A nasal mucosa administration preparation of sodium valproate and its preparation and use

Abstract

The present application relates to a kind of sodium valproate nasal mucosa administration preparation and its preparation and application, belong to medical technical field.A kind of sodium valproate nasal mucosa administration preparation, the preparation includes gastrodin and as medicinal component sodium valproate.The weight ratio of sodium valproate and gastrodin is 1:0.0025~2.The administration preparation of the present application is a kind of sodium valproate nasal mucosa administration preparation, can be delivered to brain by bypassing blood-brain barrier through nasal administration, improve brain bioavailability, prolong the effective action time of drug in brain, avoid first pass effect, reduce the risk of peripheral toxic side effect.The present application uses gastrodin as absorption promoter, by optimizing the ratio of gastrodin and sodium valproate, can reach the effect of increasing the absorption of sodium valproate in whole body and brain, further improve its brain bioavailability, enhance its therapeutic potential.

Description

Technical Field

[0001] This invention relates to a nasal mucosal delivery formulation of sodium valproate, its preparation and application, and belongs to the field of pharmaceutical technology. Background Technology

[0002] Epilepsy is a transient brain dysfunction caused by abnormal discharge of neurons in the brain. Its pathogenesis is complex. It has been shown that the lesions are mainly concentrated in the hippocampus, frontal cortex and amygdala. However, most of the potential therapeutic compounds enter the brain in very limited quantities through systemic circulation, which makes it difficult for drugs to reach the target site to exert their pharmacological effects, which has become a major challenge in the treatment of epilepsy.

[0003] Sodium valproate is one of the most prescribed antiepileptic drugs in the world to date. Its pharmacological effects include participating in enhancing the effect of gamma-aminobutyric acid (GABA) and attenuating the neuronal response to N-methyl-D-aspartate, thereby inhibiting neuronal excitation; regulating neurotransmitters (such as dopamine and serotonin) and voltage-gated ion channels (such as sodium, calcium, and potassium channels) to stabilize nerve cell membranes, etc. Sodium valproate has been widely used for the treatment of epilepsy, bipolar disorder, and other mental or neurological disorders, as well as the prevention of migraines.

[0004] Sodium valproate is the sodium salt of valproic acid, with a molecular weight of 166.198 and a pKa of 4.8. It is readily soluble in water. The most common route of administration for sodium valproate is oral, with a clinically used dose of 0.25-4.5 g / day. It can also be administered intravenously and rectally. Unlike other antiepileptic drugs, sodium valproate is believed to be transported to the brain via both passive diffusion and active transport. Therefore, even at physiological pH, sodium valproate is highly ionized and can still be rapidly transported to the brain after administration. However, it exhibits a significant asymmetric brain transport, meaning that the efflux of the drug into the brain is far greater than the influx. The steady-state brain / plasma free drug concentration ratio is less than 0.5, much lower than other antiepileptic drugs. Therefore, continuous administration and increased dosage are often used to maintain the effectiveness of sodium valproate in patients.

[0005] Sodium valproate has a narrow therapeutic window, generally considered to be 50-100 mg / L. However, in clinical applications, there is significant individual variation in blood drug concentrations. High exposure to the drug in the blood increases the incidence of adverse reactions, especially the metabolites produced by CYP450 enzymes, which can induce fatal hepatotoxicity. Therefore, it is necessary to consider the avoidance of peripheral toxicity while maximizing the antiepileptic effect of sodium valproate.

[0006] Nasal administration is a rapid, safe, non-invasive, and convenient method of drug delivery. It has its own olfactory and trigeminal nerve pathways to deliver drugs directly to the brain. At the same time, the highly vascularized epithelium and large surface area of ​​the nasal cavity provide better drug absorption sites. Drugs can also enter the brain through systemic circulation, avoiding the first-pass effect of the liver.

