A pharmaceutical composition for nasal administration of glibenclamide

Abstract

The present application relates to a pharmaceutical composition for intranasal administration of glibenclamide and a preparation method thereof, the pharmaceutical composition of glibenclamide of the present application solves the technical problem of low drug concentration in the brain and the side effect of easily causing severe hypoglycemia, the pharmaceutical composition of the present application significantly improves the solubility of the drug, realizes higher concentration in the brain without increasing the risk of hypoglycemia, improves the brain targeting, and has better compliance.

Description

[0001] This invention claims priority to the earlier application filed on November 16, 2020, with China National Intellectual Property Administration, patent application number 202011280101.0, entitled "A pharmaceutical composition for nasal administration of glibenclamide and a method for preparing the same." The entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical compositions, and more particularly, to a nasal pharmaceutical composition of glibenclamide and a method for preparing the same. Background Technology

[0003] Glibenclamide, also known as eugenol, is a sulfonylurea hypoglycemic agent. Its chemical name is N-(2-(4-(((((cyclohexylamino)carbonyl)amino)sulfonyl)phenyl)ethyl)-2-methoxy-5-chlorobenzamide. It works by inhibiting ATP-sensitive potassium channels in pancreatic islet cells, causing cell membrane depolarization and opening pressure-sensitive calcium ion channels. This allows intracellular calcium ions to permeate into the islet cells, stimulating insulin release. Recent studies have revealed that glibenclamide also has a protective effect on brain nerves.

[0004] Stroke, commonly known as apoplexy, is an acute cerebrovascular disease caused by the sudden rupture or blockage of blood vessels in the brain, leading to brain tissue damage. It is classified into ischemic stroke and hemorrhagic stroke. Ischemic stroke accounts for more than 80% of all strokes. Surveys show that stroke has become the leading cause of death in my country and the leading cause of disability among Chinese adults. Stroke is characterized by high incidence, high mortality, and high disability rates, seriously endangering human health and life. Severe stroke can cause permanent neurological damage, and if not diagnosed and treated promptly in the acute phase, it can lead to serious complications and even death. Currently, the main drug treatment for stroke is thrombolysis, but this has strict time limitations.

[0005] Recent studies have found that Sur1-Trpm4 and Sur1-Kir6.2 (K ATP Both pathways were upregulated in animal models of stroke and brain contusion. Glibenclamide can protect and repair brain nerve cells by targeting and inhibiting these two pathways, effectively reducing cerebral edema.

[0006] Currently, Biogen has completed a Phase II clinical trial of glibenclamide for stroke treatment, administered via intravenous infusion. Results showed it was effective in treating stroke, and Phase III clinical trials for stroke and Phase II clinical trials for cerebral contusion are underway. However, glibenclamide has a strong hypoglycemic effect. During intravenous stroke treatment, elevated peripheral blood glibenclamide levels can easily cause severe hypoglycemia, requiring prolonged low-flow-rate infusions to maintain low blood drug concentrations. The total dose and blood concentration are significantly lower than those in diabetic patients. Furthermore, the blood-brain barrier makes it difficult for the drug to cross and enter the brain, resulting in even lower concentrations in the target organ. All these factors contribute to glibenclamide not reaching optimal therapeutic concentrations for stroke treatment with intravenous administration, and long-term intravenous infusion also leads to poor patient compliance. Therefore, improving the brain targeting of glibenclamide to increase brain concentration without significantly increasing blood drug concentration and the risk of hypoglycemia would have significant clinical value.

[0007] In recent years, with continuous research on nasal drug delivery, it has been discovered that some drugs can bypass the blood-brain barrier (BBB) ​​and directly enter the central nervous system (CNS) via this route, exhibiting good brain targeting. This route also has advantages such as high bioavailability, minimal invasiveness, ease of use, avoidance of the first-pass effect in the liver, and rapid drug absorption. Wang Ju et al.'s research team at Shanghai Jiao Tong University found that nasal administration of glibenclamide can reach the brain and showed a certain neuroprotective effect in a brain injury model. However, whether intranasal administration of glibenclamide can improve brain targeting has not been studied or reported. Furthermore, the article used DMSO to dissolve glibenclamide, which is not a feasible formulation.

