WO2022100737A1 - Pharmaceutical composition for nasal administration of glyburide and preparation method therefor - Google Patents

Pharmaceutical composition for nasal administration of glyburide and preparation method therefor Download PDF

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WO2022100737A1
WO2022100737A1 PCT/CN2021/130723 CN2021130723W WO2022100737A1 WO 2022100737 A1 WO2022100737 A1 WO 2022100737A1 CN 2021130723 W CN2021130723 W CN 2021130723W WO 2022100737 A1 WO2022100737 A1 WO 2022100737A1
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glyburide
pharmaceutical composition
parts
sodium
combination
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PCT/CN2021/130723
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French (fr)
Chinese (zh)
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杨磊
林巧平
杨少宁
翟慧
黄琦
王鹏
任晋生
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江苏先声药业有限公司
海南先声药业有限公司
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Priority to CN202180076959.1A priority Critical patent/CN116635035A/en
Publication of WO2022100737A1 publication Critical patent/WO2022100737A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • the present invention requires the prior patent application number 202011281755.5, which was submitted to the State Intellectual Property Office of China on November 16, 2020, and the name of the invention is "a pharmaceutical composition for nasal administration of glyburide and its preparation method" the priority of the application.
  • the entire contents of the aforementioned prior application are incorporated herein by reference.
  • the present invention relates to the field of pharmaceutical compositions, in particular, to a pharmaceutical composition for nasal administration of glyburide and a preparation method thereof.
  • Glyburide also known as excellent hypoglycemic, Daan therapy, Daanning, ethyl sulfonylurea, yuglukang, chlorosulfonyl cyclohexyl urea.
  • the chemical name is N-(2-(4-((((cyclohexylamino)carbonyl)amino)sulfonyl)phenyl)ethyl)-2-methoxy-5-chlorobenzamide, which is a sulfonic acid Urea hypoglycemic drugs, by inhibiting the ATP-sensitive potassium channel of pancreatic islet cells, depolarize the cell membrane and open the pressure-sensitive calcium ion channel, causing intracellular calcium ions to penetrate into islet cells and stimulate the release of insulin.
  • glyburide can promote the protection of cranial nerves.
  • Stroke commonly known as stroke, is an acute cerebrovascular disease. It is a group of diseases that damage brain tissue due to the sudden rupture of blood vessels in the brain or the inability of blood to flow into the brain due to vascular obstruction. It is divided into ischemic stroke and hemorrhagic stroke. Among them, ischemic stroke accounts for more than 80% of strokes. The survey shows that stroke has become the first cause of death in my country and the leading cause of disability among Chinese adults. At the same time, stroke has the characteristics of high morbidity, high mortality and high disability rate, which seriously endangers human health and safety. Severe stroke can cause permanent neurological damage, and if not diagnosed and treated in time in the acute phase, serious complications and even death can result. The current drug treatment for stroke is mainly through thrombolysis, but it has a strict time limit.
  • Sur1-Trpm4 and Sur1-Kir6.2 (K ATP ) pathways are up-regulated in animal models such as stroke and cerebral contusion. Glyburide can inhibit these two pathways by targeting. It can protect and repair nerve cells in the brain and effectively reduce cerebral edema.
  • Biogen has completed the phase II clinical trial of glyburide in the treatment of stroke. It is administered by intravenous drip. The results show that it can effectively treat stroke, and phase III clinical research for stroke has been carried out. and a phase II clinical study of cerebral contusion.
  • Glyburide has a strong hypoglycemic effect. In the process of treating stroke by intravenous injection, the increase of Glyburide in peripheral blood can easily cause serious adverse reactions of hypoglycemia.
  • the total dose and blood drug concentration are significantly smaller than the corresponding dose and concentration in diabetic patients; at the same time, due to the existence of the blood-brain barrier, the drug is difficult to Entering the brain through the blood-brain barrier, the drug concentration in the target organ is lower.
  • the above reasons all lead to the intravenous administration of glyburide far from reaching the optimal drug concentration for the treatment of stroke, and the long-term intravenous infusion of patients Compliance is also poor. Therefore, improving the brain targeting of glyburide and achieving an increase in the brain concentration of the drug without significantly increasing the blood concentration and the risk of hypoglycemia will have significant clinical value.
  • the volume of nasal administration is very small (the general administration volume of the human body is less than 200 microliters), while glyburide is weakly acidic and has poor solubility, especially in neutral and low pH conditions, the solubility is extremely low, and the solubility in water It is less than 5 ⁇ g/ml, and the pH of the preparation for nasal administration should not be too high, which greatly limits the use of glyburide.
  • the reported solution preparation of glyburide is only suitable for routine intravenous administration, and there is no Development of formulations that can be used for nasal administration.
  • the brain targeting of glyburide can be significantly improved by nasal administration, i.e., it can reach a higher level without increasing its adverse effect of hypoglycemia.
  • the brain concentration will have significant clinical value.
  • the present invention provides a pharmaceutical composition for nasal administration of glyburide and a preparation method thereof, which can achieve higher drug concentration in the brain without increasing the risk of hypoglycemia, that is, increase the risk of hypoglycemia.
  • Brain targeting will be particularly suitable for the treatment of diseases of the nervous system.
  • the present invention relates to a pharmaceutical composition of glyburide for nasal administration, comprising glyburide, diethylene glycol monoethyl ether, and a solubilizing solvent.
  • the pharmaceutical composition in parts by weight, comprises 0.1-50 parts of glyburide, 1-5000 parts of diethylene glycol monoethyl ether, and 1-1000 parts of solubilizer.
  • the pharmaceutical composition in parts by weight, comprises 0.5-40 parts of glyburide; preferably, 2-20 parts of glyburide.
  • the pharmaceutical composition in parts by weight, comprises 100-4000 parts of diethylene glycol monoethyl ether; preferably, 200-1000 parts of diethylene glycol monoethyl ether.
  • the solubilizing solvent is selected from a combination of one or more of propylene glycol, polyethylene glycol, ethanol, isopropanol, and glycerin.
  • the solubilizing solvent is selected from a combination of one or more of propylene glycol, polyethylene glycol, and ethanol.
  • the pharmaceutical composition in parts by weight, contains 5-1000 parts of a solubilizing solvent, more preferably, 50-800 parts of a solubilizing solvent.
  • the pharmaceutical composition further contains a combination of one or more of a penetration enhancer and a stabilizer.
  • the penetration enhancer is selected from dodecyl- ⁇ -maltoside, sodium 8-(2-hydroxybenzamido)caprylate, sodium caprate, sodium caprylate, sodium cholate, deoxy One or more of cholic acid, ursodeoxycholic acid, taurodeoxycholic acid, sucrose monolaurate, EDTA, sodium lauryl sulfate, lauroylcarnitine, chitosan, palmitoylcarnitine combination of species.
  • the penetration enhancer is selected from one or more of dodecyl- ⁇ -maltoside, sodium caprate, sodium caprylate, sodium cholate, deoxycholic acid, and ursodeoxycholic acid combination of species.
  • the penetration enhancer is selected from a combination of one or more of dodecyl- ⁇ -maltoside, sodium caprate, and ursodeoxycholic acid.
  • the content of the penetration enhancer in parts by weight, in the pharmaceutical composition, is 0.1-10 parts; preferably, the content of the penetration enhancer is 1-5 parts; more Preferably, the content of the penetration enhancer is 2-3 parts.
  • the stabilizer is selected from the group consisting of povidone, gelatin, xanthan gum, acacia, tragacanth, dextran, sodium alginate, sodium carboxymethylcellulose, hypromellose A combination of one or more of cellulose, hydroxypropyl cellulose, methyl cellulose, carbomer, and polyvinyl alcohol.
