CN116600814A - Pharmaceutical composition of glibenclamide and preparation method thereof - Google Patents
Pharmaceutical composition of glibenclamide and preparation method thereof Download PDFInfo
- Publication number
- CN116600814A CN116600814A CN202180076960.4A CN202180076960A CN116600814A CN 116600814 A CN116600814 A CN 116600814A CN 202180076960 A CN202180076960 A CN 202180076960A CN 116600814 A CN116600814 A CN 116600814A
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- Prior art keywords
- glibenclamide
- parts
- pharmaceutical composition
- propylene glycol
- polyoxyethylene
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- 230000004112 neuroprotection Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
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- 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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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 pharmaceutical composition of glibenclamide and a preparation method thereof, which is submitted to the China national intellectual property agency on the 11 th month 17 th year 2020, with the patent application number of 202011284487.2. 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.
The volume of the nasal administration is very small (the general administration volume of a human body is less than 200 microliters), and the glibenclamide is weak acid and has poor solubility, especially has extremely low solubility in water under neutral and low pH conditions, has the solubility of less than 5 mug/ml, and in addition, the use of the glibenclamide is greatly limited because the pH of the nasal administration preparation is not too high, so that the glibenclamide solution preparation 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 existing glibenclamide has low brain penetration rate, and medicines can enter the brain only through blood brain barrier after oral administration and intravenous injection administration, so that the concentration of the medicines 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 medicine concentration 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, which comprises, by weight, 1-100 parts of glibenclamide, 100-1000 parts of a surfactant, 50-800 parts of an oil phase and 10-1000 parts of an aqueous phase.
In some embodiments, the pharmaceutical composition comprises 1-50 parts by weight of glibenclamide, preferably 2-20 parts by weight of glibenclamide.
In some embodiments, the surfactant is selected from one or more of diethylene glycol monoethyl ether, tween, polyoxyethylene ether-35 castor oil, polyoxyethylene ether-40 hydrogenated castor oil, caprylic capric polyethylene glycol glyceride, stearoyl polyoxyethylene glyceride, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene sorbitan fatty acid ester, phospholipid, polyethylene glycol-15 hydroxystearate, coconut oil C8/C10 polyethylene glycol glyceride, vitamin E polyethylene glycol succinate.
In some embodiments, the surfactant is selected from one or more of diethylene glycol monoethyl ether, tween, polyoxyethylene ether-35 castor oil, polyoxyethylene ether-40 hydrogenated castor oil, caprylic capric polyethylene glycol glyceride, stearoyl polyoxyethylene glyceride, polyoxyethylene-polyoxypropylene copolymer.
In some embodiments, the surfactant is selected from one or more of diethylene glycol monoethyl ether, tween, polyoxyethylene ether-35 castor oil, polyoxyethylene ether-40 hydrogenated castor oil, caprylic capric polyethylene glycol glyceride.
In some embodiments, the pharmaceutical composition comprises, in parts by weight, 200-900 parts of a surfactant; preferably, the surfactant is contained in an amount of 250 to 700 parts.
In some embodiments, the oil phase is selected from the group consisting of propylene glycol monocaprylate, oleoyl polyoxyethylene glyceride, caprylic capric mono-di-glyceride, monolinoleate, medium chain triglycerides, glyceryl triacetate, propylene glycol dicaprylate, glyceryl dipalmitate stearate, glyceryl monostearate, glyceryl distearate, propylene glycol monolaurate, polyglycerol oleate, stearyl, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, corn oil, soybean oil, olive oil, oleic acid, linoleic acid, and combinations of one or more thereof.
In some embodiments, the oil phase is selected from the group consisting of propylene glycol monocaprylate, oleic acid, oleoyl polyoxyethylene glyceride, caprylic capric acid mono-di-glyceride, glyceryl distearate, propylene glycol monolaurate, polyglycerol oleate, stearyl, glyceryl monooleate, isopropyl myristate, isopropyl palmitate.