[0007] Currently, marketed formulations of sodium valproate include injections, oral tablets, and syrups, but there are no patents or products related to nasal formulations. Clinical studies have shown that the combined use of oral sodium valproate and gastrodin can improve the efficacy of sodium valproate. However, the clinical dosage of gastrodin is relatively high, reaching 200-400 mg / day via intramuscular injection and 600 mg / day via intravenous infusion. Therefore, leveraging the advantages of nasal administration, and using gastrodin at a much lower clinical dosage as an absorption enhancer, an optimized ratio of the two could be developed to create a nasal mucosal delivery formulation of sodium valproate. This would significantly improve the absorption and brain tissue distribution of sodium valproate, which is of great significance for the efficient and non-invasive treatment of epilepsy. No nasal formulations of sodium valproate using gastrodin as an absorption enhancer have been reported to date. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide a sodium valproate nasal mucosal delivery formulation with gastrodin as an absorption enhancer, characterized by a simple preparation process, suitability for industrial production, low production cost, and good absorption, as well as its preparation method and application. Nasal mucosal administration reduces sodium valproate exposure in the blood, decreases its distribution in the liver, prolongs its effective duration of action in the brain, and minimizes nasal mucosal irritation, thus significantly improving therapeutic efficacy and safety.

[0009] A nasal mucosal administration formulation of sodium valproate, the formulation comprising gastrodin and sodium valproate as a pharmaceutical component.

[0010] In the nasal mucosal administration formulation of sodium valproate described in this invention, the weight ratio of sodium valproate to gastrodin is 1:0.0025-2, preferably 1:0.0025-0.5, and more preferably 1:0.005-0.05.

[0011] The nasal mucosal drug delivery preparations of the present invention are nasal drops, sprays, and aerosols.

[0012] Preferably, the nasal mucosa administration formulation includes sodium valproate, gastrodin, a pH adjuster, an osmotic pressure adjuster, and a solvent.

[0013] Preferably, the content of gastrodin in the nasal mucosa administration preparation is 0.0625–12.5 wt.%, more preferably 0.125–1.25 wt.%.

[0014] Preferably, the pH of the nasal mucosa administration preparation is 4-8, more preferably 5.0-6.5.

[0015] Preferably, the sodium valproate is provided in its own form or in the form of a pharmaceutically acceptable salt, solvate, or prodrug.

[0016] Preferably, the nasal mucosa administration formulation includes an antibacterial agent selected from one or more of ethylparaben, potassium sorbate, propylparaben, benzyl alcohol, benzalkonium chloride, and benzalkonium bromide, wherein the antibacterial agent accounts for 0.01 to 0.2% of the mass of the nasal mucosa administration formulation.

[0017] Preferably, the pH adjuster is selected from any one or more of phosphoric acid, hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium citrate, phosphate buffer, acetate buffer, and citrate buffer.

[0018] Preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol, and mannitol.

[0019] Preferably, the solvent is selected from one or more of ethanol, propylene glycol, and purified water.

[0020] Another object of the present invention is to provide a method for preparing the above-mentioned sodium valproate nasal mucosal administration formulation.

[0021] A method for preparing a nasal mucosal drug delivery formulation of sodium valproate involves adding the prescribed amount of sodium valproate to a pre-dissolved solution containing gastrodin and other components under stirring conditions.

[0022] Another object of the present invention is to provide the application of the above-mentioned sodium valproate nasal mucosal delivery formulation.

[0023] The use of sodium valproate nasal mucosal delivery formulations in the preparation of drugs for the treatment or prevention of mental or neurological diseases.

[0024] Furthermore, the application of sodium valproate nasal mucosal administration formulations in the preparation of drugs for treating epilepsy, wherein the epilepsy is petit mal epilepsy, myoclonic epilepsy, focal seizure epilepsy, grand mal epilepsy, and mixed epilepsy.

[0025] Furthermore, the use of nasal mucosal delivery formulations of sodium valproate in the preparation of drugs for the treatment of bipolar disorder and other mental or neurological disorders.

[0026] Furthermore, the application of sodium valproate nasal mucosal delivery formulations in the preparation of migraine prevention formulations.

[0027] The beneficial effects of this invention are as follows: The drug delivery formulation of this invention is a nasal mucosal delivery formulation of sodium valproate. Nasal administration can bypass the blood-brain barrier to deliver the drug to the brain, improve the bioavailability in the brain, prolong the effective duration of action of the drug in the brain, reduce the exposure of the drug in the blood, avoid the first-pass effect, and reduce the risk of peripheral toxic side effects. This invention uses gastrodin as an absorption enhancer. By optimizing the ratio of gastrodin to sodium valproate, the absorption of sodium valproate in the brain can be increased, further improving its bioavailability in the brain and enhancing its therapeutic potential. Attached Figure Description

[0028] Figure 1 The effects of gastrodin dosage on the nasal absorption behavior of sodium valproate were investigated, where (a) the effect of gastrodin dosage on the amount of sodium valproate absorbed through the nasal mucosa, and (b) the effect of gastrodin dosage on the absorption rate of sodium valproate through the nasal mucosa.