  • the stabilizer is selected from a combination of one or more of povidone, gelatin, xanthan gum, sodium carboxymethylcellulose, hydroxypropylcellulose, and hypromellose .
  • the stabilizer is selected from a combination of one or more of povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, and hypromellose.
  • the pharmaceutical composition in parts by weight, contains 0.5-200 parts of stabilizer; preferably, 1-100 parts of stabilizer; more preferably, 10-80 parts of stabilizer.
  • the present invention relates to a preparation method of the described pharmaceutical composition: take the diethylene glycol monoethyl ether and the solubilizing solvent of the recipe and mix them uniformly, add the recipe amount of glyburide to ultrasonically dissolve, and get .
  • the preparation method further includes the step of adding a combination of one or more of a penetration enhancer and a stabilizer.
  • the pharmaceutical composition is a pharmaceutical composition for nasal administration.
  • the use of the pharmaceutical composition in stroke, brain contusion in stroke, brain contusion.
  • the intranasal administration of the pharmaceutical composition can achieve significantly higher levels in the brain than when administered intravenously, with a higher brain entry rate and cerebral blood ratio, without increasing Risk of hypoglycemia.
  • the pharmaceutical composition of the present invention can significantly improve the brain content of the drug, increase the brain entry rate and the cerebral blood ratio through nasal administration, achieve brain targeting without increasing the risk of hypoglycemia, and has significant clinical value.
  • the pharmaceutical composition of the present invention significantly improves the solubility of the drug, so that the composition is suitable for nasal administration;
  • the pharmaceutical composition of the present invention can significantly improve the intracerebral content of the drug, increase the brain entry rate and the cerebral blood ratio through nasal administration, and has a clear brain target It is tropic and does not increase the risk of hypoglycemia, which effectively avoids the technical problem of low drug concentration in the brain caused by the risk of hypoglycemia when intravenous injection is used in the treatment of stroke, brain contusion and other neurological diseases;
  • the nasal administration of the present invention has better compliance, does not damage the body barrier, and has better safety.
  • composition effect Dosage (mg) Glyburide main ingredient 16 Transcutol P solvent 900 Propylene Glycol Solubilizer 100 dodecyl-beta-maltoside Penetration enhancer 3
  • composition effect Dosage (mg) Glyburide main ingredient 8 Transcutol P solvent 900 Propylene Glycol Solubilizer 100 dodecyl-beta-maltoside Penetration enhancer 3
  • the Transcutol P and propylene glycol of the recipe quantity are weighed and mixed uniformly, the glyburide of the recipe quantity is added for ultrasonic dissolving, the sodium caprate of the recipe quantity is added and stirred to dissolve to obtain the glyburide nasal administration preparation.
  • composition effect Dosage (mg) Glyburide main ingredient 15 Transcutol P solvent 900 Propylene Glycol Solubilizer 100 Sodium caprate Penetration enhancer 3
  • the Transcutol P and dehydrated alcohol of the recipe quantity were weighed and mixed uniformly, and the glyburide of the recipe quantity was added for ultrasonic dissolution to obtain the glyburide nasal administration preparation.
  • composition effect Dosage (mg) Glyburide main ingredient 6 anhydrous ethanol Solubilizer 200 Transcutol P solvent 800 Hypromellose stabilizer 50
  • the Transcutol P of the recipe quantity was weighed, and the glyburide of the recipe quantity was added for ultrasonic dissolution to obtain the glyburide nasal administration preparation.
  • composition effect Dosage (mg) Glyburide main ingredient 10 Transcutol P solvent 700 polyethylene glycol 400 Solubilizer 300 Ursodeoxycholic acid Penetration enhancer 3
  • glyburide injection Weigh 20 mg of glyburide, add dimethyl sulfoxide (DMSO) to 10 ml, prepare 2 mg/ml stock solution, and then dilute to 0.02 mg/ml medicinal solution with normal saline.
  • DMSO dimethyl sulfoxide
  • B1 group 4 rats were instilled in the left and right nasal cavity of 10 ⁇ l of the drug combination of Example 1 in the awake state.
  • group A1 4 rats were injected with the pharmaceutical composition of Glyburide of Comparative Example 2 via tail vein at a dose of 0.1 mg/kg, before administration and at 0.083h, 0.33h, and 0.67h after administration.
  • 1h, 2h, 4h, 8h, 10h, 24h to take 250 ⁇ l of blood from the jugular venous plexus;
  • group C1 6 rats were instilled 3 ⁇ l of the pharmaceutical composition of Glyburide of Example 1 in the left and right nasal cavities in the awake state.
  • group D1 group 6 rats were instilled in the left and right nasal cavities in the awake state.
  • the pharmaceutical composition of glyburide in Example 2 250 ⁇ l of blood was collected from the jugular venous plexus before administration and at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration.
  • group B2 18 rats were instilled 10 ⁇ l of the pharmaceutical composition of Glyburide of Example 1 into each of the left and right nasal cavities while awake.
  • group A2 18 rats were injected with Glyburide of Comparative Example 2 through the tail vein.
  • the pharmaceutical composition of the drug was measured at a dose of 0.1 mg/kg, and blood glucose and jugular venous plexus blood were measured before administration. blood sugar, brain tissue;
  • group C2 12 rats were instilled 3 ⁇ l of the pharmaceutical composition of Glyburide of Example 1 in each of the left and right nasal cavities when they were awake.
  • group D2 12 rats were instilled in 6 ⁇ l in each of the left and right nasal cavities when they were awake.
  • blood glucose and jugular venous plexus blood were measured before administration, and 0.25h, 1h, 4h, and 24h were followed by jugular venous plexus blood collection, blood sugar measurement, and brain collection. organize.
  • the concentration of glyburide in plasma and brain tissue was determined by LC/MS method (Table 9), and the cerebral blood ratio was calculated (Table 10).
  • the concentration of the pharmaceutical composition of glyburide in the brain tissue at each time point after nasal administration significantly increased to 1.6-24%. times (Table 9), the brain-to-blood ratio at each time point increased to 1.3-3 times (Table 10), indicating that there is a nasal-brain direct transport pathway for glyburide and has significant brain targeting.
  • the blood drug concentration is associated with the occurrence of hypoglycemia. Combined with the plasma pharmacokinetic characteristics (Table 8) and blood glucose value (Table 9), hypoglycemia may occur due to excessive blood drug concentration in group B1 after nasal administration.
  • the pharmaceutical composition for nasal administration of glyburide of the present invention can significantly increase the amount of the drug entering the brain, increase the rate of brain entry and the cerebral blood ratio, and improve the brain targeting ability.
  • the hypoglycemia side effects caused by glyburide in peripheral blood can not be increased, and it is expected to have significant clinical application value.

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Abstract

The present invention relates to a pharmaceutical composition for the nasal administration of glyburide and a preparation method therefor, the glyburide pharmaceutical composition of the present invention solves the technical problems in which the drug concentration within the brain is relatively low and the side effect of severe hypoglycemia can easily occur. The pharmaceutical composition of the present invention significantly improves drug solubility, achieving a higher concentration within the brain without increasing the risk of hypoglycemia, improves brain targeting, and has better compliance.