[0008] Because nasal administration involves very small volumes (generally less than 200 microliters for human administration), and because glibenclamide is weakly acidic and has poor solubility, especially under neutral and low pH conditions (its solubility in water is less than 5 μg / ml), and because the pH of nasal administration formulations should not be too high, the use of glibenclamide is greatly limited. Currently reported glibenclamide solution formulations are only suitable for routine intravenous infusion administration, and no formulations suitable for nasal administration have been developed.

[0009] Therefore, if a glibenclamide drug composition with high solubility is developed and administered via nasal route, it can significantly improve the brain targeting of glibenclamide, that is, achieve a higher brain concentration without increasing its hypoglycemic adverse reaction, which will have significant clinical value. Summary of the Invention

[0010] To address the technical problems of poor brain penetration of glibenclamide, which requires oral and intravenous administration to cross the blood-brain barrier to reach the brain, resulting in low brain drug concentrations and the risk of severe hypoglycemia in peripheral circulation, this invention provides a pharmaceutical composition for glibenclamide administration via nasal inhalation and its preparation method. This achieves higher brain drug concentrations without increasing the risk of hypoglycemia, thus improving brain targeting and making it particularly suitable for the treatment of diseases of the nervous system.

[0011] On one hand, the present invention relates to a pharmaceutical composition of glibenclamide for nasal administration, comprising, by weight, 1-30 parts of glibenclamide, 10-1000 parts of inclusion solubilizer, and 1000 parts of solvent.

[0012] In some embodiments, the weight ratio of glibenclamide to inclusion solubilizer in the pharmaceutical composition is 1:6 to 1:200, by weight parts; preferably, the weight ratio of glibenclamide to inclusion solubilizer is 1:10 to 1:200.

[0013] In some embodiments, the pharmaceutical composition contains 3-15 parts by weight of glibenclamide; preferably, the content of glibenclamide is 8-10 parts.

[0014] In some embodiments, the inclusion solubilizer is selected from one or more combinations of cyclodextrin, Tween, Span, polyoxyethylene castor oil, sodium dodecyl sulfate, and diethylene glycol monoethyl ether.

[0015] In some implementations, the inclusion solubilizer is a cyclodextrin.

[0016] In some embodiments, the cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and pharmaceutically acceptable cyclodextrin derivatives; preferably, the pharmaceutically acceptable cyclodextrin derivative is selected from one or more combinations of dimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and trimethyl-β-cyclodextrin.

[0017] In some embodiments, the cyclodextrin is selected from β-cyclodextrin and its pharmaceutically acceptable cyclodextrin derivatives; preferably, the pharmaceutically acceptable cyclodextrin derivative is selected from one or more combinations of 2-hydroxypropyl-β-cyclodextrin and 3-hydroxypropyl-β-cyclodextrin.

[0018] In some embodiments, the inclusion solubilizer content in the pharmaceutical composition is 20-800 parts by weight; preferably, the inclusion solubilizer content is 40-600 parts; more preferably, the inclusion solubilizer content is 60-400 parts.

[0019] In some embodiments, the pharmaceutical composition further includes one or more of a penetration enhancer, a stabilizer, a pH adjuster, and an antibacterial agent.

[0020] In some embodiments, the penetration enhancer is selected from one or more combinations of dodecyl-β-maltodextrin, sodium 8-(2-hydroxybenzamido)octanoate, sodium decanoate, sodium octanoate, sodium cholate, deoxycholic acid, taurideoxycholic acid, ursodeoxycholic acid, sucrose monolaurate, EDTA, sodium dodecyl sulfate, lauroylcarnitine, chitosan, and palmitoylcarnitine.

