and the peripheral area were analyzed to evaluate the spontaneous activity of the experimental animal. The results showed that the ratio of the center area movement distance to the total distance was significantly decreased in the PD model group mice compared to the blank group, whereas the center area ratio was significantly increased in the true solution group and the suspension group mice, and the efficacy of the true solution group was superior to that of the suspension group (B in fig. 1). In addition, the results of the duration of stay in the central zone also show (fig. 1C), that the PD model group mice have significantly reduced time in the central zone compared to the blank group, whereas the true solution group mice have significantly improved time in the central zone, and that the suspension group mice have improved central stay time, but no significant difference is seen (p= 0.1154). These results indicate that oral administration of 10-hydroxydecenoic acid improves the motor capacity and anxiety-like behavior of PD mice, and that meglumine is useful as a cosolvent for drug efficacy.
The exercise ability of the experimental mice was evaluated using a rotating bar fatigue tester. The experimental animals were allowed to rest for 30min after being acclimatized on a rotarod at a speed of 4rpm/min for 10 min. The rotational speed was set at 35rpm/min, the time was 5min, the acceleration time was 30s, and the time (latency) for each experimental animal to remain on the rotor was recorded. The experimental results showed (D in fig. 1) that the latency of PD model mice on the rotating rod was significantly reduced compared to the empty control group, while the latency of dosing mice was significantly increased, and the true solution group was better than the suspension group. Stick rotation experiments show that 10-hydroxydecenoic acid can improve the movement capacity of PD mice, and meglumine is used as a cosolvent to be beneficial to further playing the drug effect.
Cognitive impairment is one of the common non-motor symptoms of PD, including mild cognitive impairment of parkinson's disease (PD-MCI) and dementia of parkinson's disease (PDD), and is also an important cause for affecting the quality of life of patients and accelerating the progression of the disease. The spatial memory and cognitive ability of the experimental mice were evaluated using a Y maze test. The alternating behavior is the nature of the experimental animal to explore the new different environment, and in the searching process, the experimental animal needs to memorize the direction explored before so as not to repeatedly enter, so that the Y-shaped maze experiment can effectively determine the spatial memory capacity of the experiment. The experimental mice were placed at the end of either arm, and were left free to explore in the Y maze for 5min, and the total number of mice entering each arm was recorded. The four feet of the mice all enter the arm considered once, alternatively one time refers to three different arms (123, 132, 312, etc. all can be) entering the maze in turn, and the maximum number of turns refers to the total number of arm-entering times-2, and the alternation percentage=total number of turns/maximum number of turns×100%. Experimental results show that MPTP-modelled mice exhibit a decrease in alternating percentage, indicating that MPTP-induced PD models are also accompanied by cognitive impairment and memory decline. The alternation percentage of the mice of the 10-hydroxydecenoic acid administration group is obviously improved, the MPTP-induced spatial memory cognitive impairment is relieved, the exploration desire is enhanced, and the level of the mice is equivalent to that of a blank control group. 10-hydroxydecenoic acid was shown to enhance MPTP-induced cognitive impairment and memory impairment.
In conclusion, the administration of 10-hydroxydecenoic acid can obviously improve the autonomous locomotion and memory cognition of MPTP-induced PD model mice, and the behavioral effect of mice in a true solution group is better than that of mice in a suspension group, which indicates that meglumine in an oral solution is beneficial to the 10-hydroxydecenoic acid to better exert the PD-resistant effect.
Test example 2 effect of meglumine on drug concentration of 10-hydroxydecenoic acid in rat plasma and tissues
Animal and dosing method: 16 SD rats (weight 200+ -20 g) of 6-7 weeks old were obtained, and each half was randomly divided into 2 groups of 8 rats (each half) according to the weight. The drinking water is taken freely to adapt to the environment for one week before administration. The diet was fasted for 12 hours before the experiment, and no water was forbidden. The meglumine-free suspension and meglumine-containing solution of examples 2 and 3, respectively, were used for intragastric administration (180 mg/kg). Blood samples of 200. Mu.L were collected 2, 5, 10, 20, 40, 60, 120, 240, 360 minutes after dosing, heparin sodium EP tube was added, centrifuged at 5000rpm for 5 minutes, and the plasma supernatant was isolated and stored in a-80℃refrigerator for use. Animals were grouped and dosed in the same manner as above, rats were sacrificed under anesthesia at 10 and 40 minutes after dosing, and hippocampus, cortex, striatum were collected, and tissues were washed with ice physiological saline solution, blotted with absorbent paper, and stored in-80 ℃ refrigerator, respectively, for use.
Quantitative determination method of 10-hydroxydecenoic acid: LC-MS/MS analysis was performed using an Shimadzu high performance liquid chromatograph (including SIL-20ACXR constant temperature autosampler, CTO-20A column incubator, DGU-20A3 on-line vacuum degasser), tandem US AB mass spectrometry (API 5500), electrospray ion source (ESI), and Analyst 1.6.1 workstation.