Description

一种格列本脲的经鼻给药的药物组合物及其制备方法A kind of pharmaceutical composition for nasal administration of glyburide and preparation method thereof
本发明要求2020年11月16日向中国国家知识产权局提交的，专利申请号为202011281755.5，发明名称为“一种格列本脲的经鼻给药的药物组合物及其制备方法”的在先申请的优先权。上述在先申请的全文通过引用的方式结合于本发明中。The present invention requires the prior patent application number 202011281755.5, which was submitted to the State Intellectual Property Office of China on November 16, 2020, and the name of the invention is "a pharmaceutical composition for nasal administration of glyburide and its preparation method" the priority of the application. The entire contents of the aforementioned prior application are incorporated herein by reference.
技术领域technical field
本发明涉及药物组合物领域，具体而言，涉及格列本脲的经鼻给药的药物组合物及其制备方法。The present invention relates to the field of pharmaceutical compositions, in particular, to a pharmaceutical composition for nasal administration of glyburide and a preparation method thereof.
背景技术Background technique
格列本脲，又名优降糖、达安疗、达安宁、乙磺己脲、优格鲁康、氯磺环己脲。化学名为N-(2-(4-((((环己氨基)羰基)氨基)磺酰基)苯基)乙基)-2-甲氧基-5-氯苯甲酰胺，是一种磺酰脲类降糖药，通过抑制胰岛细胞的ATP敏感钾通道，使细胞膜去极化、打开压敏钙离子通道，导致细胞内的钙离子渗透到胰岛细胞，刺激胰岛素的释放。近些年来，随着对其药理作用的更深层次研究发现，格列本脲对脑神经的保护具有促进作用。Glyburide, also known as excellent hypoglycemic, Daan therapy, Daanning, ethyl sulfonylurea, yuglukang, chlorosulfonyl cyclohexyl urea. The chemical name is N-(2-(4-((((cyclohexylamino)carbonyl)amino)sulfonyl)phenyl)ethyl)-2-methoxy-5-chlorobenzamide, which is a sulfonic acid Urea hypoglycemic drugs, by inhibiting the ATP-sensitive potassium channel of pancreatic islet cells, depolarize the cell membrane and open the pressure-sensitive calcium ion channel, causing intracellular calcium ions to penetrate into islet cells and stimulate the release of insulin. In recent years, with further research on its pharmacological effects, it has been found that glyburide can promote the protection of cranial nerves.
脑卒中，俗称中风，一种急性脑血管疾病，是由于脑部血管突然破裂或因血管阻塞导致血液不能流入大脑而引起脑组织损伤的一组疾病，分为缺血性卒中和出血性卒中。其中，缺血性脑卒中占到脑卒中的80％以上。调查显示，脑卒中已成为我国第一位死亡原因，也是中国成年人残疾的首要原因，同时脑卒中具有发病率高、死亡率高和致残率高的特点，严重危害了人体健康生命安全。严重脑卒中可造成永久性神经损伤，急性期如果不及时诊断和治疗可造成严重的并发症，甚至死亡。目前对于脑卒中的药物治疗主要通过溶栓，但是具有严格的时间限制。Stroke, commonly known as stroke, is an acute cerebrovascular disease. It is a group of diseases that damage brain tissue due to the sudden rupture of blood vessels in the brain or the inability of blood to flow into the brain due to vascular obstruction. It is divided into ischemic stroke and hemorrhagic stroke. Among them, ischemic stroke accounts for more than 80% of strokes. The survey shows that stroke has become the first cause of death in my country and the leading cause of disability among Chinese adults. At the same time, stroke has the characteristics of high morbidity, high mortality and high disability rate, which seriously endangers human health and safety. Severe stroke can cause permanent neurological damage, and if not diagnosed and treated in time in the acute phase, serious complications and even death can result. The current drug treatment for stroke is mainly through thrombolysis, but it has a strict time limit.
近些年研究发现，Sur1-Trpm4和Sur1-Kir6.2(K ATP)两条通路在脑卒中、脑挫伤等动物模型中的表达均有上调，格列本脲能够通过靶向抑制这两条通路，从而对脑内神经细胞产生保护与修复作用，有效减轻脑水肿。 In recent years, studies have found that the expressions of Sur1-Trpm4 and Sur1-Kir6.2 (K ATP ) pathways are up-regulated in animal models such as stroke and cerebral contusion. Glyburide can inhibit these two pathways by targeting. It can protect and repair nerve cells in the brain and effectively reduce cerebral edema.
目前，Biogen公司已经完成格列本脲治疗脑卒中的II期临床试验，其通过静脉滴注的方式进行给药，结果显示能够有效地治疗脑卒中，并且已正在开展脑卒中的Ⅲ期临床研究和脑挫伤的Ⅱ期临床研究。但是，格列本脲具有较强的降血糖的作用，在通过静注的方式治疗脑卒中的过程中，外周血中格列本脲含量升高极容易引起低血糖的严重不良反应，因此需长时间低流速滴注来将血药浓度控制在较低水平，总的给药剂量和血药浓度均显著小于在糖尿病人中对应的剂量和浓度；同时由于血脑屏障的存在，药物很难透过血脑屏障进入脑内，靶器官中药物浓度更低，以上原因均导致静脉给药方式下格列本脲远未达到治疗卒中的最佳药效浓度，并且静脉长期滴注的方式患者依从性也较差。因此，提高格列本脲脑靶向性，实现药物脑内浓度增加的同时不显著增加血药浓度和低血糖风险，将具有显著的临床价值。At present, Biogen has completed the phase II clinical trial of glyburide in the treatment of stroke. It is administered by intravenous drip. The results show that it can effectively treat stroke, and phase III clinical research for stroke has been carried out. and a phase II clinical study of cerebral contusion. However, Glyburide has a strong hypoglycemic effect. In the process of treating stroke by intravenous injection, the increase of Glyburide in peripheral blood can easily cause serious adverse reactions of hypoglycemia. Therefore, it is necessary to Long-term low-flow infusion to control the blood drug concentration at a low level, the total dose and blood drug concentration are significantly smaller than the corresponding dose and concentration in diabetic patients; at the same time, due to the existence of the blood-brain barrier, the drug is difficult to Entering the brain through the blood-brain barrier, the drug concentration in the target organ is lower. The above reasons all lead to the intravenous administration of glyburide far from reaching the optimal drug concentration for the treatment of stroke, and the long-term intravenous infusion of patients Compliance is also poor. Therefore, improving the brain targeting of glyburide and achieving an increase in the brain concentration of the drug without significantly increasing the blood concentration and the risk of hypoglycemia will have significant clinical value.
近年来随着对经鼻给药的不断研究，发现部分药物可以通过此给药途径绕过血脑屏障(blood brain barrier，BBB)直接进入中枢神经(Central Nervous System，CNS)，具有良好的脑靶向性，并且该途径还具有生物利度较高、损伤性小、使用方便、避免肝脏首过效应、药物吸收迅速等优点。王矩等上海交通大学的研究团队发现经鼻给予格列本脲后可以到达脑部，并在脑损伤模型中表现出一定的神经保护作用，但对于鼻腔给予格列本脲是否可以提高 脑靶向未作研究和报道，同时该文章中采用的是DMSO溶解格列本脲，并不是一种可行的制剂处方。In recent years, with the continuous research on nasal administration, it has been found that some drugs can bypass the blood brain barrier (BBB) and directly enter the central nervous system (CNS) through this route of administration. Targeting, and this approach also has the advantages of high bioavailability, less damage, convenient use, avoidance of liver first-pass effect, and rapid drug absorption. The research team from Shanghai Jiaotong University such as Wang Ju and others found that glyburide can reach the brain after intranasal administration, and showed a certain neuroprotective effect in a brain injury model, but whether intranasal administration of glyburide can improve the brain target No research or report was made to Xiang, and the article used DMSO to dissolve glyburide, which is not a feasible formulation.