[0021] In some embodiments, the penetration enhancer is selected from one or more combinations of dodecyl-β-maltodextrin, sodium decanoate, sodium octanoate, ursodeoxycholic acid, taurine deoxycholic acid, and sodium 8-(2-hydroxybenzamido)octanoate.

[0022] In some embodiments, the penetration enhancer is selected from one or more combinations of dodecyl-β-maltodextrin, sodium decanoate, and sodium octanoate.

[0023] In some embodiments, the penetration enhancer content in the pharmaceutical composition is 0.1-10 parts by weight; preferably, the penetration enhancer content is 1-8 parts; more preferably, the penetration enhancer content is 2-5 parts.

[0024] In some embodiments, the stabilizer is selected from one or more combinations of povidone, gelatin, xanthan gum, gum arabic, tragacanth gum, dextran, sodium alginate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carbomer, and polyvinyl alcohol.

[0025] In some embodiments, the stabilizer is selected from one or more combinations of povidone, gelatin, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and carbomer.

[0026] In some embodiments, the stabilizer is selected from one or more combinations of povidone, gelatin, xanthan gum, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose.

[0027] In some embodiments, the stabilizer content in the pharmaceutical composition is 10-200 parts by weight; preferably, the stabilizer content is 50-150 parts; more preferably, the stabilizer content is 80-100 parts.

[0028] In some embodiments, the pH adjuster is selected from inorganic acids, inorganic bases, organic acids, organic bases and their buffer salt systems; preferably, the pH adjuster is selected from one or more combinations of sodium hydroxide, hydrochloric acid, glycine, hydrofluoric acid, triethylamine, acetic acid, phosphoric acid, malic acid, citric acid, acetate buffer salt, phosphate buffer salt and their aqueous solutions; preferably, the pH adjuster is selected from one or more combinations of sodium hydroxide, potassium hydroxide, hydrochloric acid, glacial acetic acid, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium bicarbonate.

[0029] In some embodiments, the antibacterial agent is selected from one or more combinations of methylparaben, propylparaben, sodium methylparaben, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, benzalkonium chloride, and chlorobutanol.

[0030] In some embodiments, the antibacterial agent is selected from one or more combinations of sodium methylparaben, sodium benzoate, benzalkonium chloride, and chlorobutanol.

[0031] In some embodiments, the antibacterial agent content in the pharmaceutical composition is 0.1-10 parts by weight; preferably, the antibacterial agent content is 0.2-5 parts; more preferably, the antibacterial agent content is 0.5-2 parts.

[0032] In some implementations, the solvent is water.

[0033] In some embodiments, the pH value of the pharmaceutical composition is 6.5-8.0.

[0034] On the other hand, the present invention also provides a method for preparing the pharmaceutical composition, comprising the following steps: weighing glibenclamide according to the prescription amount, adding inclusion solubilizer to a solvent, adjusting the pH to 10-13 using a pH adjuster, sonicating, and adjusting the pH of the pharmaceutical composition to between 7.0 and 7.5 with hydrochloric acid to obtain a nasal-administered pharmaceutical composition of glibenclamide.

[0035] In some embodiments, the preparation method further includes the step of adding one or more of a penetration enhancer, a stabilizer, and an antibacterial agent.

[0036] In some embodiments, the method for preparing the pharmaceutical composition includes the following steps: weighing glibenclamide according to the prescribed amount, adding an inclusion solubilizer to a solvent, adjusting the pH to 10-13 using a pH adjuster, sonicating, adding one or more of a penetration enhancer, a stabilizer, and an antibacterial agent, and adjusting the pH of the pharmaceutical composition to between 7.0 and 7.5 with hydrochloric acid to obtain a nasal-administered pharmaceutical composition of glibenclamide.

[0037] In some embodiments, the preparation method of the pharmaceutical composition includes the following steps: weighing glibenclamide according to the prescription amount, adding inclusion solubilizer to the solvent, adjusting the pH to 10-13 using a pH adjuster, sonicating, adjusting the pH of the pharmaceutical composition to between 7.0 and 7.5 with hydrochloric acid, and adding one or more of a penetration enhancer, a stabilizer, and an antibacterial agent to obtain a nasal pharmaceutical composition of glibenclamide.

