CN116635035A - Pharmaceutical composition for nasal administration of glibenclamide and preparation method thereof - Google Patents
Pharmaceutical composition for nasal administration of glibenclamide and preparation method thereof Download PDFInfo
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- CN116635035A CN116635035A CN202180076959.1A CN202180076959A CN116635035A CN 116635035 A CN116635035 A CN 116635035A CN 202180076959 A CN202180076959 A CN 202180076959A CN 116635035 A CN116635035 A CN 116635035A
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- Prior art keywords
- glibenclamide
- pharmaceutical composition
- parts
- sodium
- stabilizer
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- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 title claims abstract description 101
- 229960004580 glibenclamide Drugs 0.000 title claims abstract description 100
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 26
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 25
- 239000003961 penetration enhancing agent Substances 0.000 claims description 19
- 230000003381 solubilizing effect Effects 0.000 claims description 18
- 239000003381 stabilizer Substances 0.000 claims description 18
- 208000006011 Stroke Diseases 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 11
- NLEBIOOXCVAHBD-QKMCSOCLSA-N dodecyl beta-D-maltoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 NLEBIOOXCVAHBD-QKMCSOCLSA-N 0.000 claims description 10
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 claims description 7
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims description 7
- 229960001661 ursodiol Drugs 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229940069328 povidone Drugs 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 206010052346 Brain contusion Diseases 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 4
- 229940014259 gelatin Drugs 0.000 claims description 4
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- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 4
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
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- 229960005480 sodium caprylate Drugs 0.000 claims description 3
- XOMRRQXKHMYMOC-NRFANRHFSA-N (3s)-3-hexadecanoyloxy-4-(trimethylazaniumyl)butanoate Chemical compound CCCCCCCCCCCCCCCC(=O)O[C@@H](CC([O-])=O)C[N+](C)(C)C XOMRRQXKHMYMOC-NRFANRHFSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- FUJLYHJROOYKRA-QGZVFWFLSA-N O-lauroyl-L-carnitine Chemical compound CCCCCCCCCCCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C FUJLYHJROOYKRA-QGZVFWFLSA-N 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- KGUHOFWIXKIURA-VQXBOQCVSA-N [(2r,3s,4s,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl dodecanoate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)CCCCCCCCCCC)O[C@@H]1O[C@@]1(CO)[C@@H](O)[C@H](O)[C@@H](CO)O1 KGUHOFWIXKIURA-VQXBOQCVSA-N 0.000 claims description 2
- 239000000305 astragalus gummifer gum Substances 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
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- 235000010413 sodium alginate Nutrition 0.000 claims description 2
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- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 claims description 2
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- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims 2
- 229940083542 sodium Drugs 0.000 claims 2
- 235000015424 sodium Nutrition 0.000 claims 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 1
- 229920000084 Gum arabic Polymers 0.000 claims 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 claims 1
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
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- -1 ethylsul-hexide Chemical compound 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
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- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
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- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
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- 102000016924 KATP Channels Human genes 0.000 description 1
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- HZYCAKGEXXKCDM-UHFFFAOYSA-N Methyl 2-(methylthio)acetate Chemical compound COC(=O)CSC HZYCAKGEXXKCDM-UHFFFAOYSA-N 0.000 description 1
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- 229960003901 dacarbazine Drugs 0.000 description 1
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- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition for nasal administration of glibenclamide and a preparation method thereof, and solves the technical problems that the concentration of the glibenclamide in the brain is low and serious hypoglycemic side effects are easy to cause.
Description
The invention claims the priority of the prior application of a nasal drug composition of glibenclamide and a preparation method thereof, which is submitted to the China national intellectual property agency on 11/16 th of 2020, with the patent application number of 202011281755.5. The entire contents of the above-mentioned prior application are incorporated by reference into the present invention.
The invention relates to the field of pharmaceutical compositions, in particular to a pharmaceutical composition for nasal administration of glibenclamide and a preparation method thereof.