由于鼻腔给药的体积很小(人体一般给药体积小于200微升)，而格列本脲呈弱酸性，溶解度差，尤其是在中性和低pH条件下溶解度极低，在水中的溶解度低于5μg/ml，另外由于鼻腔给药制剂pH不宜过高，大大限制了格列本脲的使用，目前已报道的格列本脲溶液制剂只适用于常规的静脉滴注给药，尚未有可用于鼻腔给药的制剂开发。Because the volume of nasal administration is very small (the general administration volume of the human body is less than 200 microliters), while glyburide is weakly acidic and has poor solubility, especially in neutral and low pH conditions, the solubility is extremely low, and the solubility in water It is less than 5μg/ml, and the pH of the preparation for nasal administration should not be too high, which greatly limits the use of glyburide. The reported solution preparation of glyburide is only suitable for routine intravenous administration, and there is no Development of formulations that can be used for nasal administration.
因此，如果开发一种具有高溶解度的格列本脲药物组合物，采用经鼻给药能显著提高格列本脲的脑靶向性，即在不增加其低血糖不良反应的同时达到更高的脑内浓度，将会有着显著的临床价值。Therefore, if a pharmaceutical composition of glyburide with high solubility is developed, the brain targeting of glyburide can be significantly improved by nasal administration, i.e., it can reach a higher level without increasing its adverse effect of hypoglycemia. The brain concentration will have significant clinical value.
发明内容SUMMARY OF THE INVENTION
针对目前格列本脲的透脑率差，口服和静脉注射给药后药物需要通过血脑屏障才能入脑，从而导致脑内药物浓度低且外周循环***中的格列本脲易引起严重低血糖的副作用的技术问题，本发明提供了一种用于经鼻给药的格列本脲的药物组合物及其制备方法，实现脑内更高药物浓度的同时不增加低血糖风险，即提高脑靶向性，将特别适用于神经***的疾病的治疗。In view of the current poor brain penetration rate of glyburide, after oral and intravenous administration, the drug needs to pass through the blood-brain barrier to enter the brain, resulting in low drug concentration in the brain and glyburide in the peripheral circulatory system. The technical problem of side effects of blood sugar, the present invention provides a pharmaceutical composition for nasal administration of glyburide and a preparation method thereof, which can achieve higher drug concentration in the brain without increasing the risk of hypoglycemia, that is, increase the risk of hypoglycemia. Brain targeting will be particularly suitable for the treatment of diseases of the nervous system.
一方面，本发明涉及一种用于鼻腔给药的格列本脲的药物组合物，包含格列本脲、二乙二醇单乙基醚、增溶溶剂。In one aspect, the present invention relates to a pharmaceutical composition of glyburide for nasal administration, comprising glyburide, diethylene glycol monoethyl ether, and a solubilizing solvent.
在一些实施方案中，以重量份计，所述的药物组合物，包含格列本脲0.1-50份，二乙二醇单乙基醚1-5000份、增溶溶剂1～1000份。In some embodiments, in parts by weight, the pharmaceutical composition comprises 0.1-50 parts of glyburide, 1-5000 parts of diethylene glycol monoethyl ether, and 1-1000 parts of solubilizer.
在一些实施方案中，以重量份计，所述的药物组合物，包含格列本脲0.5-40份；优选地，包含格列本脲2-20份。In some embodiments, in parts by weight, the pharmaceutical composition comprises 0.5-40 parts of glyburide; preferably, 2-20 parts of glyburide.
在一些实施方案中，以重量份计，所述的药物组合物，包含二乙二醇单乙基醚100-4000份；优选地，包含二乙二醇单乙基醚200-1000份。In some embodiments, in parts by weight, the pharmaceutical composition comprises 100-4000 parts of diethylene glycol monoethyl ether; preferably, 200-1000 parts of diethylene glycol monoethyl ether.
在一些实施方案中，所述的增溶溶剂选自丙二醇、聚乙二醇、乙醇、异丙醇、甘油中的一种或多种的组合。In some embodiments, the solubilizing solvent is selected from a combination of one or more of propylene glycol, polyethylene glycol, ethanol, isopropanol, and glycerin.
在一些实施方案中，所述的增溶溶剂选自丙二醇、聚乙二醇、乙醇中的一种或多种的组合。In some embodiments, the solubilizing solvent is selected from a combination of one or more of propylene glycol, polyethylene glycol, and ethanol.
在一些实施方案中，以重量份计，所述的药物组合物包含增溶溶剂5-1000份，更优选地，包含增溶溶剂50-800份。In some embodiments, in parts by weight, the pharmaceutical composition contains 5-1000 parts of a solubilizing solvent, more preferably, 50-800 parts of a solubilizing solvent.
在一些实施方案中，所述的药物组合物还含有促渗剂、稳定剂中的一种或多种的组合。In some embodiments, the pharmaceutical composition further contains a combination of one or more of a penetration enhancer and a stabilizer.
在一些实施方案中，所述的促渗剂选自十二烷基-β-麦芽糖苷、8-(2-羟基苯甲酰胺基)辛酸钠、癸酸钠、辛酸钠、胆酸钠、脱氧胆酸、熊去氧胆酸、牛磺去氧胆酸、蔗糖单月桂酸酯、EDTA、十二烷基硫酸钠、月桂酰基肉碱、壳聚糖、棕榈酰肉碱中的一种或多种的组合。In some embodiments, the penetration enhancer is selected from dodecyl-β-maltoside, sodium 8-(2-hydroxybenzamido)caprylate, sodium caprate, sodium caprylate, sodium cholate, deoxy One or more of cholic acid, ursodeoxycholic acid, taurodeoxycholic acid, sucrose monolaurate, EDTA, sodium lauryl sulfate, lauroylcarnitine, chitosan, palmitoylcarnitine combination of species.
在一些实施方案中，所述的促渗剂选自十二烷基-β-麦芽糖苷、癸酸钠、辛酸钠、胆酸钠、脱氧胆酸、熊去氧胆酸中的一种或多种的组合。In some embodiments, the penetration enhancer is selected from one or more of dodecyl-β-maltoside, sodium caprate, sodium caprylate, sodium cholate, deoxycholic acid, and ursodeoxycholic acid combination of species.
在一些实施方案中，所述的促渗剂选自十二烷基-β-麦芽糖苷、癸酸钠、熊去氧胆酸中的一种或多种的组合。In some embodiments, the penetration enhancer is selected from a combination of one or more of dodecyl-β-maltoside, sodium caprate, and ursodeoxycholic acid.
在一些实施方案中，以重量份数计，所述的药物组合物中，所述的促渗剂含量为0.1-10 份；优选地，所述的促渗剂含量为1-5份；更优选地，所述的促渗剂含量为2-3份。In some embodiments, in parts by weight, in the pharmaceutical composition, the content of the penetration enhancer is 0.1-10 parts; preferably, the content of the penetration enhancer is 1-5 parts; more Preferably, the content of the penetration enhancer is 2-3 parts.
在一些实施方案中，所述的稳定剂选自聚维酮、明胶、黄原胶、***胶、西黄蓍胶、葡聚糖、海藻酸钠、羧甲基纤维素钠、羟丙甲纤维素、羟丙基纤维素、甲基纤维素、卡波姆、聚乙烯醇中的一种或多种的组合。In some embodiments, the stabilizer is selected from the group consisting of povidone, gelatin, xanthan gum, acacia, tragacanth, dextran, sodium alginate, sodium carboxymethylcellulose, hypromellose A combination of one or more of cellulose, hydroxypropyl cellulose, methyl cellulose, carbomer, and polyvinyl alcohol.