Plasma and tissue samples were subjected to precipitation with organic solvent protein, centrifuged twice (4 ℃ C., 18000rpm for 5 min), and 5. Mu.L of supernatant was sampled. The column was Agilent ZORBAX Eclipse Plus C (2.1X105 mm, 3.5-. Mu.m) and the column temperature: the mobile phase is methanol-0.02% ammonium formate aqueous solution at 40 ℃. Gradient elution was carried out at a flow rate of 0.3ml/min. Electrospray ionization (ESI) mode, ion spray voltage: -4500V; the auxiliary gases 1 and 2 are nitrogen: 50Arb, 55Arb; the temperature of the auxiliary gas is 500 ℃; a curtain gas of 30Arb; collision gas: 10Arb; inlet voltage EP: -10V; outlet voltage CXP: -5V. Multiple Reaction Monitoring (MRM) mode for detecting anions, 10-hydroxydecenoic acid for detecting ion pairs: 185.00→ 139.00, set CE: -22eV; DP: -70V. The internal standard is chlorzoxazone, and the ion pair is 168.00-132.00 under the ESI negative ion mode. In addition, a series of standard solutions were prepared, the sample assay was performed, working curves were plotted, and 10-hydroxydecenoic acid concentration levels in plasma and tissue samples were calculated.
Results: after administration of the solutions and suspensions, the drug concentration in the plasma increased rapidly in a short period of time (10 minutes after administration) followed by a significant decrease (fig. 2A), suggesting that 10-hydroxydecenoic acid may be rapidly absorbed in the gastrointestinal tract. Furthermore, the plasma exposure levels of 10-hydroxydecenoic acid after administration in true solution were significantly higher than that of suspension, suggesting that meglumine solubilization was beneficial in increasing the exposure levels of 10-hydroxydecenoic acid in the circulatory system.
The level of central hippocampal and striatal drug concentration increased shortly after administration (10 minutes after administration) followed by a significant decrease, suggesting that 10-hydroxydecenoic acid readily enters the central tissue. Furthermore, the overall exposure levels of 10-hydroxydecenoic acid in the hippocampus and striatum were higher than those of the suspension (fig. 2B, 2C) following administration of 10-hydroxydecenoic acid in true solution, suggesting that meglumine solubilization is beneficial in increasing the exposure levels of 10-hydroxydecenoic acid in the central nervous system, particularly in tissues such as the hippocampus and striatum.
Conclusion: after the gastric lavage administration of 10-hydroxydecenoic acid, the exposure level of meglumine in blood and brain tissues (hippocampus, cortex and striatum) of SD rats is higher, and the meglumine can obviously increase the exposure level of 10-hydroxydecenoic acid in blood plasma, hippocampus and striatum, which suggests that the effect of PD resistance is exerted.
Test example 3 dissolution of 10-hydroxydecenoic acid tablet in vitro simulated artificial gastric fluid/intestinal fluid
1. Dissolution in artificial gastric juice:
The simulated artificial gastric juice is prepared according to a pharmacopoeia method by adopting a slurry method, the pH is regulated to about 1.5, 900 milliliters of artificial gastric juice is respectively added into the dissolution cups, after the temperature reaches 37 ℃, 10-hydroxydecenoic acid tablets without meglumine in the example 4 and 1 tablet of 10-hydroxydecenoic acid tablets with meglumine in the example 5 are respectively put into the six dissolution cups, and the rotating speed is regulated to 80 revolutions per minute. 1ml of each filtrate was taken at 5, 15, 30, 45 and 60 minutes, the method was carried out by measuring 10-hydroxydecenoic acid by LC-MS/MS in the above-mentioned test example 2, the elution amount of 10-hydroxydecenoic acid was calculated, the elution percentage was calculated by comparing the calculated elution amount with the labeled amount, and the elution curve was drawn, and the elution difference of the two tablets was compared.
Results: both tablets disintegrated faster in artificial gastric juice and the dissolution became turbid. The measurement results showed that 10-hydroxydecenoic acid slowly eluted in artificial gastric juice, the dissolution rate increased with time, the average dissolution rate of meglumine-free 10-hydroxydecenoic acid tablet at 60 minutes was 32.3%, and the average dissolution rate of meglumine-containing 10-hydroxydecenoic acid tablet was 44.8%, as shown in fig. 3A.
Conclusion: the dissolution of 10-hydroxydecenoic acid in artificial gastric juice is slow, and meglumine has a certain promotion effect on the dissolution of 10-hydroxydecenoic acid in artificial gastric juice.