Glibenclamide, also known as glyburide, dacarbazine, ethylsul-hexide, glyburide, chlorsul-cyclohexamide. The chemical name is N- (2- (4- ((((cyclohexylamino) carbonyl) amino) sulfonyl) phenyl) ethyl) -2-methoxy-5-chlorobenzamide, which is a sulfonylurea hypoglycemic agent, and by inhibiting ATP sensitive potassium channels of islet cells, cell membranes are depolarized, pressure sensitive calcium ion channels are opened, so that intracellular calcium ions permeate the islet cells, and insulin release is stimulated. In recent years, with a deeper study of its pharmacological actions, glibenclamide has been found to have a promoting effect on the protection of cerebral nerves.
Cerebral apoplexy, commonly known as stroke, is an acute cerebrovascular disease, which is a group of diseases in which brain tissue is damaged due to sudden rupture of cerebral blood vessels or failure of blood to flow into the brain due to vessel occlusion, and is classified into ischemic stroke and hemorrhagic stroke. Wherein ischemic cerebral apoplexy accounts for more than 80% of cerebral apoplexy. Investigation shows that cerebral apoplexy is the first cause of death in China, is the primary cause of disability of adults in China, has the characteristics of high morbidity, high mortality and high disability rate, and seriously endangers the health and life safety of human bodies. Severe stroke can cause permanent nerve damage, and acute phase can cause serious complications and even death if not diagnosed and treated in time. Current drug therapies for stroke are mainly through thrombolysis, but have strict time constraints.
In recent years studies have found that Sur1-Trpm4 and Sur1-Kir6.2 (K ATP ) The two paths are up-regulated in the expression of animal models such as cerebral apoplexy, cerebral contusion and the like, and glibenclamide can inhibit the two paths in a targeted way, so that the protection and repair effects on nerve cells in the brain are generated, and cerebral edema is effectively relieved.
Currently, the Biogen company has completed a phase II clinical trial of glibenclamide for treating cerebral stroke, which is administered by intravenous drip, and the results show that the glibenclamide can effectively treat cerebral stroke, and a phase iii clinical study of cerebral stroke and a phase II clinical study of cerebral contusion have been developed. However, the glibenclamide has a strong effect of reducing blood sugar, and in the process of treating cerebral apoplexy by intravenous injection, the increase of the content of the glibenclamide in peripheral blood is extremely easy to cause serious adverse reaction of hypoglycemia, so that long-time low-flow-rate instillation is needed to control the blood concentration at a lower level, and the total administration dosage and the blood concentration are obviously smaller than the corresponding dosage and concentration in diabetics; meanwhile, due to the existence of a blood brain barrier, the medicine is difficult to penetrate through the blood brain barrier to enter the brain, the concentration of the medicine in a target organ is lower, the above reasons all lead to that the glibenclamide in a intravenous administration mode does not reach the optimal medicine effect concentration for treating the apoplexy, and the compliance of patients in a long-term intravenous drip mode is poor. Therefore, the glibenclamide brain targeting is improved, the blood concentration and the hypoglycemia risk are not obviously increased while the increase of the concentration in the medicine brain is realized, and the glibenclamide brain targeting has obvious clinical value.
With continuous research on nasal administration in recent years, it is found that part of drugs can bypass the blood brain barrier (blood brain barrier, BBB) through the administration route and directly enter the central nervous system (Central Nervous System, CNS), so that the administration route has good brain targeting property, and the route has the advantages of higher bioavailability, small injury, convenient use, avoidance of liver first pass effect, rapid drug absorption and the like. The research team of Shanghai university such as Wang Ju finds that the brain can be reached after the administration of glibenclamide through the nose and a certain neuroprotection effect is shown in a brain injury model, but whether the brain targeting can be improved by the nasal administration of glibenclamide is not studied and reported, and meanwhile, the DMSO is adopted in the article to dissolve the glibenclamide, so that the preparation formula is not a feasible preparation formula.
Since the volume of nasal administration is very small (the general administration volume of a human body is less than 200 microliters), and glibenclamide is weak acid and has poor solubility, especially has very low solubility in water under neutral and low pH conditions, has a solubility of less than 5 mug/ml, and in addition, since the pH of a preparation for nasal administration is not too high, the use of glibenclamide is greatly limited, the preparation of the solution of the glibenclamide which is reported at present is only suitable for conventional intravenous drip administration, and no preparation development for nasal administration exists.