在一些实施方案中，所述的稳定剂选自聚维酮、明胶、黄原胶、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素中的一种或多种的组合。In some embodiments, the stabilizer is selected from a combination of one or more of povidone, gelatin, xanthan gum, sodium carboxymethylcellulose, hydroxypropylcellulose, and hypromellose .
在一些实施方案中，所述的稳定剂选自聚维酮、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素中的一种或多种的组合。In some embodiments, the stabilizer is selected from a combination of one or more of povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, and hypromellose.
在一些实施方案中，以重量份计，所述的药物组合物包含稳定剂0.5～200份；优选地，包含稳定剂1-100份；更优选地，包含稳定剂10-80份。In some embodiments, in parts by weight, the pharmaceutical composition contains 0.5-200 parts of stabilizer; preferably, 1-100 parts of stabilizer; more preferably, 10-80 parts of stabilizer.
另一方面，本发明涉及一种所述的药物组合物的制备方法：取处方量的二乙二醇单乙基醚和增溶溶剂混合均匀，加入处方量格列本脲超声溶解，即得。On the other hand, the present invention relates to a preparation method of the described pharmaceutical composition: take the diethylene glycol monoethyl ether and the solubilizing solvent of the recipe and mix them uniformly, add the recipe amount of glyburide to ultrasonically dissolve, and get .
在一些实施方案中，所述的制备方法还包括加入促渗剂、稳定剂中的一种或多种的组合的步骤。In some embodiments, the preparation method further includes the step of adding a combination of one or more of a penetration enhancer and a stabilizer.
在一些实施方案中，所述药物组合物为经鼻给药用药物组合物。In some embodiments, the pharmaceutical composition is a pharmaceutical composition for nasal administration.
另一方面，本发明所述的药物组合物在治疗神经***疾病中的用途。On the other hand, the use of the pharmaceutical composition of the present invention in the treatment of nervous system diseases.
在一些实施方案中，所述的药物组合物在中风、脑挫伤的用途。In some embodiments, the use of the pharmaceutical composition in stroke, brain contusion.
在一些实施方案中，所述的药物组合物经鼻给药可实现在脑内的含量显著高于静脉给药时的脑内含量，有着更高的入脑率和脑血比，且不增加低血糖风险。In some embodiments, the intranasal administration of the pharmaceutical composition can achieve significantly higher levels in the brain than when administered intravenously, with a higher brain entry rate and cerebral blood ratio, without increasing Risk of hypoglycemia.
本发明所述的药物组合物通过经鼻给药可显著提高药物的脑内含量、增加入脑率和脑血比，实现脑靶向性，且不增加低血糖风险，具有显著的临床价值。The pharmaceutical composition of the present invention can significantly improve the brain content of the drug, increase the brain entry rate and the cerebral blood ratio through nasal administration, achieve brain targeting without increasing the risk of hypoglycemia, and has significant clinical value.
综上所述，本发明的有益效果为：To sum up, the beneficial effects of the present invention are:
(1)本发明的药物组合物与现有技术相比，显著改善了药物的溶解度，使得组合物适合用于鼻腔给药；(1) Compared with the prior art, the pharmaceutical composition of the present invention significantly improves the solubility of the drug, so that the composition is suitable for nasal administration;
(2)与现有的静脉给药技术相比，本发明所述的药物组合物通过经鼻给药可显著提高药物的脑内含量、增加入脑率和脑血比，具有明确的脑靶向性，且不增加低血糖风险，有效避免了静脉注射在治疗中风、脑挫伤等神经***疾病时因低血糖风险而导致的脑内药物浓度低的技术问题；(2) Compared with the existing intravenous administration technology, the pharmaceutical composition of the present invention can significantly improve the intracerebral content of the drug, increase the brain entry rate and the cerebral blood ratio through nasal administration, and has a clear brain target It is tropic and does not increase the risk of hypoglycemia, which effectively avoids the technical problem of low drug concentration in the brain caused by the risk of hypoglycemia when intravenous injection is used in the treatment of stroke, brain contusion and other neurological diseases;
(3)本发明的鼻腔给药与静脉长期滴注相比具有更好的依从性，不破坏机体屏障，有着更好的安全性。(3) Compared with the long-term intravenous drip infusion, the nasal administration of the present invention has better compliance, does not damage the body barrier, and has better safety.
具体实施方式Detailed ways
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。The present invention will be further described below with reference to specific embodiments, and the advantages and characteristics of the present invention will become clearer with the description. If the specific conditions are not indicated in the examples, it is carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used without the manufacturer's indication are conventional products that can be purchased from the market.
本发明实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。The embodiments of the present invention are only exemplary, and do not constitute any limitation on the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the protection scope of the present invention.
实施例1Example 1
称取处方量的Transcutol P(二乙二醇单乙基醚)、丙二醇混合均匀，加入处方量的格列本脲超声溶解，加入处方量十二烷基-β-麦芽糖苷搅拌溶解，制得格列本脲鼻用给药制剂。Take the Transcutol P (diethylene glycol monoethyl ether) of recipe quantity, propylene glycol and mix, add the glyburide ultrasonic dissolving of recipe quantity, add recipe quantity dodecyl-beta-maltoside stirring and dissolving, make Glyburide for nasal administration.
表1格列本脲鼻用制剂处方Table 1 Glibenclamide nasal preparation prescription
组成composition 作用effect 用量(mg)Dosage (mg)
格列本脲Glyburide 主成分main ingredient 1616
Transcutol PTranscutol P 溶剂solvent 900900
丙二醇Propylene Glycol 增溶溶剂Solubilizer 100100
十二烷基-β-麦芽糖苷dodecyl-beta-maltoside 促渗剂Penetration enhancer 33
实施例2Example 2
称取处方量的Transcutol P(二乙二醇单乙基醚)、丙二醇混合均匀，加入处方量的格列本脲超声溶解，加入处方量十二烷基-β-麦芽糖苷搅拌溶解，制得格列本脲鼻用给药制剂。Take the Transcutol P (diethylene glycol monoethyl ether) of recipe quantity, propylene glycol and mix, add the glyburide ultrasonic dissolving of recipe quantity, add recipe quantity dodecyl-beta-maltoside stirring and dissolving, make Glyburide for nasal administration.
表2格列本脲鼻用制剂处方Table 2 Glyburide nasal preparation prescription
组成composition 作用effect 用量(mg)Dosage (mg)
格列本脲Glyburide 主成分main ingredient 88
Transcutol PTranscutol P 溶剂solvent 900900
丙二醇Propylene Glycol 增溶溶剂Solubilizer 100100
十二烷基-β-麦芽糖苷dodecyl-beta-maltoside 促渗剂Penetration enhancer 33
实施例3Example 3
称取处方量的Transcutol P、丙二醇混合均匀，加入处方量的格列本脲超声溶解，加入处方量癸酸钠搅拌溶解，制得格列本脲鼻用给药制剂。The Transcutol P and propylene glycol of the recipe quantity are weighed and mixed uniformly, the glyburide of the recipe quantity is added for ultrasonic dissolving, the sodium caprate of the recipe quantity is added and stirred to dissolve to obtain the glyburide nasal administration preparation.