[0029] Figure 2 The effect of gastrodin dosage on the pharmacokinetic behavior of sodium valproate.

[0030] Figure 3 The effect of gastrodin dosage on the distribution of sodium valproate in the brain.

[0031] Figure 4 The effect of gastrodin dosage on the liver distribution of sodium valproate.

[0032] Figure 5 The results of observing the ciliary toxicity of sodium valproate nasal mucosal administration formulation under a 10×40x optical microscope. Detailed Implementation

[0033] The following non-limiting embodiments are intended to enable those skilled in the art to more fully understand the invention, but do not limit the invention in any way.

[0034] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0035] The technical solution of this invention is as follows:

[0036] In the first aspect, a sodium valproate nasal mucosal delivery formulation is provided, which mainly contains sodium valproate, gastrodin, an osmotic pressure regulator and a solvent.

[0037] More preferably, a sodium valproate nasal mucosal delivery formulation comprising sodium valproate, gastrodin, a pH adjuster, an osmotic pressure adjuster, and a solvent.

[0038] The sodium valproate may be provided in its own form or in the form of a pharmaceutically acceptable salt, solvate, or prodrug.

[0039] Further, the mass percentage of sodium valproate in the nasal mucosa administration formulation is 0.5-25%, and the mass ratio of sodium valproate to gastrodin is 1:(0.0025-2), preferably 1:(0.0025-0.5), more preferably 1:(0.005-0.05).

[0040] Furthermore, the mass percentage of gastrodin in the nasal mucosa administration formulation is 0.0625–12.5%, preferably 0.125–1.25%.

[0041] The pH adjuster described in this invention is selected from any one or more of phosphoric acid, hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium citrate, phosphate buffer, acetate buffer, and citrate buffer.

[0042] The pH range of the sodium valproate nasal mucosal delivery formulation of the present invention is 4 to 8, preferably 5.0 to 6.5.

[0043] The osmotic pressure regulator described in this invention is selected from one or more of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol, and mannitol, with sodium chloride being preferred.

[0044] The sodium valproate nasal mucosal administration formulation of the present invention may contain no antibacterial agent or may contain an antibacterial agent as needed. The antibacterial agent is selected from one or more of ethylparaben, potassium sorbate, propylparaben, benzyl alcohol, benzalkonium chloride, and benzalkonium bromide. The mass percentage of the antibacterial agent in the nasal mucosal administration formulation is 0.01 to 0.2%.

[0045] The solvent used in this invention is selected from one or more of ethanol, propylene glycol, and purified water.

[0046] Secondly, the present invention provides a method for preparing a sodium valproate nasal mucosal administration formulation, comprising the following steps: adding a prescribed amount of sodium valproate to a pre-dissolved solution containing gastrodin and other excipients under stirring conditions to prepare a formulation suitable for nasal mucosal administration.

[0047] The nasal mucosa drug delivery formulations obtained above can be further prepared into nasal drops, sprays, and aerosols. The preparation methods are conventional techniques in this field and will not be described here.

[0048] Thirdly, the present invention provides the application of the above-mentioned sodium valproate nasal mucosal administration formulation in various types of epilepsy, such as petit mal seizures, myoclonic epilepsy, focal seizures, grand mal seizures, and mixed epilepsy.

[0049] Fourthly, the present invention provides the application of the above-mentioned sodium valproate nasal mucosal administration formulation in the treatment of bipolar disorder and other mental or neurological diseases, as well as in the prevention of migraines.

[0050] Example 1

[0051] Prescription composition

[0052]

[0053]

[0054] Preparation process: Accurately weigh the prescribed amount of gastrodin and osmotic pressure regulator into a vial, add half of the prescribed amount of purified water, stir magnetically to mix the components evenly, continue to add the prescribed amount of sodium valproate while stirring, add the remaining purified water to completely dissolve the sodium valproate, adjust the pH to 6.5 with 1 mol / L hydrochloric acid to obtain a sodium valproate nasal mucosal administration preparation with a gastrodin content of 0.125%, which is recorded as Example 1.