Therefore, if a glibenclamide pharmaceutical composition with high solubility is developed, the brain targeting of glibenclamide can be improved obviously by nasal administration, namely, the higher concentration in the brain can be achieved without increasing the hypoglycemia adverse reaction of the glibenclamide, and the glibenclamide pharmaceutical composition has obvious clinical value.
Disclosure of Invention
Aiming at the technical problems that the prior glibenclamide has poor brain permeability, and the drug can be fed into the brain only through a blood brain barrier after oral administration and intravenous injection, so that the concentration of the drug in the brain is low and the glibenclamide in the peripheral circulatory system is easy to cause serious hypoglycemic side effects, the invention provides a pharmaceutical composition for nasal administration of the glibenclamide and a preparation method thereof, which realize higher concentration of the drug in the brain without increasing the risk of hypoglycemia, namely improve brain targeting, and are particularly suitable for treating diseases of the nervous system.
In one aspect, the invention relates to a pharmaceutical composition of glibenclamide for nasal administration, comprising glibenclamide, diethylene glycol monoethyl ether, and a solubilizing solvent.
In some embodiments, the pharmaceutical composition comprises, in parts by weight, 0.1 to 50 parts glibenclamide, 1 to 5000 parts diethylene glycol monoethyl ether, and 1 to 1000 parts solubilizing solvent.
In some embodiments, the pharmaceutical composition comprises, in parts by weight, 0.5 to 40 parts glibenclamide; preferably, 2-20 parts of glibenclamide are contained.
In some embodiments, the pharmaceutical composition comprises, in parts by weight, from 100 to 4000 parts of diethylene glycol monoethyl ether; preferably, the diethylene glycol monoethyl ether is comprised in 200-1000 parts.
In some embodiments, the solubilizing solvent is selected from the group consisting of propylene glycol, polyethylene glycol, ethanol, isopropanol, glycerol, and combinations of one or more thereof.
In some embodiments, the solubilizing solvent is selected from the group consisting of propylene glycol, polyethylene glycol, ethanol, and combinations of one or more thereof.
In some embodiments, the pharmaceutical composition comprises 5-1000 parts by weight of the solubilizing solvent, more preferably, 50-800 parts by weight of the solubilizing solvent.
In some embodiments, the pharmaceutical composition further comprises a combination of one or more of a permeation enhancer, a stabilizer.
In some embodiments, the permeation enhancer is selected from the group consisting of one or more of dodecyl- β -maltoside, sodium 8- (2-hydroxybenzoamido) octoate, sodium caprate, sodium caprylate, sodium cholate, deoxycholate, ursodeoxycholic acid, taurodeoxycholate, sucrose monolaurate, EDTA, sodium dodecyl sulfate, lauroyl carnitine, chitosan, palmitoyl carnitine.
In some embodiments, the permeation enhancer is selected from one or more of dodecyl- β -maltoside, sodium caprate, sodium caprylate, sodium cholate, deoxycholate, ursodeoxycholic acid.
In some embodiments, the permeation enhancer is selected from one or more of dodecyl- β -maltoside, sodium caprate, ursodeoxycholic acid.
In some embodiments, the penetration enhancer is present in the pharmaceutical composition in an amount of 0.1 to 10 parts by weight; preferably, the content of the penetration enhancer is 1-5 parts; more preferably, the penetration enhancer is 2-3 parts.
In some embodiments, the stabilizing agent is selected from one or more of povidone, gelatin, xanthan gum, acacia, tragacanth gum, dextran, sodium alginate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carbomers, polyvinyl alcohol.
In some embodiments, the stabilizing agent is selected from one or more of povidone, gelatin, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose.
In some embodiments, the stabilizer is selected from one or more of povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, and combinations thereof.
In some embodiments, the pharmaceutical composition comprises 0.5 to 200 parts by weight of a stabilizer; preferably, 1 to 100 parts of stabilizer is contained; more preferably, the stabilizer is contained in an amount of 10 to 80 parts.