表3格列本脲鼻用制剂处方Table 3 Glyburide nasal preparation prescription
组成composition 作用effect 用量(mg)Dosage (mg)
格列本脲Glyburide 主成分main ingredient 1515
Transcutol PTranscutol P 溶剂solvent 900900
丙二醇Propylene Glycol 增溶溶剂Solubilizer 100100
癸酸钠Sodium caprate 促渗剂Penetration enhancer 33
实施例4Example 4
称取处方量的Transcutol P、聚乙二醇400混合均匀，加入处方量的格列本脲混超声溶解，加入处方量PVPK30溶解，制得格列本脲鼻用给药制剂。Take the recipe quantity of Transcutol P and polyethylene glycol 400 and mix well, add the recipe quantity of Glyburide and dissolve by ultrasonic, add the recipe quantity of PVPK30 to dissolve, and make the glyburide nasal administration preparation.
表4格列本脲鼻用制剂处方Table 4 Glyburide nasal preparation prescription
组成composition 作用effect 用量(mg)Dosage (mg)
格列本脲Glyburide 主成分main ingredient 22
Transcutol PTranscutol P 溶剂solvent 200200
聚乙二醇400polyethylene glycol 400 增溶溶剂Solubilizer 800800
PVP K30PVP K30 稳定剂stabilizer 6060
实施例5Example 5
称取处方量的Transcutol P、无水乙醇混合均匀，加入处方量的格列本脲超声溶解，制得格列本脲鼻用给药制剂。The Transcutol P and dehydrated alcohol of the recipe quantity were weighed and mixed uniformly, and the glyburide of the recipe quantity was added for ultrasonic dissolution to obtain the glyburide nasal administration preparation.
表5格列本脲鼻用制剂处方Table 5 Glyburide nasal preparation prescription
组成composition 作用effect 用量(mg)Dosage (mg)
格列本脲Glyburide 主成分main ingredient 66
无水乙醇anhydrous ethanol 增溶溶剂Solubilizer 200200
Transcutol PTranscutol P 溶剂solvent 800800
羟丙甲纤维素Hypromellose 稳定剂stabilizer 5050
实施例6Example 6
称取处方量的Transcutol P，加入处方量的格列本脲超声溶解，制得格列本脲鼻用给药制剂。The Transcutol P of the recipe quantity was weighed, and the glyburide of the recipe quantity was added for ultrasonic dissolution to obtain the glyburide nasal administration preparation.
表6格列本脲鼻用制剂处方Table 6 Glyburide nasal preparation prescription
组成composition 作用effect 用量(mg)Dosage (mg)
格列本脲Glyburide 主成分main ingredient 1010
Transcutol PTranscutol P 溶剂solvent 700700
聚乙二醇400polyethylene glycol 400 增溶溶剂Solubilizer 300300
熊去氧胆酸Ursodeoxycholic acid 促渗剂Penetration enhancer 33
对比例1Comparative Example 1
取处方量的格列本脲溶于二甲基亚砜中，超声至完全溶解，加入丙二醇，Solutol(聚乙二醇-15羟基硬脂酸酯)，水混合均匀。Dissolve glyburide in dimethyl sulfoxide in the prescribed amount, sonicate until completely dissolved, add propylene glycol and Solutol (polyethylene glycol-15 hydroxystearate), and mix with water evenly.
表7格列本脲制剂处方Table 7 Glyburide formulation prescription
组成composition 用量Dosage
格列本脲Glyburide 20mg20mg
DMSODMSO 1.0ml1.0ml
丙二醇Propylene Glycol 2.0ml2.0ml
SolutolSolutol 2.0ml2.0ml
水water 5.0ml5.0ml
实验结果：制剂澄清透明，室温放置2h后有析出，检测溶液浓度为1.41mg/ml，结果表明，格列本脲在DMSO和丙二醇体系中的溶解稳定性较差。Experimental results: The preparation was clear and transparent, and precipitated after being placed at room temperature for 2 hours. The concentration of the detected solution was 1.41 mg/ml. The results showed that the dissolution stability of glyburide in the DMSO and propylene glycol system was poor.
对比例2Comparative Example 2
格列本脲注射液的制备：称取20mg格列本脲，加二甲基亚砜(DMSO)至10ml，配置2mg/ml 储备液，再用生理盐水稀释至0.02mg/ml药液。Preparation of glyburide injection: Weigh 20 mg of glyburide, add dimethyl sulfoxide (DMSO) to 10 ml, prepare 2 mg/ml stock solution, and then dilute to 0.02 mg/ml medicinal solution with normal saline.
药代动力学特点：Pharmacokinetic characteristics:
(1)格列本脲经鼻给药在正常大鼠体内的血浆药代动力学研究(1) Plasma pharmacokinetics study of glyburide administered intranasally in normal rats
健康的SD大鼠20只，正常饮水饮食，随机分为4组，分别为：B1组，4只大鼠在清醒状态下，左右鼻腔各滴入10μl实施例1的格列本脲的药物组合物，A1组，4只大鼠经尾静脉注射对比例2的格列本脲的药物组合物，剂量为0.1mg/kg，均于给药前和给药后0.083h、0.33h、0.67h、1h、2h、4h、8h、10h、24h颈静脉丛取血250μl；20 healthy SD rats, drinking and eating normally, were randomly divided into 4 groups, namely: B1 group, 4 rats were instilled in the left and right nasal cavity of 10 μl of the drug combination of Example 1 in the awake state. In group A1, 4 rats were injected with the pharmaceutical composition of Glyburide of Comparative Example 2 via tail vein at a dose of 0.1 mg/kg, before administration and at 0.083h, 0.33h, and 0.67h after administration. , 1h, 2h, 4h, 8h, 10h, 24h to take 250μl of blood from the jugular venous plexus;
C1组，6只大鼠在清醒状态下，左右鼻腔各滴入3μl实施例1的格列本脲的药物组合物，D1组，6只大鼠在清醒状态下，左右鼻腔各滴入6μl实施例2的格列本脲的药物组合物，均于给药前和给药后0.083h、0.25h、0.5h、1h、2h、4h、8h、24h颈静脉丛取血250μl。In group C1, 6 rats were instilled 3 μl of the pharmaceutical composition of Glyburide of Example 1 in the left and right nasal cavities in the awake state. In the D1 group, 6 rats were instilled in the left and right nasal cavities in the awake state. For the pharmaceutical composition of glyburide in Example 2, 250 μl of blood was collected from the jugular venous plexus before administration and at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration.
所取血样均置于涂有EDTA-K2的1.5mL抗凝管中，12000rpm离心5min后取血浆。采用液质联用的方法测定不同时间点所得血浆中格列本脲的浓度，并利用WinNonLin软件计算主要药代动力学参数(表8)。All blood samples were placed in 1.5mL anticoagulation tubes coated with EDTA-K2, and the plasma was collected after centrifugation at 12000rpm for 5min. The concentration of glyburide in plasma obtained at different time points was determined by LC/MS, and the main pharmacokinetic parameters were calculated by WinNonLin software (Table 8).