[0055] Example 2

[0056] Prescription composition

[0057] Sodium valproate 50mg Gastrodin 25mg Sodium chloride 90mg Purified water 9835mg

[0058] Preparation process: Same as in Example 1, a sodium valproate nasal mucosa administration preparation with a gastrodin content of 0.25% was obtained, which is referred to as Example 2.

[0059] Example 3

[0060] Prescription composition

[0061] Sodium valproate 50mg Gastrodin 50mg Sodium chloride 90mg Purified water 9810mg

[0062] Preparation process: Same as in Example 1, a sodium valproate nasal mucosa preparation with a gastrodin content of 0.5% was obtained, which is recorded as Example 3.

[0063] Example 4

[0064] Prescription composition

[0065] Sodium valproate 50mg Gastrodin 100mg Sodium chloride 90mg Purified water 9760mg

[0066] Preparation process: Same as in Example 1, a sodium valproate nasal mucosa administration preparation with a gastrodin content of 1% was obtained, which is recorded as Example 4.

[0067] Example 5

[0068] Prescription composition

[0069] Sodium valproate 2500mg Gastrodin 6.25mg Sodium chloride 90mg Purified water 7403.75mg

[0070] Preparation process: Same as in Example 1, a sodium valproate nasal mucosa preparation with a gastrodin content of 0.0625% was obtained, which is recorded as Example 5.

[0071] Example 6

[0072] Prescription composition

[0073] Sodium valproate 2500mg Gastrodin 12.5mg Sodium chloride 90mg Purified water 7397.5mg

[0074] Preparation process: Same as in Example 1, a sodium valproate nasal mucosa preparation with a gastrodin content of 0.125% was obtained, which is referred to as Example 6.

[0075] Example 7

[0076] Prescription composition

[0077] Sodium valproate 2500mg Gastrodin 25mg Sodium chloride 90mg Purified water 7385mg

[0078] Preparation process: Same as in Example 1, a sodium valproate nasal mucosa preparation with a gastrodin content of 0.25% was obtained, which is referred to as Example 7.

[0079] Example 8

[0080] Prescription composition

[0081] Sodium valproate 2500mg Gastrodin 125mg Sodium chloride 90mg Purified water 7285mg

[0082] Preparation process: Same as in Example 1, a sodium valproate nasal mucosal administration preparation with a gastrodin content of 1.25% was obtained, referred to as Example 8.

[0083] Example 9

[0084] Prescription composition

[0085] Sodium valproate 2500mg Gastrodin 1250mg Sodium chloride 90mg Purified water 6785mg

[0086] Preparation process: Same as in Example 1, a sodium valproate nasal mucosa preparation with a gastrodin content of 12.5% ​​was obtained, which is referred to as Example 9.

[0087] Effect of Gastrodin Dosage on Nasal Absorption Behavior of Sodium Valproate

[0088] The effect of gastrodin dosage on the nasal absorption behavior of sodium valproate was studied using an in vivo nasal circulation method. A 5 mg / mL sodium valproate solution was used as a control group to investigate the effects of different concentrations of gastrodin (Examples 1-4) on the nasal absorption behavior of sodium valproate.

[0089] Rats were anesthetized and fixed on a rodent board. The skin around their necks was incised to expose the trachea and esophagus. A polyethylene tube was connected to the tracheal incision to ensure respiration. After sealing the nasal-palatine passage with adhesive, another polyethylene tube was inserted into the posterior part of the nasal cavity through the esophagus, with the other end connected to a silicone tube extending into a diffusion chamber containing the drug solution. The diffusion chamber was placed in a 37°C constant-temperature water bath, and a peristaltic pump was used to circulate the drug solution through the nasal cavity. 100 μL samples were taken from the circulating fluid at 0, 10, 20, 30, 45, 60, 90, and 120 min, and an equal volume of blank physiological saline was added. The percentage of remaining drug at time n was calculated by HPLC using the following formula:

[0090]

[0091] Q n =C′ n ·V n

[0092] In the formula C' n For concentration correction; C n The concentration measured at time n; V is the sampling volume; V n Q represents the total volume of the liquid medicine in the receiving pool. n Let n be the remaining amount of medicine at time n.

[0093] The logarithmic changes over time of the nasal absorption and remaining percentage of the drug solution are shown in the attached figure. Figure 1 As shown in Table 1, the nasal absorption rate constant K of sodium valproate in the first 45 minutes was calculated.

[0094] Table 1: Nasal absorption rate constant K (n=3) of sodium valproate after the addition of different concentrations of gastrodin.