[0038] Preferably, in the method for preparing the pharmaceutical composition, the pH adjuster adjusts the pH to 12-13.

[0039] Preferably, the pH adjuster is selected from inorganic acids, inorganic bases, organic acids, organic bases and their buffer salt systems; preferably, the pH adjuster is selected from one or more combinations of sodium hydroxide, hydrochloric acid, glycine, hydrofluoric acid, triethylamine, acetic acid, phosphoric acid, malic acid, citric acid, acetate buffer salt, phosphate buffer salt and their aqueous solutions; preferably, the pH adjuster is selected from one or more combinations of sodium hydroxide, potassium hydroxide, hydrochloric acid, glacial acetic acid, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium bicarbonate.

[0040] In some embodiments, the pharmaceutical composition is a nasal administration pharmaceutical composition.

[0041] On the other hand, the use of the pharmaceutical composition described in this invention in the treatment of nervous system diseases.

[0042] In some embodiments, the pharmaceutical composition is used in the treatment of stroke and cerebral contusion.

[0043] In some embodiments, nasal administration of the pharmaceutical composition can achieve significantly higher brain concentrations than intravenous administration, resulting in a higher brain penetration rate and brain-blood ratio, without increasing the risk of hypoglycemia.

[0044] The pharmaceutical composition of the present invention can significantly increase the brain content, increase the brain penetration rate and brain-blood ratio when administered via nasal route, thereby achieving brain targeting, without increasing the risk of hypoglycemia, and has significant clinical value.

[0045] In summary, the beneficial effects of the present invention are as follows:

[0046] (1) Compared with the prior art, the pharmaceutical composition of the present invention significantly improves the solubility of the drug, making the composition suitable for nasal administration;

[0047] (2) Compared with existing intravenous drug delivery technology, the drug composition of the present invention can significantly increase the brain content, increase the brain entry rate and brain blood ratio by nasal administration, has clear brain targeting, and does not increase the risk of hypoglycemia. It effectively avoids the technical problem of low brain drug concentration caused by hypoglycemia when intravenously injecting drugs to treat neurological diseases such as stroke and brain contusion.

[0048] (3) Nasal administration of the present invention has better compliance than long-term intravenous infusion, does not damage the body barrier, and has better safety. Attached Figure Description

[0049] Unless otherwise defined in this invention, the scientific and technical terms associated with this invention shall have the meanings understood by one of ordinary skill in the art.

[0050] Figure 1 The figure shows the blood concentration-time curves of glibenclamide in rats after administration via different routes of administration.

[0051] Figure 2 The figure shows the distribution-time curves of brain tissue in rats after administration of glibenclamide via different routes of administration. Detailed Implementation

[0052] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer with the description. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0053] The embodiments of the present invention are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0054] Example 1

[0055] Weigh out glibenclamide and 2-hydroxypropyl-β-cyclodextrin according to the prescription amount and add them to purified water. Adjust the pH to 12.0 with 2 mol / L sodium hydroxide, sonicate for 15 min, add the prescribed amount of dodecyl-β-maltodextrin to dissolve, and adjust the pH of the sample to between 7.0 and 7.5 with 1 mol / L hydrochloric acid to obtain a pharmaceutical composition of glibenclamide for nasal administration.

[0056] Table 1. Pharmaceutical composition formulations of glibenclamide for nasal administration.

[0057] composition effect Dosage (mg) Glibenclamide principal component 8 2-Hydroxypropyl-β-cyclodextrin Solubilization and inclusion 60 Dodecyl-β-maltodextrin Promote penetration 3 Purified water solvent 1000

[0058] Example 2

[0059] Weigh out glibenclamide and 2-hydroxypropyl-β-cyclodextrin according to the prescription and add them to purified water. Adjust the pH to 12.0 with 2 mol / L sodium hydroxide, sonicate for 15 min, add the prescribed amount of dodecyl-β-maltodextrin and PVPK30 to dissolve, and adjust the sample pH to between 7.0 and 7.5 with 1 mol / L hydrochloric acid to obtain a pharmaceutical composition of glibenclamide for nasal administration.