In some embodiments, the oil phase is selected from one or more of propylene glycol monocaprylate, oleic acid, oleoyl polyoxyethylene glyceride, caprylic capric acid mono-diglyceride.
In some embodiments, the pharmaceutical composition comprises 100-500 parts by weight of an oil phase; preferably, 130-400 parts of oil phase are included.
In some embodiments, the pharmaceutical composition comprises 50-800 parts by weight of the aqueous phase, preferably 100-350 parts by weight of the aqueous phase.
In some embodiments, the pharmaceutical composition further comprises a combination of one or more of a cosurfactant, a stabilizer.
In some embodiments, the cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, glycerol, ethanol, isopropanol, propylene glycol monolaurate, polyglycerol oleate, diethylene glycol monoethyl ether, propylene glycol monocaprylate.
In some embodiments, the cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, glycerol, ethanol, isopropanol, diethylene glycol monoethyl ether, propylene glycol monocaprylate.
In some embodiments, the cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, propylene glycol monocaprylate.
In some embodiments, the cosurfactant is used in an amount of 10 to 800 parts by weight; preferably, the cosurfactant is used in an amount of 50-600 parts; more preferably, the cosurfactant is used in an amount of 80-300 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, hypromellose, hydroxypropyl cellulose, methylcellulose, carbomer, polyvinyl alcohol; preferably, the stabilizer is selected from one or more of povidone, gelatin, xanthan gum, sodium carboxymethylcellulose and hydroxypropyl cellulose; more preferably, the stabilizer is selected from one or more of povidone, sodium carboxymethyl cellulose and hydroxypropyl cellulose.
In some embodiments, the pharmaceutical composition comprises 10-200 parts of a stabilizer, in parts by weight; preferably, the pharmaceutical composition comprises 50-150 parts of a stabilizer; more preferably, the pharmaceutical composition comprises 80-120 parts of stabilizer.
On the other hand, the invention also relates to a preparation method of the glibenclamide pharmaceutical composition for nasal administration, which comprises the steps of uniformly mixing a surfactant and an oil phase according to the prescription amount, adding glibenclamide for ultrasonic dissolution, and adding water phase for uniform mixing.
In some embodiments, the method of preparing a pharmaceutical composition further comprises the step of adding a combination of one or more of a cosurfactant, a stabilizer.
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, nasal administration of the pharmaceutical composition achieves a significantly higher level in the brain than when administered intravenously, without increasing the risk of hypoglycemia.
The pharmaceutical composition provided by the invention can be administered through nose to obviously improve the brain content of the medicine, improve brain targeting, and 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 nasal administration of the pharmaceutical composition can obviously improve the brain content of the medicine, 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 intravenous injection is used for treating nervous system diseases such as apoplexy, brain 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 the diethylene glycol monoethyl ether and the propylene glycol monocaprylate with the prescription amount, uniformly mixing, adding the glibenclamide with the prescription amount for ultrasonic dissolution, adding the PVPK30 with the prescription amount for dissolution, and adding the purified water with the prescription amount for uniform mixing to obtain the clear and transparent glibenclamide microemulsion.
Table 1 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 11 |
| Diethylene glycol monoethyl ether | Surface active agent | 700 |
| Propylene glycol monocaprylate | Oil phase | 200 |
| Water and its preparation method | Aqueous phase | 100 |
| pvpk30 | Stabilizing agent | 100 |
Example 2
Weighing the diethylene glycol monoethyl ether and the propylene glycol monocaprylate with the prescription amount, uniformly mixing, adding the glibenclamide with the prescription amount for ultrasonic dissolution, adding the purified water with the prescription amount for uniform mixing, and obtaining the clear and transparent glibenclamide microemulsion.