[0095]

[0096]

[0097] Note: Compared with sodium valproate solution as a control group, *p<0.05.

[0098] The experimental results show that the addition of 0.125%, 0.25%, 0.5%, and 1% w / w gastrodin all increased the nasal absorption rate of sodium valproate to varying degrees. The promoting effect of gastrodin on the nasal absorption of sodium valproate is not linear. Among them, the absorption-promoting effects of 0.125% w / w (Example 1) and 0.25% w / w (Example 2) gastrodin are the best.

[0099] Effects of Gastrodin Dosage on the In vivo Behavior of Sodium Valproate

[0100] Effect of gastrodin dosage on the pharmacokinetic behavior of sodium valproate:

[0101] Using direct nasal administration of sodium valproate solution as a control group, the effects of adding different concentrations of gastrodin (Examples 5-9) on the in vivo behavior of sodium valproate were studied.

[0102] Rats were divided into six groups of five each. Sodium valproate was administered at a dose of 100 mg / kg in all groups. Group 1 was the nasal control group; Group 2 was the group in Example 5 (0.25 mg / kg gastrodin); Group 3 was the group in Example 6 (0.5 mg / kg gastrodin); Group 4 was the group in Example 7 (1 mg / kg gastrodin); Group 5 was the group in Example 8 (5 mg / kg gastrodin); and Group 6 was the group in Example 9 (50 mg / kg gastrodin). For the nasal administration groups, a microsyringe with a soft tube was used, inserted to a fixed depth of 6 mm into each nostril, with administration to both nostrils. At 3, 5, 15, 30, 45, 60, 90, 120, 180, and 360 minutes after administration, 0.5 mL of blood was collected from the orbital venous plexus in each group. After centrifugation at 12000 rpm for 10 minutes, 200 μL of plasma was precisely measured to determine the drug content.

[0103] The drug concentration-time curves for each treatment group are shown in the appendix. Figure 2 The main pharmacokinetic parameters are shown in Table 2.

[0104] Table 2: Main pharmacokinetic parameters in blood of sodium valproate nasal mucosal formulations containing different doses of gastrodin (n=5).

[0105]

[0106] Note: Compared with the nasal cavity control group, *p<0.05, **p<0.01.

[0107] The results showed that sodium valproate was rapidly absorbed after intranasal administration in all treatment groups. The addition of gastrodin did not affect the elimination half-life of sodium valproate in the blood, but it did affect its distribution in the blood in a concentration-dependent manner. Pharmacokinetic parameters from Examples 5-8 showed that the addition of 0.0625-1.25% w / w gastrodin increased the serum AUC of sodium valproate. (0-t) Compared with the control group, the concentration increased by 45.60% to 78.80%, but in the high concentration group such as 12.5% ​​w / w gastrodin in Example 9, the maximum blood concentration and AUC were not significantly different from the nasal control group.

[0108] Effects of gastrodin dosage on the brain distribution of sodium valproate:

[0109] The effects of different concentrations of gastrodin added (Examples 5-8) on the distribution of sodium valproate in the brain were studied by direct intravenous injection and nasal administration of sodium valproate solution as the intravenous group and nasal control group, respectively.

[0110] Rats were divided into six groups of five each. Sodium valproate was administered at a dose of 100 mg / kg. Group 1 was the intravenous injection group, administered via tail vein injection. Group 2 was the nasal control group. Group 3 was the group described in Example 6 (0.5 mg / kg gastrodin), Group 4 in Example 7 (1 mg / kg gastrodin), Group 5 in Example 8 (5 mg / kg gastrodin), and Group 6 in Example 9 (50 mg / kg gastrodin). Nasal administration was performed using the same method. Rats in each group were sacrificed at 5, 15, 30, and 60 minutes after administration. Brains were rapidly removed, rinsed with physiological saline, and the surface blood was aspirated. After homogenization, the drug content was determined.

[0111] The drug concentration-time curves in the brain of each treatment group are shown in the appendix. Figure 3 The main pharmacokinetic parameters are shown in Table 3.

[0112] Table 3: Major pharmacokinetic parameters in the brain of sodium valproate nasal mucosal formulations containing different doses of gastrodin (n=5).

[0113]

[0114] Note: Compared with the intravenous group, *p<0.05, **p<0.01; compared with the nasal control group, #p<0.05, ##p<0.01.