[0060] Table 2. Pharmaceutical composition formulations of glibenclamide for nasal administration.

[0061] composition effect Dosage (mg) Glibenclamide principal component 10 2-Hydroxypropyl-β-cyclodextrin Solubilization and inclusion 100 Dodecyl-β-maltodextrin Promote penetration 3 PVPK30 Stablize 100 Purified water solvent 1000

[0062] Example 3

[0063] Weigh out glibenclamide and 2-hydroxypropyl-β-cyclodextrin according to the prescription and add them to purified water. Adjust the pH to 13.0 with 2 mol / L sodium hydroxide, sonicate for 15 min, add sodium decanoate and hydroxypropyl methylcellulose according to the prescription and dissolve. Adjust the pH of the sample to between 7.0 and 7.5 with 1 mol / L hydrochloric acid, add sodium methylparaben according to the prescription and dissolve to obtain the pharmaceutical composition of glibenclamide for nasal administration.

[0064] Table 3. Pharmaceutical composition formulations for glibenclamide for nasal administration.

[0065] composition effect Dosage (mg) Glibenclamide principal component 10 2-Hydroxypropyl-β-cyclodextrin Solubilization and inclusion 100 Sodium decanoate Promote penetration 3 Hydroxypropyl methylcellulose Stablize 80

[0066] Sodium methylparaben Antibacterial 2 Purified water solvent 1000

[0067] Example 4

[0068] Weigh out glibenclamide and 2-hydroxypropyl-β-cyclodextrin according to the prescription amount and add them to purified water. Adjust the pH to 12.0 with 2 mol / L sodium hydroxide, sonicate for 15 min, adjust the pH of the sample to between 7.0 and 7.5 with 1 mol / L hydrochloric acid, add the prescribed amount of sodium benzoate to dissolve, and prepare a pharmaceutical composition of glibenclamide for nasal administration.

[0069] Table 4. Pharmaceutical composition formulations of glibenclamide for nasal administration.

[0070] composition effect Dosage (mg) Glibenclamide principal component 3 2-Hydroxypropyl-β-cyclodextrin Solubilization and inclusion 400 Sodium benzoate Antibacterial 0.5 Purified water solvent 1000

[0071] Example 5

[0072] Weigh out glibenclamide and 2-hydroxypropyl-β-cyclodextrin according to the prescription and add them to purified water. Adjust the pH to 12.0 with 2 mol / L sodium hydroxide, sonicate for 15 min, add the prescribed amount of sodium caprylate to dissolve, adjust the pH of the sample to between 7.0 and 7.5 with 1 mol / L hydrochloric acid, add the prescribed amount of sodium benzoate to dissolve, and obtain the pharmaceutical composition of glibenclamide for nasal administration.

[0073] Table 5. Pharmaceutical composition formulations for glibenclamide for nasal administration.

[0074] composition effect Dosage (mg) Glibenclamide principal component 6 2-Hydroxypropyl-β-cyclodextrin Solubilization and inclusion 200 Sodium benzoate Antibacterial 0.5 Sodium caprylate Promote penetration 2 Purified water solvent 1000

[0075] Comparative Example 1

[0076] Weigh out the prescribed amount of glibenclamide mixed with 2-hydroxypropyl-β-cyclodextrin and add it to purified water. Adjust the pH to 13.0 with 2 mol / L sodium hydroxide, sonicate for 15 min, and then adjust the pH of the sample to 6.0 with 1 mol / L hydrochloric acid.

[0077] Table 6. Pharmaceutical composition formulations of glibenclamide for nasal administration.

[0078] composition effect Dosage (mg) Glibenclamide principal component 4 2-Hydroxypropyl-β-cyclodextrin Solubilization and inclusion 60 Purified water solvent 1000

[0079] Experimental results: The preparation was in a white suspension state with a solution concentration of 1.03 mg / ml.