Table 2 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 12 |
| Diethylene glycol monoethyl ether | Surface active agent | 700 |
| Propylene glycol monocaprylate | Oil phase | 200 |
| Water and its preparation method | Aqueous phase | 100 |
Example 3
Weighing the diethylene glycol monoethyl ether and the propylene glycol monocaprylate with the prescription amount, uniformly mixing, adding the glibenclamide with the prescription amount for ultrasonic dissolution, adding the purified water with the prescription amount for uniform mixing, and obtaining the clear and transparent glibenclamide microemulsion.
Table 3 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 6 |
| Diethylene glycol monoethyl ether | Surface active agent | 700 |
| Propylene glycol monocaprylate | Oil phase | 200 |
| Water and its preparation method | Aqueous phase | 100 |
Example 4
Weighing and mixing the Tween 80, propylene glycol monocaprylate and propylene glycol with the prescription amount, adding the glibenclamide with the prescription amount for ultrasonic dissolution, adding the purified water with the prescription amount for uniform mixing, and obtaining the clear and transparent glibenclamide microemulsion.
Table 4 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 10 |
| Tween 80 | Surface active agent | 500 |
| Propylene glycol monocaprylate | Oil phase | 200 |
| Propylene glycol | Cosurfactant | 200 |
| Water and its preparation method | Aqueous phase | 100 |
Example 5
Weighing polyoxyethylene ether-35 castor oil, propylene glycol monocaprylate and diethylene glycol monoethyl ether with a prescription amount, uniformly mixing, adding the glibenclamide with the prescription amount for ultrasonic dissolution, adding the purified water with the prescription amount for uniform mixing, and obtaining the clear and transparent glibenclamide microemulsion.
Table 5 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 2.5 |
| Polyoxyethylene ether-35 castor oil | Surface active agent | 272 |
| Propylene glycol monocaprylate | Oil phase | 142 |
| Diethylene glycol monoethyl ether | Cosurfactant | 278 |
| Water and its preparation method | Aqueous phase | 308 |
Example 6
Weighing and uniformly mixing Tween 80, oleic acid and propylene glycol in a prescription amount, adding glibenclamide in the prescription amount for ultrasonic dissolution, adding purified water in the prescription amount for uniform mixing, and obtaining clear and transparent glibenclamide microemulsion.
Table 6 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 4 |
| Tween 80 | Surface active agent | 500 |
| Oleic acid | Oil phase | 200 |
| Propylene glycol | Cosurfactant | 200 |
| Water and its preparation method | Aqueous phase | 100 |
Example 7
Weighing and mixing the caprylic-capric acid polyethylene glycol glyceride, the oleoyl polyoxyethylene glyceride, the propylene glycol monocaprylate and the diethylene glycol monoethyl ether with the prescription dose, adding the prescription dose of glibenclamide for ultrasonic dissolution, adding the prescription dose of purified water, and mixing uniformly to obtain the clear and transparent glibenclamide microemulsion.
Table 7 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 4 |
| Caprylic capric polyethylene glycol glyceride | Surface active agent | 500 |
| Oleoyl polyoxyethylene glyceride | Oil phase | 200 |
| Diethylene glycol monoethyl ether | Surface active agent | 120 |
| Propylene glycol monocaprylate | Cosurfactant | 80 |
| Water and its preparation method | Aqueous phase | 100 |
Example 8
And weighing the caprylic/capric acid mono/diglyceride, polyoxyethylene ether-35 castor oil and polyethylene glycol 400 according to the prescription amount, stirring, and performing ultrasonic treatment until the mixture is a uniform transparent solution to obtain the self-emulsifying matrix. Adding the glibenclamide with the prescription amount, and performing ultrasonic treatment until the glibenclamide is completely dissolved.
Table 8 prescription of pharmaceutical compositions of glibenclamide
| Composition of the composition | Action | Dosage (mg) |
| Glibenclamide | Main component | 3 |
| Caprylic capric acid mono-diglyceride | Oil phase | 400 |
| Polyoxyethylene ether-35 castor oil | Surface active agent | 400 |
| Polyethylene glycol 400 | Cosurfactant | 100 |
| Water and its preparation method | Aqueous phase | 100 |
Comparative example 1
Weighing the prescribed amount of glibenclamide, dissolving in dimethyl sulfoxide, carrying out ultrasonic treatment until the glibenclamide is completely dissolved, adding propylene glycol, solutol and water, and uniformly mixing.