[0115] The results showed that intranasal administration delayed the time to peak concentration of the drug in the brain to varying degrees, ranging from approximately 14.93 to 22.5 minutes, and significantly prolonged the half-life of the drug in the brain. Drug distribution in the brain was detectable after 60 minutes. The addition of gastrodin increased the concentration-dependent distribution of the drug in the brain; the AUC of sodium valproate in the brain increased after the addition of 0.5–5 mg / kg gastrodin. (0-t) It was 1.08 to 1.59 times that of the nasal cavity control group, with Example 7 (Gastrodin dose 1 mg / kg) showing the highest concentration. max and AUC (0-t) All results were comparable to the intravenous administration group, but the addition of high concentrations of gastrodin, such as 50 mg / kg gastrodin in Example 9, actually reduced the AUC in the brain. (0-t) It was reduced by 17.79% compared to the nasal cavity control group.

[0116] The drug targeting index (DTI) and the nasal direct transport percentage (DTP) of the drug in the brain were calculated for each drug administration group using the following formula:

[0117]

[0118]

[0119]

[0120] Among them B i.v P i.v These represent the AUC and B in brain tissue and plasma after intravenous administration, respectively. i.n P i.n These represent the AUC and B in brain tissue and plasma after intranasal administration in each drug administration group, respectively. x This indicates the proportion of drugs that, after nasal administration, cross the blood-brain barrier through systemic circulation and enter the brain.

[0121] The calculated DTI and DTP parameters for each drug administration group are shown in Table 4.

[0122] Table 4: DTI and DTP of sodium valproate nasal mucosal administration formulations containing different doses of gastrodin.

[0123] DTI DTP (%) Nasal control group 2.89±0.54 62.24±7.14 Example 6 2.15±0.06 53.36±1.34 Example 7 2.91±0.52 67.57±5.53 Example 8 2.40±0.49 57.01±8.76 Example 9 2.50±0.58 60.90±2.08

[0124] The results showed no significant differences between the groups. The DTP of the nasal control group and each example group was around 60%. This indicates that the addition of gastrodin did not significantly promote the proportion of sodium valproate entering the brain through the nasobrain pathway. That is, the increased drug concentration in the brain may be due to the fact that gastrodin increased the amount of sodium valproate participating in the systemic circulation after nasal administration, thereby increasing the amount of drug that crosses the blood-brain barrier and reaches the brain.

[0125] Effect of gastrodin dosage on the liver distribution behavior of sodium valproate:

[0126] Similarly, intravenous injection and nasal administration of sodium valproate solution were used as the intravenous group and nasal control group, respectively, to study the effect of different concentrations of gastrodin on the distribution of sodium valproate in the liver (Examples 6-8).

[0127] The administration method and dosage were the same as above. Rats in each administration group were sacrificed at 5, 15, 30 and 60 minutes after administration. The livers were quickly removed, rinsed with physiological saline, and the surface blood was dried. The drug content was determined after processing the tissue homogenate samples.

[0128] The liver drug concentration-time curves for each treatment group are shown in the appendix. Figure 4 The main pharmacokinetic parameters are shown in Table 5.

[0129] Table 5: Major pharmacokinetic parameters in the liver of sodium valproate nasal mucosal formulations containing different doses of gastrodin (n=5).

[0130]

[0131] Note: Compared with the intravenous group, **p<0.01; compared with the nasal control group, #p<0.05.

[0132] The results showed that the highest hepatic drug concentration was detected at 30 min after both intravenous and nasal administration. However, at each monitored time point, the hepatic drug distribution in the nasal administration group was significantly lower than that in the intravenous administration group. The AUC in the liver of each nasal administration group was... (0-t) The nasal administration rate was 39.84%–52.09% of the intravenous administration group, indicating that nasal administration itself reduces peripheral drug distribution and has better safety compared to intravenous administration. In each group supplemented with gastrodin, the liver AUC was [not specified]. (0-t) There was no significant difference compared to the control group, indicating that gastrodin itself does not have the ability to reduce the accumulation of sodium valproate in the liver, and its safety is good.

[0133] Safety study of sodium valproate nasal mucosal delivery formulation

[0134] Using Example 7 as the experimental subject, the ciliary toxicity of the formulation was investigated using the mucous membrane of the toad's upper jaw. The negative control group and the positive control group were physiological saline and 1% sodium deoxycholate, respectively.