[0080] Conclusion: When neutralized to pH 6.0, glibenclamide precipitates out at a low concentration, indicating that glibenclamide has low solubility at pH 6.0.

[0081] Comparative Example 2

[0082] Preparation of glibenclamide injection: Weigh 20 mg of glibenclamide, add dimethyl sulfoxide (DMSO) to 10 ml to prepare a 2 mg / ml stock solution, and then dilute with physiological saline to a 0.02 mg / ml solution.

[0083] Pharmacokinetic characteristics:

[0084] (1) Plasma pharmacokinetic study of glibenclamide administered intranasally in normal rats

[0085] Eleven healthy SD rats, with normal drinking water and diet, were randomly divided into three groups: Group B1 (n=3 rats), in which 10 μl of the glibenclamide drug composition of Example 1 was instilled into each nostril while the rats were awake, and 250 μl of blood was collected from the jugular venous plexus before administration and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration; Group C1 (n=4 rats), in which 10 μl of the glibenclamide drug composition of Example 2 was instilled into each nostril while the rats were awake; and Group A1 (n=4 rats), in which glibenclamide injection of Comparative Example 2 was injected via the tail vein at a dose of 0.1 mg / kg, and 250 μl of blood was collected from the jugular venous plexus before administration and at 0.083 h, 0.33 h, 0.67 h, 1 h, 2 h, 4 h, 8 h, 10 h, and 24 h after administration.

[0086] All blood samples were placed in 1.5 mL anticoagulant tubes coated with EDTA-K2, centrifuged at 12000 rpm for 5 min, and then plasma was collected. The concentration of glibenclamide in the plasma at different time points was determined using liquid chromatography-mass spectrometry (LC-MS), and a drug-time curve was plotted. Figure 1 The main pharmacokinetic parameters were calculated using WinNonLin software (Table 7).

[0087] Table 7. Pharmacokinetic parameters of glibenclamide in rat plasma of each group (Mean ± SD, n = 3, 4)

[0088] parameter unit Group B1 Group C1 Group A1 <![CDATA[t 1 / 2z ]]> h 30.25±32.03 6.57±1.09 5.85±0.97 <![CDATA[T max ]]> h 8.00±NA 7.33±NA 0.08±NA <![CDATA[C max ]]> ng / mL 60.43±17.02 107.51±36.29 90.08±4.78 <![CDATA[AUC last ]]> h*ng / mL 870.10±323.42 1351.88±112.37 263.44±80.68 <![CDATA[AUC INF ]]> h*ng / mL 1582.38±561.91 1485.99±152.93 287.82±63.94 Vz / F mL / kg 11587.43±9454.19 5086.07±354.67 3041.01±756.29 Cl / F mL / h / kg 336.48±141.47 542.14±55.16 364.44±102.27 <![CDATA[MRT last ]]> h 9.40±1.05 8.06±1.03 5.46±1.44

[0089] (2) Study on the brain tissue distribution of glibenclamide administered intranasally in normal rats

[0090] Forty-two healthy SD rats, with normal access to water and food, were randomly divided into three groups of three rats each at each time point:

[0091] Group B2 consisted of 6 rats. In an conscious state, 10 μl of the glibenclamide drug composition of Example 1 was instilled into each nostril. Brain tissue was collected at 0.25 h and 1 h after administration, and blood glucose was measured at 0.25 h. Blood vessels were removed from the brain tissue, water was absorbed, and homogenization was performed. The concentration of glibenclamide in the brain tissue was determined by liquid chromatography-mass spectrometry (LC-MS / MS) (Table 8).

[0092] Group C2 consisted of 18 rats. While the rats were awake, 10 μl of the glibenclamide drug composition of Example 2 was instilled into each nostril. Group A2 consisted of 18 rats. The rats were injected with glibenclamide injection of Comparative Example 2 via the tail vein at a dose of 0.1 mg / kg. Blood glucose and jugular venous plexus blood samples were measured before administration. Blood samples were collected from the jugular venous plexus, blood glucose was measured, and brain tissue was collected at 0.25 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration.