表8各组大鼠血浆中格列本脲的药代动力学参数(Mean±SD,n＝4,6)Table 8 Pharmacokinetic parameters of glyburide in plasma of rats in each group (Mean±SD, n=4,6)
参数parameter 单位unit B1组Group B1 C1组Group C1 D1组Group D1 A1组Group A1
t 1/2z t 1/2z hh 7.78±6.647.78±6.64 8.17±2.548.17±2.54 10.30±7.3410.30±7.34 5.85±0.975.85±0.97
T max Tmax hh 0.08±NA0.08±NA 4.00±NA4.00±NA 0.08±NA0.08±NA 0.08±NA0.08±NA
C max Cmax ng/mLng/mL 264.05±102.59264.05±102.59 52.72±21.6552.72±21.65 61.59±45.0061.59±45.00 90.08±4.7890.08±4.78
AUC last AUC last h*ng/mLh*ng/mL 2251.45±685.522251.45±685.52 638.22±161.32638.22±161.32 508.35±200.75508.35±200.75 263.44±80.68263.44±80.68
AUC INF AUC INF h*ng/mLh*ng/mL 2757.68±1412.822757.68±1412.82 746.81±198.92746.81±198.92 634.43±312.37634.43±312.37 287.82±63.94287.82±63.94
Vz/FVz/F mL/kgmL/kg 6029.49±2004.056029.49±2004.05 7869.02±2992.077869.02±2992.07 11420.16±4469.5611420.16±4469.56 3041.01±756.293041.01±756.29
Cl/FCl/F mL/h/kgmL/h/kg 709.35±367.50709.35±367.50 677.00±155.11677.00±155.11 915.84±409.41915.84±409.41 364.44±102.27364.44±102.27
MRT last MRT last hh 7.20±2.227.20±2.22 7.89±1.287.89±1.28 8.04±1.218.04±1.21 5.46±1.445.46±1.44
(2)格列本脲经鼻给药在正常大鼠体内的脑组织分布研究(2) Study on the distribution of glibenclamide in the brain tissue of normal rats after intranasal administration
健康的SD大鼠60只，正常饮水饮食，随机分为4组，每个时间点3只大鼠，分别为：60 healthy SD rats, with normal drinking water and diet, were randomly divided into 4 groups, with 3 rats at each time point, respectively:
B2组，18只大鼠在清醒状态下，左右鼻腔各滴入10μl实施例1的格列本脲的药物组合物，A2组，18只大鼠经尾静脉注射对比例2的格列本脲的药物组合物，剂量为0.1mg/kg，均于给药前测定血糖和颈静脉丛取血，给药后0.25h、1h、2h、4h、8h、24h依次进行颈静脉丛取血、测定血糖、取脑组织；In group B2, 18 rats were instilled 10 μl of the pharmaceutical composition of Glyburide of Example 1 into each of the left and right nasal cavities while awake. In Group A2, 18 rats were injected with Glyburide of Comparative Example 2 through the tail vein. The pharmaceutical composition of the drug was measured at a dose of 0.1 mg/kg, and blood glucose and jugular venous plexus blood were measured before administration. blood sugar, brain tissue;
C2组，12只大鼠在清醒状态下，左右鼻腔各滴入3μl实施例1的格列本脲的药物组合物，D2组，12只大鼠在清醒状态下，左右鼻腔各滴入6μl实施例2的格列本脲的药物组合物，均于给药前测定血糖和颈静脉丛取血，给药后0.25h、1h、4h、24h依次进行颈静脉丛取血、测定血糖、取脑组织。In group C2, 12 rats were instilled 3 μl of the pharmaceutical composition of Glyburide of Example 1 in each of the left and right nasal cavities when they were awake. In group D2, 12 rats were instilled in 6 μl in each of the left and right nasal cavities when they were awake. For the pharmaceutical composition of glyburide in Example 2, blood glucose and jugular venous plexus blood were measured before administration, and 0.25h, 1h, 4h, and 24h were followed by jugular venous plexus blood collection, blood sugar measurement, and brain collection. organize.
采用液质联用的方法测定血浆和脑组织中格列本脲的浓度(表9)，并计算脑血比(表10)。The concentration of glyburide in plasma and brain tissue was determined by LC/MS method (Table 9), and the cerebral blood ratio was calculated (Table 10).
表9各组大鼠各时间点脑匀浆中格列本脲浓度和血糖值(Mean±SD,n＝3)Table 9 Glyburide concentration and blood glucose value in brain homogenate of rats in each group at each time point (Mean±SD, n=3)
Figure PCTCN2021130723-appb-000001
Figure PCTCN2021130723-appb-000001
Figure PCTCN2021130723-appb-000002
Figure PCTCN2021130723-appb-000002
注：BQL为低于定量下限0.15ng/gNote: BQL is 0.15ng/g below the lower limit of quantification
表10各组大鼠各时间点在脑组织与血浆中格列本脲的浓度比(Mean±SD,n＝3,％)Table 10 Concentration ratio of glyburide in brain tissue and plasma of rats in each group at each time point (Mean±SD, n=3,%)
时间(h)time (h) B2组Group B2 C2组Group C2 D2组Group D2 A2组Group A2
0.250.25 1.81±0.781.81±0.78 1.25±0.251.25±0.25 0.83±0.290.83±0.29 0.65±0.100.65±0.10
11 0.91±0.160.91±0.16 1.20±0.241.20±0.24 0.82±0.200.82±0.20 0.45±NA0.45±NA
22 0.99±0.250.99±0.25 // // 0.29±NA0.29±NA
44 1.07±0.261.07±0.26 0.84±0.180.84±0.18 0.74±0.060.74±0.06 //
88 2.60±1.352.60±1.35 // // //
24twenty four 5.11±NA5.11±NA // // //
由上述表中结果分析可知，以现有注射给药的A2组为对比例，格列本脲的药物组合物经鼻给药后在各个时间点的脑组织中的浓度显著增加到1.6-24倍(表9)，各时间点的脑血比提高到1.3-3倍(表10)，说明格列本脲存在鼻-脑直接转运途径，有显著的脑靶向性。同时，血药浓度与发生低血糖现象相关联，结合血浆药代动力学特性(表8)和血糖值(表9)，B1组经鼻给药后因血药浓度过高可能会出现低血糖现象，所以，C和D组减少了药物组合物中的格列本脲用量，结果显示C1和D1组经鼻给药的C max均低于静脉给药组，C2和D2组的最低血糖值均高于静脉给药组的最低血糖值，说明了本发明的格列本脲的药物组合物经鼻给药后低血糖风险不高于静脉给药组。因此，与静脉给药组相比，本发明的经鼻给药格列本脲的药物组合物能够显著提高其药物入脑量，增加入脑率和脑血比，在提高脑靶向性的同时可不增加外周血中格列本脲引起的低血糖副作用，预期将有着显著的临床应用价值。 As can be seen from the analysis of the results in the above table, taking the existing injection-administered A2 group as a comparative example, the concentration of the pharmaceutical composition of glyburide in the brain tissue at each time point after nasal administration significantly increased to 1.6-24%. times (Table 9), the brain-to-blood ratio at each time point increased to 1.3-3 times (Table 10), indicating that there is a nasal-brain direct transport pathway for glyburide and has significant brain targeting. At the same time, the blood drug concentration is associated with the occurrence of hypoglycemia. Combined with the plasma pharmacokinetic characteristics (Table 8) and blood glucose value (Table 9), hypoglycemia may occur due to excessive blood drug concentration in group B1 after nasal administration. Therefore, groups C and D reduced the dosage of glyburide in the pharmaceutical composition, and the results showed that the Cmax of C1 and D1 groups by nasal administration were lower than the intravenous administration group, and the lowest blood glucose values of C2 and D2 groups All are higher than the lowest blood sugar value of the intravenous administration group, indicating that the risk of hypoglycemia after nasal administration of the pharmaceutical composition of glyburide of the present invention is not higher than that of the intravenous administration group. Therefore, compared with the intravenous administration group, the pharmaceutical composition for nasal administration of glyburide of the present invention can significantly increase the amount of the drug entering the brain, increase the rate of brain entry and the cerebral blood ratio, and improve the brain targeting ability. At the same time, the hypoglycemia side effects caused by glyburide in peripheral blood can not be increased, and it is expected to have significant clinical application value.

Claims (10)

  1. 一种用于鼻腔给药的格列本脲的药物组合物，其特征在于，包含格列本脲、二乙二醇单乙基醚、增溶溶剂。A pharmaceutical composition of glyburide for nasal administration, characterized in that it comprises glyburide, diethylene glycol monoethyl ether, and a solubilizer.