[0135] After destroying the toad's spinal cord with a probe, the toad was fixed to a wooden board with its mouth open at 60°. 500 μL of the drug solution was dripped onto the mucous membrane of each toad's palate and kept for 30 minutes to completely saturate the mucous membrane. The drug solution was then washed away with physiological saline, and the palate mucous membrane was separated and placed on a glass slide. The movement of the cilia was observed under a 10×40x optical microscope. Three additional groups of toads, four toads in each group, were selected. The experimental method was the same as above. After observation, the prepared glass slides were placed in a chromatography tank saturated with physiological saline. Subsequently, the glass slides were removed at appropriate intervals and the ciliary movement was observed under a microscope. If the movement continued, the sample was put back into the chromatography tank until the ciliary movement was observed to stop. The duration of continuous movement of the cilia in each group from the start of drug administration (Persistent Vibration Duration, PVD) was recorded. The percentage of persistent movement of the cilia (PPV) was obtained by dividing the PVD of each drug administration group by the PVD of the physiological saline control group. The higher the percentage, the less toxic the drug is to the cilia.

[0136] The morphology of the toad palatal mucosa after 30 minutes of contact between the drug solution and the toad's palatal mucosa is shown in the appendix. Figure 5 The PVD and PPV for each group are calculated and shown in Table 6.

[0137] Table 6: Effect of sodium valproate nasal mucosal administration formulation on the ciliary movement time of the maxillary mucosa in toads (n=4).

[0138] PVD(min) PPV (%) physiological saline 643.75±11.00 100.00 1% sodium deoxycholate <30.00 <4.67 Example 7 583.25±15.80 90.60±2.45

[0139] The results showed that after 30 minutes of full contact with the palatal mucosa, only local mucosal damage was observed in the 7th group, with most cilia remaining intact and actively moving. The percentage of continuous ciliary movement was calculated to be 90.60%, indicating that the preparation has little effect on ciliary movement and no obvious ciliary toxicity, and can be used for nasal administration.

Claims

1. A nasal mucosal administration preparation of sodium valproate, characterized by: The preparation comprises gastrodin and sodium valproate as a medicinal component, the weight ratio of sodium valproate to gastrodin is 1:0.005-0.05, and the nasal mucosa administration preparation is a nasal drop, a spray or an aerosol.

2. The formulation of claim 1, characterized in that: The nasal mucosa administration preparation comprises sodium valproate, gastrodin, a pH regulator, an osmotic pressure regulator and a solvent, wherein the sodium valproate is provided in the form of itself or a pharmaceutically acceptable salt thereof.

3. Formulation according to claim 1 or 2, characterized in that: The content of the gastrodin in the nasal mucosa administration preparation is 0.125-1.25 wt%.

4. The formulation of claim 1, wherein: The pH of the nasal mucosa administration preparation is 4-8.

5. The formulation of claim 4, characterized in that: The pH of the nasal mucosa administration preparation is 5.0-6.

5.

6. The formulation of claim 1, wherein: The nasal mucosa administration preparation comprises a bacteriostatic agent selected from one or more of a mixture of ethyl p-hydroxybenzoate, potassium sorbate, propyl p-hydroxybenzoate, benzyl alcohol, benzalkonium chloride and benzalkonium bromide, and the mass percentage of the bacteriostatic agent in the nasal mucosa administration preparation is 0.01-0.2%.

7. The formulation of claim 2, wherein: The pH regulator is selected from any one or more of phosphoric acid, hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium citrate, phosphate buffer, acetate buffer and citrate buffer; The osmotic pressure regulator is selected from one or more of sodium chloride, glycerol, anhydrous glucose, potassium chloride, sorbitol and mannitol; The solvent is selected from one or more of ethanol, propylene glycol and purified water.

8. A method for preparing the nasal mucosal administration preparation of sodium valproate according to any one of claims 1 to 7, characterized by: The prescription amount of sodium valproate is added to a solution containing gastrodin and other components which has been previously dissolved under stirring, and the nasal mucosa administration preparation is obtained.

9. Use of the preparation according to claim 1 for the manufacture of a medicament for the treatment or prevention of psychiatric or neurological disorders, characterized in that: The mental or neurological disease is simple partial epilepsy, myoclonic epilepsy, partial epilepsy, grand mal epilepsy, mixed epilepsy, bipolar disorder or migraine.

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