[0093] The concentrations of glibenclamide in plasma and brain tissue were determined using liquid chromatography-mass spectrometry (LC-MS / MS) (Table 8). Figure 2 ), and calculate the brain-blood ratio (Table 9).

[0094] Table 8. Glibenclamide concentration and blood glucose levels in brain homogenates of rats in each group at different time points (Mean±SD, n=3)

[0095]

[0096] Note: BQL is 0.15 ng / g below the lower limit of quantification.

[0097] Table 9. Concentration ratio of glibenclamide in brain tissue and plasma of rats at different time points (Mean±SD, n=3, %)

[0098] Time (h) Group B2 Group C2 Group A2 0.25 6.58±4.17 1.39±0.26 0.65±0.10 1 3.51±1.08 1.19±0.28 0.45±NA 2 / 1.18±0.83 0.29±NA 4 / 1.14±0.34 / 8 / 0.97±0.04 / 24 / 0.43±NA /

[0099] Analysis of the results in the table above shows that, compared with the existing injectable A2 group, the concentration of glibenclamide in brain tissue at various time points after intranasal administration significantly increased by 4-10 times (Table 8). Figure 2 The brain-to-blood ratio increased by 2 times or more at each time point (Table 9), indicating that glibenclamide has a direct nasal-brain transport pathway and significant brain targeting. Simultaneously, blood drug concentration was correlated with the occurrence of hypoglycemia, combined with plasma pharmacokinetic characteristics (Table 7). Figure 1 ) and blood glucose levels (Table 8), C in group B1 administered via nasal administration max The C1 group had lower C levels than the intravenous administration group. max The lowest blood glucose levels in groups B2 and C2 were slightly higher than those in the intravenous administration group, but these values ​​were also higher, indicating that the risk of hypoglycemia after nasal administration of the glibenclamide pharmaceutical composition of the present invention is not higher than that after intravenous administration. Therefore, compared with the intravenous administration group, the nasal administration of glibenclamide pharmaceutical composition of the present invention can significantly increase the amount of drug entering the brain, increase the brain entry rate and brain-blood ratio, and improve brain targeting, while not increasing the hypoglycemic side effect caused by glibenclamide in peripheral blood, and is expected to have significant clinical application value.

Claims

1. A pharmaceutical composition for glibenclamide, characterized in that, By weight, it consists of 8 parts glibenclamide, 60 parts inclusion solubilizer, 1000 parts solvent, 3 parts penetration enhancer and pH adjuster; The inclusion solubilizer is selected from 2-hydroxypropyl-β-cyclodextrin; The solvent is water; The penetration enhancer is dodecyl-β-maltoside; The pH adjuster is sodium hydroxide and hydrochloric acid; the pH value of the pharmaceutical composition is 7.0-7.

5.

2. A method for preparing the pharmaceutical composition according to claim 1, characterized in that, Includes the following steps: Weigh out glibenclamide and inclusion solubilizer according to the prescription and add them to the solvent. Adjust the pH to 10-13 using sodium hydroxide as a pH adjuster, sonicate, add a penetration enhancer, and adjust the pH of the drug composition to between 7.0 and 7.5 with hydrochloric acid to obtain a nasal drug composition of glibenclamide.

3. A method for preparing the pharmaceutical composition according to claim 2, characterized in that, Includes the following steps: Weigh out glibenclamide and inclusion solubilizer according to the prescription and add them to the solvent. Adjust the pH to 12 using sodium hydroxide as a pH adjuster, sonicate, add a penetration enhancer, and adjust the pH of the drug composition to between 7.0 and 7.5 with hydrochloric acid to obtain a nasal drug composition of glibenclamide.

4. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for treating nervous system diseases.

5. The use according to claim 4, wherein the neurological disease is selected from stroke or cerebral contusion.

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