In another aspect, the invention relates to a method of preparing the pharmaceutical composition: and uniformly mixing the diethylene glycol monoethyl ether with the prescription amount and the solubilizing solvent, and adding the prescription amount of glibenclamide for ultrasonic dissolution to obtain the aqueous emulsion.
In some embodiments, the method of preparation further comprises the step of adding one or more of a permeation enhancer, a stabilizer, or a combination thereof.
In some embodiments, the pharmaceutical composition is a pharmaceutical composition for nasal administration.
In another aspect, the pharmaceutical composition of the invention is for use in the treatment of neurological disorders.
In some embodiments, the pharmaceutical composition is used in stroke, brain contusion.
In some embodiments, the pharmaceutical composition can be administered nasally to achieve a significantly higher level of brain content than when administered intravenously, with higher brain penetration rates and brain-to-blood ratios, without increasing the risk of hypoglycemia.
The pharmaceutical composition can obviously improve the content of the medicine in the brain, increase the brain incidence rate and the brain blood ratio through nasal administration, realize brain targeting, does not increase the risk of hypoglycemia, and has obvious clinical value.
In summary, the beneficial effects of the invention are as follows:
(1) Compared with the prior art, the medicine composition of the invention obviously improves the solubility of the medicine, so that the composition is suitable for nasal administration;
(2) Compared with the existing intravenous administration technology, the pharmaceutical composition can obviously improve the content of the medicine in the brain, increase the cerebral incidence rate and the cerebral blood ratio through nasal administration, has definite brain targeting, does not increase the risk of hypoglycemia, and effectively avoids the technical problem of low concentration of the medicine in the brain caused by the risk of hypoglycemia when the intravenous injection is used for treating nervous system diseases such as apoplexy, cerebral contusion and the like;
(3) Compared with intravenous drip, the nasal cavity medicine has better compliance, does not destroy the barrier of the organism and has better safety.
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The present embodiments are merely examples and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
Example 1
Weighing a prescribed amount of Transcutol P (diethylene glycol monoethyl ether) and propylene glycol, uniformly mixing, adding a prescribed amount of glibenclamide for ultrasonic dissolution, adding a prescribed amount of dodecyl-beta-maltoside for stirring dissolution, and preparing the glibenclamide nasal administration preparation.
Table 1 glibenclamide nasal formulation recipe
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 16 |
| Transcutol P | Solvent(s) | 900 |
| Propylene glycol | Solubilizing solvent | 100 |
| Dodecyl-beta-maltoside | Penetration enhancer | 3 |
Example 2
Weighing a prescribed amount of Transcutol P (diethylene glycol monoethyl ether) and propylene glycol, uniformly mixing, adding a prescribed amount of glibenclamide for ultrasonic dissolution, adding a prescribed amount of dodecyl-beta-maltoside for stirring dissolution, and preparing the glibenclamide nasal administration preparation.
Table 2 glibenclamide nasal formulation recipe
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 8 |
| Transcutol P | Solvent(s) | 900 |
| Propylene glycol | Solubilizing solvent | 100 |
| Dodecyl-beta-maltoside | Penetration enhancer | 3 |
Example 3
Weighing the prescribed amount of Transcutol P and propylene glycol, uniformly mixing, adding the prescribed amount of glibenclamide for ultrasonic dissolution, adding the prescribed amount of sodium caprate for stirring dissolution, and preparing the glibenclamide nasal administration preparation.
Table 3 glibenclamide nasal formulation recipe
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 15 |
| Transcutol P | Solvent(s) | 900 |
| Propylene glycol | Solubilizing solvent | 100 |
| Capric acid sodium salt | Penetration enhancer | 3 |
Example 4
Weighing the Transcutol P and the polyethylene glycol 400 with the prescription amount, uniformly mixing, adding the glibenclamide with the prescription amount, mixing and dissolving by ultrasonic, and adding the PVPK30 with the prescription amount for dissolving to prepare the glibenclamide nasal administration preparation.