2. Dissolution in artificial intestinal juice:
The simulated artificial intestinal juice is prepared according to a pharmacopoeia method, the pH is regulated to about 6.8, 900 milliliters of the artificial intestinal juice is respectively added into the dissolution cups, after the temperature reaches 37 ℃ and the temperature is balanced, 10-hydroxydecenoic acid tablets without meglumine in the example 4 and 1 tablet of 10-hydroxydecenoic acid tablets with meglumine in the example 5 are respectively put into the six dissolution cups, and the rotating speed is regulated to 80 revolutions per minute. 1 ml of filtrate is taken at 5, 15, 30, 45 and 60 minutes respectively, after dilution, the acidity of 10-hydroxydecene is measured by an LC/MS method, the dissolution amount of the 10-hydroxydecene is calculated, the dissolution percentage is calculated by comparing the calculated dissolution amount with the marked amount, a dissolution curve is drawn, and the dissolution difference of two tablets is compared.
Results: both tablets disintegrated faster in artificial intestinal fluid and the dissolution became turbid. The measurement results showed that 10-hydroxydecenoic acid eluted relatively rapidly in the artificial intestinal juice, the dissolution rate increased with time, the average dissolution rate of meglumine-free 10-hydroxydecenoic acid tablet at 60 minutes was 69.7%, and the average dissolution rate of meglumine-containing 10-hydroxydecenoic acid tablet was 98.2%, as shown in fig. 3B.
Conclusion: the dissolution of 10-hydroxydecenoic acid in artificial intestinal juice is faster, wherein the dissolution of 10-hydroxydecenoic acid in meglumine-containing tablets is sufficient at 60 minutes, suggesting that meglumine can promote the dissolution of 10-hydroxydecenoic acid in intestinal physiological environment. Compared with artificial gastric juice, the 10-hydroxydecenoic acid is easier to dissolve in the simulated intestinal physiological environment, which suggests that the in vivo absorption is facilitated.
Test example 410-Effect of hydroxydecenoic acid on dopamine levels in the brain of AD model rats
Animal species selection: SD rats (males, 6-7 weeks, purchased from Beijing Vitolihua laboratory animal technologies Co., ltd., body weight 200+ -20 g) were adapted to one week in a standard feeding environment (free diet and drinking water, alternating between day and night, 12 hours each).
Building an animal model: amanita (ibotenic acid, IBO) is a neurotoxin, which is used to destroy the Meynert basal nucleus by intracranial injection of IBO, destroy its cholinergic nervous system, and cause neuronal damage and cognitive impairment in animal models. Seven days after the SD rats were adaptively cultured, IBO was injected into the striatal brain region using a brain stereotactic apparatus. After the abdominal cavity is anesthetized, the experimental animal is fixed on a brain stereotactic instrument, the head skin is disinfected and cut off, subcutaneous tissue is separated, and the skull is exposed. Referring to the Paxinos rat brain stereotactic map (coordinates: 1.0mm posterior to bregma, 2.7mm lateral to midline, 7.0mm deep), the skull was drilled at the site using a skull drill, 2. Mu.L IBO solution (dissolved in sterile saline, 1.25. Mu.g/. Mu.L) was slowly injected on each side, and the control group was injected with the same volume of sterile saline.
Dosing and sample collection: PD model mice were given a 180mg/kg dose of 10-hydroxydecenoic acid (true solution and suspension) by gavage as in example 2 and example 3, respectively, and an equal volume of 0.5% CMC-Na solution was administered to the control and model groups. Brain tissue samples such as striatum, hippocampus, cortex and the like are collected after one week of administration, the dopamine level is measured by adopting an LC-MS/MS technology, and DA difference is compared after administration of the true solution and the suspension.
Results: DA levels were reduced in striatal and hippocampal tissues in the IBO model rats compared to the control, whereas 10-hydroxydecenoic acid increased DA levels in striatal and hippocampal tissues, and the potency of the eusolution of 10-hydroxydecenoic acid with meglumine was more pronounced (fig. 4A-B).
Conclusion: 10-hydroxydecenoic acid can increase DA level in hippocampus and striatum of rats in IBO model, and 10-hydroxydecenoic acid solution containing meglumine can significantly increase DA level in hippocampus and striatum, which suggests that 10-hydroxydecenoic acid can exert better anti-PD effect.
Claims (5)
- Use of 10-hydroxydecenoic acid in the manufacture of a medicament for the treatment of parkinson's disease.
- 2. The use according to claim 1, wherein the therapeutic agent is an oral preparation, an injection, a suppository, a transdermal preparation.
- The application of the 3, 10-hydroxydecenoic acid oral preparation in preparing medicines for treating parkinsonism.
- 4. The use according to claim 3, wherein the oral formulation is selected from the group consisting of oral solutions, granules, capsules, plain tablets, drop pills, micropellets, buccal patches, dispersible tablets, effervescent tablets, sustained release tablets.
- 5. The use according to claim 4, wherein the oral formulation contains meglumine.
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| CN202311074095.7A CN118976016A (en) | 2023-08-24 | 2023-08-24 | Application of 10-hydroxydecenoic acid in the preparation of drugs for the treatment of Parkinson's disease |
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| CN202311074095.7A CN118976016A (en) | 2023-08-24 | 2023-08-24 | Application of 10-hydroxydecenoic acid in the preparation of drugs for the treatment of Parkinson's disease |
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