  2. 一种根据权利要求1所述的格列本脲的药物组合物，其特征在于，以重量份计，所述的药物组合物，包含格列本脲0.1-50份，二乙二醇单乙基醚1-5000份、增溶溶剂1-1000份。A pharmaceutical composition for glyburide according to claim 1, characterized in that, in parts by weight, the pharmaceutical composition comprises 0.1-50 parts of glyburide, diethylene glycol monoethyl 1-5000 parts of base ether, 1-1000 parts of solubilizer.
  3. 一种根据权利要求1所述的格列本脲的药物组合物，其特征在于，以重量份计，所述的药物组合物，包含格列本脲0.5-40份；优选地，包含格列本脲2-20份；以重量份计，所述的药物组合物，包含二乙二醇单乙基醚100-4000份；优选地，包含二乙二醇单乙基醚200-1000份。A pharmaceutical composition of glyburide according to claim 1, characterized in that, in parts by weight, the pharmaceutical composition comprises 0.5-40 parts of glyburide; preferably, it comprises glyburide 2-20 parts of this urea; in parts by weight, the pharmaceutical composition includes 100-4000 parts of diethylene glycol monoethyl ether; preferably, 200-1000 parts of diethylene glycol monoethyl ether.
  4. 一种根据权利要求1所述的格列本脲的药物组合物，其特征在于，所述的增溶溶剂选自丙二醇、聚乙二醇、乙醇、异丙醇、甘油中的一种或多种的组合；优选地，所述的增溶溶剂选自丙二醇、聚乙二醇、乙醇中的一种或多种的组合；优选地，以重量份计，所述的药物组合物包含增溶溶剂5-1000份，更优选地，包含增溶溶剂50-800份。A kind of pharmaceutical composition of glyburide according to claim 1, is characterized in that, described solubilizing solvent is selected from one or more in propylene glycol, polyethylene glycol, ethanol, isopropanol, glycerol a combination of species; preferably, the solubilizing solvent is selected from one or more combinations of propylene glycol, polyethylene glycol, and ethanol; preferably, in parts by weight, the pharmaceutical composition comprises a solubilizing agent 5-1000 parts of solvent, more preferably, 50-800 parts of solubilizing solvent.
  5. 一种根据权利要求1所述的格列本脲的药物组合物，其特征在于，所述的药物组合物还含有促渗剂、稳定剂中的一种或多种的组合。A pharmaceutical composition of glyburide according to claim 1, characterized in that, the pharmaceutical composition further contains a combination of one or more of a penetration enhancer and a stabilizer.
  6. 一种根据权利要求5所述的格列本脲的药物组合物，其特征在于，所述的促渗剂选自十二烷基-β-麦芽糖苷、8-(2-羟基苯甲酰胺基)辛酸钠、癸酸钠、辛酸钠、胆酸钠、脱氧胆酸、熊去氧胆酸、牛磺去氧胆酸、蔗糖单月桂酸酯、EDTA、十二烷基硫酸钠、月桂酰基肉碱、壳聚糖、棕榈酰肉碱中的一种或多种的组合；优选地，所述的促渗剂选自十二烷基-β-麦芽糖苷、癸酸钠、辛酸钠、胆酸钠、脱氧胆酸、熊去氧胆酸中的一种或多种的组合；更优选地，所述的促渗剂选自十二烷基-β-麦芽糖苷、癸酸钠、熊去氧胆酸中的一种或多种的组合；优选地，以重量份计，所述的促渗剂含量为0.1-10份；更优选地，所述的促渗剂含量为1-5份；进一步优选地，所述的促渗剂含量为2-3份。A kind of pharmaceutical composition of glyburide according to claim 5, is characterized in that, described penetration enhancer is selected from dodecyl-β-maltoside, 8-(2-hydroxybenzamide group ) sodium caprylate, sodium caprate, sodium caprylate, sodium cholate, deoxycholic acid, ursodeoxycholic acid, taurodeoxycholic acid, sucrose monolaurate, EDTA, sodium lauryl sulfate, lauroyl meat A combination of one or more of alkali, chitosan and palmitoylcarnitine; preferably, the penetration enhancer is selected from dodecyl-β-maltoside, sodium caprate, sodium caprylate, cholic acid A combination of one or more of sodium, deoxycholic acid, and ursodeoxycholic acid; more preferably, the penetration enhancer is selected from dodecyl-β-maltoside, sodium caprate, ursodeoxy One or more combinations of cholic acid; preferably, in parts by weight, the content of the penetration enhancer is 0.1-10 parts; more preferably, the content of the penetration enhancer is 1-5 parts; Further preferably, the content of the penetration enhancer is 2-3 parts.
  7. 一种根据权利要求5所述的格列本脲的药物组合物，其特征在于，所述的稳定剂选自聚维酮、明胶、黄原胶、***胶、西黄蓍胶、葡聚糖、海藻酸钠、羧甲基纤维素钠、羟丙甲纤维素、羟丙基纤维素、甲基纤维素、卡波姆、聚乙烯醇中的一种或多种的组合；优选地，所述的稳定剂选自聚维酮、明胶、黄原胶、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素中的一种或多种的组合；更优选地，所述的稳定剂选自聚维酮、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素中的一种或多种的组合；优选地，以重量份计，所述的药物组合物包含稳定剂0.5-200份；优选地，包含稳定剂1-100份；更优选地，包含稳定剂10-80份。A kind of pharmaceutical composition of glyburide according to claim 5, is characterized in that, described stabilizer is selected from povidone, gelatin, xanthan gum, acacia, tragacanth, glucan , a combination of one or more of sodium alginate, sodium carboxymethyl cellulose, hypromellose, hydroxypropyl cellulose, methyl cellulose, carbomer, and polyvinyl alcohol; preferably, the Described stabilizer is selected from the combination of one or more in povidone, gelatin, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose; more preferably, described The stabilizer is selected from the combination of one or more of povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose; preferably, in parts by weight, the pharmaceutical combination The product contains 0.5-200 parts of stabilizer; preferably, 1-100 parts of stabilizer; more preferably, 10-80 parts of stabilizer.
  8. 一种根据权利要求1-7任一项所述的格列本脲的药物组合物的制备方法，其特征在于，取处方量的二乙二醇单乙基醚和增溶溶剂混合均匀，加入处方量格列本脲超声溶解，即得；优选地，所述的制备方法还包括加入促渗剂、稳定剂中的一种或多种的组合的步骤。A preparation method of the pharmaceutical composition of glyburide according to any one of claims 1-7, it is characterized in that, take the diethylene glycol monoethyl ether of recipe quantity and solubilizing solvent to mix homogeneously, add The recipe quantity of glyburide is dissolved by ultrasonic, and it is obtained; preferably, the preparation method further includes the step of adding one or more combinations of penetration enhancers and stabilizers.
  9. 一种根据权利要求1-7任一项所述的格列本脲的药物组合物，其特征在于，所述药物组合物为经鼻给药用药物组合物。A pharmaceutical composition of glyburide according to any one of claims 1-7, wherein the pharmaceutical composition is a pharmaceutical composition for nasal administration.
  10. 一种根据权利要求1-7任一项所述的格列本脲的药物组合物在治疗神经***疾病中的用途；优选地，所述的格列本脲的药物组合物在治疗中风、脑挫伤中的用途。A use of the pharmaceutical composition of glyburide according to any one of claims 1-7 in the treatment of nervous system diseases; preferably, the pharmaceutical composition of glyburide is used in the treatment of stroke, brain Use in contusions.
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