Table 4 glibenclamide nasal formulation prescription
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 2 |
| Transcutol P | Solvent(s) | 200 |
| Polyethylene glycol 400 | Solubilizing solvent | 800 |
| PVP K30 | Stabilizing agent | 60 |
Example 5
Weighing the Transcutol P with the prescription amount, uniformly mixing the Transcutol P with absolute ethyl alcohol, adding the glibenclamide with the prescription amount, and carrying out ultrasonic dissolution to obtain the glibenclamide nasal administration preparation.
Table 5 glibenclamide nasal formulation recipe
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 6 |
| Absolute ethyl alcohol | Solubilizing solvent | 200 |
| Transcutol P | Solvent(s) | 800 |
| Hydroxypropyl methylcellulose | Stabilizing agent | 50 |
Example 6
Weighing a prescribed amount of Transcutol P, adding a prescribed amount of glibenclamide for ultrasonic dissolution, and preparing the glibenclamide nasal administration preparation.
Table 6 glibenclamide nasal formulation recipe
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 10 |
| Transcutol P | Solvent(s) | 700 |
| Polyethylene glycol 400 | Solubilizing solvent | 300 |
| Ursodeoxycholic acid | Penetration enhancer | 3 |
Comparative example 1
Dissolving glibenclamide in dimethyl sulfoxide, ultrasonic treating to dissolve completely, adding propylene glycol and Solutol (polyethylene glycol-15 hydroxystearate), and mixing with water.
Table 7 glibenclamide formulation recipe
| Composition of the composition | Dosage of |
| Glibenclamide | 20mg |
| DMSO | 1.0ml |
| Propylene glycol | 2.0ml |
| Solutol | 2.0ml |
| Water and its preparation method | 5.0ml |
Experimental results: the preparation is clear and transparent, and is separated out after being placed for 2 hours at room temperature, the concentration of the detection solution is 1.41mg/ml, and the result shows that the dissolution stability of glibenclamide in a DMSO and propylene glycol system is poor.
Comparative example 2
Preparation of glibenclamide injection: 20mg of glibenclamide is weighed, dimethyl sulfoxide (DMSO) is added to 10ml, 2mg/ml stock solution is prepared, and then physiological saline is used for diluting to 0.02mg/ml liquid medicine.
Pharmacokinetic characteristics:
(1) Plasma pharmacokinetic study of nasal administration of glibenclamide in normal rats
Healthy SD rats, 20, were on a normal drinking diet, randomized into 4 groups, each: group B1, in which 10. Mu.l of the pharmaceutical composition of example 1 was instilled into the left and right nasal cavities of 4 rats in a conscious state, group A1, in which the pharmaceutical composition of comparative example 2 was injected into the 4 rats via the tail vein, at a dose of 0.1mg/kg, and 250. Mu.l of blood was collected from the jugular vein plexus of 0.083h, 0.33h, 0.67h, 1h, 2h, 4h, 8h, 10h, 24h before and after administration;
in group C1, 3. Mu.l of the pharmaceutical composition of glibenclamide of example 1 was instilled into the left and right nasal cavities of 6 rats, and in group D1, 6. Mu.l of the pharmaceutical composition of glibenclamide of example 2 was instilled into the left and right nasal cavities of 6 rats, and 250. Mu.l of blood was collected from the jugular vein plexus before and after administration for 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24 h.
The blood samples were placed in 1.5mL anticoagulant tubes coated with EDTA-K2 and centrifuged at 12000rpm for 5min before taking plasma. The concentration of glibenclamide in plasma obtained at different time points was determined by liquid chromatography and the principal pharmacokinetic parameters were calculated using the WinNonLin software (table 8).
Table 8 pharmacokinetic parameters of glibenclamide in rat plasma of each group (mean±sd, n=4, 6)
| Parameters (parameters) | Unit (B) | B1 group | C1 group | D1 group | Group A1 |
| t 1/2z | h | 7.78±6.64 | 8.17±2.54 | 10.30±7.34 | 5.85±0.97 |
| T max | h | 0.08±NA | 4.00±NA | 0.08±NA | 0.08±NA |
| C max | ng/mL | 264.05±102.59 | 52.72±21.65 | 61.59±45.00 | 90.08±4.78 |
| AUC last | h*ng/mL | 2251.45±685.52 | 638.22±161.32 | 508.35±200.75 | 263.44±80.68 |
| AUC INF | h*ng/mL | 2757.68±1412.82 | 746.81±198.92 | 634.43±312.37 | 287.82±63.94 |
| Vz/F | mL/kg | 6029.49±2004.05 | 7869.02±2992.07 | 11420.16±4469.56 | 3041.01±756.29 |
| Cl/F | mL/h/kg | 709.35±367.50 | 677.00±155.11 | 915.84±409.41 | 364.44±102.27 |
| MRT last | h | 7.20±2.22 | 7.89±1.28 | 8.04±1.21 | 5.46±1.44 |
(2) Brain tissue distribution study of glibenclamide nasal administration in normal rats
Healthy SD rats, 60, were randomly divided into 4 groups of 3 rats at each time point, each:
group B2, in which 10. Mu.l of the pharmaceutical composition of example 1 was instilled into the left and right nasal cavities of 18 rats in a conscious state, and group A2, in which the pharmaceutical composition of comparative example 2 was injected into the tail vein of 18 rats at a dose of 0.1mg/kg, blood glucose and jugular plexus were measured before administration, and jugular plexus blood collection, blood glucose measurement and brain tissue collection were sequentially performed for 0.25h, 1h, 2h, 4h, 8h, and 24h after administration;
in group C2, 3. Mu.l of the pharmaceutical composition of glibenclamide of example 1 was instilled into the left and right nasal cavities of 12 rats in the awake state, and 6. Mu.l of the pharmaceutical composition of glibenclamide of example 2 was instilled into the left and right nasal cavities of 12 rats in the awake state, blood glucose and jugular plexus blood were measured before administration, and jugular plexus blood was collected, and blood glucose and brain tissue were measured in this order 0.25h, 1h, 4h, and 24h after administration.
The plasma and brain tissue concentrations of glibenclamide were determined by liquid chromatography-mass spectrometry (table 9) and the cerebral blood ratio was calculated (table 10).
Table 9 glibenclamide concentration and blood glucose value (mean±sd, n=3) in brain homogenates at each time point for each group of rats
Note that: BQL is below the lower limit of quantification by 0.15ng/g
Table 10 concentration ratio of glibenclamide in brain tissue to plasma at each time point (mean±sd, n=3,%)
| Time (h) | B2 group | C2 group | D2 group | A2 group |
| 0.25 | 1.81±0.78 | 1.25±0.25 | 0.83±0.29 | 0.65±0.10 |
| 1 | 0.91±0.16 | 1.20±0.24 | 0.82±0.20 | 0.45±NA |
| 2 | 0.99±0.25 | / | / | 0.29±NA |
| 4 | 1.07±0.26 | 0.84±0.18 | 0.74±0.06 | / |
| 8 | 2.60±1.35 | / | / | / |
| 24 | 5.11±NA | / | / | / |
From the analysis of the results in the above table, it is known that, by taking the conventional injection administration A2 group as a comparative example, the concentration of the pharmaceutical composition of glibenclamide in brain tissue at each time point after nasal administration is remarkably increased to 1.6-24 times (table 9), and the cerebral blood ratio at each time point is increased to 1.3-3 times (table 10), which indicates that the glibenclamide has a nasal-brain direct transport route and remarkable brain targeting. Meanwhile, the blood concentration is related to the occurrence of hypoglycemia, and the blood plasma pharmacokinetic characteristics (Table 8) and the blood sugar value (Table 9) are combined, and the hypoglycemia can occur due to the excessive blood concentration after nasal administration of the B1 group, so that the consumption of glibenclamide in the pharmaceutical composition is reduced by the C and D groups, and the results show that the C1 and D1 groups are subjected to nasal administration max Are lower than those of intravenous administration group, and the lowest blood sugar values of C2 and D2 groups are higher than those of the intravenous administration groupThe minimum blood glucose value of the intravenous administration group indicates that the pharmaceutical composition of glibenclamide of the present invention has no higher risk of hypoglycemia than that of the intravenous administration group after nasal administration. Therefore, compared with intravenous administration groups, the pharmaceutical composition for nasal administration of glibenclamide can remarkably improve the cerebral input of the pharmaceutical composition, increase the cerebral input rate and the cerebral blood ratio, improve the cerebral targeting and simultaneously avoid the hypoglycemia side effect caused by glibenclamide in peripheral blood, and is expected to have remarkable clinical application value.
Claims (10)
- A pharmaceutical composition of glibenclamide for nasal administration, comprising glibenclamide, diethylene glycol monoethyl ether, and a solubilizing solvent.
- A pharmaceutical composition of glibenclamide according to claim 1, characterized in that it comprises, in parts by weight, 0.1-50 parts of glibenclamide, 1-5000 parts of diethylene glycol monoethyl ether and 1-1000 parts of solubilising solvent.
- A pharmaceutical composition of glibenclamide according to claim 1, characterized in that it comprises, in parts by weight, 0.5-40 parts of glibenclamide; preferably, comprises 2-20 parts of glibenclamide; the pharmaceutical composition comprises 100-4000 parts by weight of diethylene glycol monoethyl ether; preferably, the diethylene glycol monoethyl ether is comprised in 200-1000 parts.
- A pharmaceutical composition of glibenclamide according to claim 1, characterized in that the solubilising solvent is selected from one or more of propylene glycol, polyethylene glycol, ethanol, isopropanol, glycerol; preferably, the solubilizing solvent is selected from one or more of propylene glycol, polyethylene glycol and ethanol; preferably, the pharmaceutical composition comprises 5 to 1000 parts by weight of the solubilizing solvent, more preferably, 50 to 800 parts by weight of the solubilizing solvent.
- A pharmaceutical composition of glibenclamide according to claim 1, characterized in that it further comprises one or more combinations of permeation promoters, stabilizers.
- A pharmaceutical composition of glibenclamide according to claim 5, characterized in that the permeation enhancer is selected from the group consisting of sodium dodecyl- β -maltoside, sodium 8- (2-hydroxybenzoamide) octoate, sodium caprate, sodium octoate, sodium cholate, deoxycholic acid, ursodeoxycholic acid, taurodeoxycholic acid, sucrose monolaurate, EDTA, sodium dodecyl sulfate, lauroyl carnitine, chitosan, palmitoyl carnitine; preferably, the penetration enhancer is selected from one or more of dodecyl-beta-maltoside, sodium caprate, sodium caprylate, sodium cholate, deoxycholic acid and ursodeoxycholic acid; more preferably, the penetration enhancer is selected from one or more of dodecyl-beta-maltoside, sodium caprate and ursodeoxycholic acid; preferably, the content of the penetration enhancer is 0.1-10 parts by weight; more preferably, the penetration enhancer is 1-5 parts; further preferably, the penetration enhancer is contained in an amount of 2 to 3 parts.
- A pharmaceutical composition of glibenclamide according to claim 5, characterized in that the stabilizer is selected from one or more of povidone, gelatin, xanthan gum, acacia gum, tragacanth gum, dextran, sodium alginate, sodium carboxymethylcellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, carbomer, polyvinyl alcohol; preferably, the stabilizer is selected from one or more of povidone, gelatin, xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose and hypromellose; more preferably, the stabilizer is selected from one or more of povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, and hypromellose; preferably, the pharmaceutical composition comprises 0.5 to 200 parts by weight of a stabilizer; preferably, 1 to 100 parts of stabilizer is contained; more preferably, the stabilizer is contained in an amount of 10 to 80 parts.
- A method for preparing a pharmaceutical composition of glibenclamide according to any one of claims 1 to 7, characterized in that the preparation method comprises the steps of uniformly mixing a prescribed amount of diethylene glycol monoethyl ether and a solubilizing solvent, and adding the prescribed amount of glibenclamide for ultrasonic dissolution; preferably, the preparation method further comprises the step of adding one or more of a permeation enhancer and a stabilizer.
- A pharmaceutical composition of glibenclamide according to any one of claims 1 to 7, characterized in that it is a pharmaceutical composition for nasal administration.
- Use of a pharmaceutical composition of glibenclamide according to any one of claims 1 to 7 in the treatment of neurological diseases; preferably, the pharmaceutical composition of glibenclamide is used for treating apoplexy and cerebral contusion.
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