Table 9 prescription of pharmaceutical compositions of glibenclamide
| 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, 7, were randomized into 2 groups, each: group B1, 3 rats were given dropwise 10 μl of the pharmaceutical composition of example 4 to the left and right nasal cavities in a conscious state, 250 μl of blood was collected from the jugular vein plexus of 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h, and the A1 group, and 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 μl of blood was collected from the jugular vein plexus of 0.083h, 0.33h, 0.67h, 1h, 2h, 4h, 8h, 10h, and 24h before and after administration; the blood samples were placed in 1.5mL anticoagulant tubes coated with EDTA-K2 and centrifuged at 12000rpm for 5min before taking plasma. The plasma concentrations of glibenclamide obtained at the various time points were determined by means of liquid chromatography and the principal pharmacokinetic parameters were calculated using the WinNonLin software (table 10).
Table 10 pharmacokinetic parameters of glibenclamide in rat plasma of each group (mean±sd, n=3, 4)
| Parameters (parameters) | Unit (B) | B1 group | Group A1 |
| t 1/2z | h | 8.01±1.13 | 5.85±0.97 |
| T max | h | 4.03±NA | 0.08±NA |
| C max | ng/mL | 68.02±11.25 | 90.08±4.78 |
| AUC last | h*ng/mL | 937.30±93.03 | 263.44±80.68 |
| AUC INF | h*ng/mL | 1063.44±136.13 | 287.82±63.94 |
| Vz/F | mL/kg | 8702.24±682.14 | 3041.01±756.29 |
| Cl/F | mL/h/kg | 760.86±100.85 | 364.44±102.27 |
| MRT last | h | 7.96±0.53 | 5.46±1.44 |
(2) Brain tissue distribution study of glibenclamide nasal administration in normal rats
Healthy SD rats, 24, were randomly divided into 2 groups of 3 rats at each time point, each: group B2, in which 10. Mu.l of the pharmaceutical composition of glibenclamide of example 4 was instilled into the left and right nasal cavities of 6 rats in a conscious state, and blood glucose was measured at 0.25h and 1h after administration, and blood glucose was measured at 0.25h, and group A2, in which 18 rats were injected with the pharmaceutical composition of glibenclamide of comparative example 2 via the tail vein at a dose of 0.1mg/kg, blood glucose and jugular plexus were measured before administration, and jugular plexus blood was measured, and blood glucose was measured and brain tissue was measured at 0.25h, 1h, 2h, 4h, 8h, and 24h after administration; the obtained brain tissue was homogenized by removing blood vessels, sucking out water. Determination of glibenclamide concentration in brain tissue by LC-MS (Table 11)
Table 11 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
As can be seen from the analysis of the results in the above table, the concentration of the pharmaceutical composition of glibenclamide in brain tissue after nasal administration is significantly increased to 7-8 times by taking the conventional A2 group for injection administration as a comparative example (Table 11); meanwhile, the blood concentration was associated with the occurrence of hypoglycemia, and group B1 was nasally administered C in combination with the plasma pharmacokinetic properties (Table 10) and blood glucose values (Table 11) max Lower than the intravenous administration group, and the blood sugar value after administration is higher than the lowest blood sugar value of the intravenous administration group, which indicates that the hypoglycemia risk of the glibenclamide pharmaceutical composition provided by the invention after nasal administration is not higher than that of the intravenous administration group. Therefore, compared with intravenous administration groups, the pharmaceutical composition of the invention for nasal administration of glibenclamide can significantly improve the brain penetration of the drug, and simultaneously does not increase the hypoglycemia side effect caused by glibenclamide in peripheral blood, and is expected to beHas remarkable clinical application value.
Claims (10)
- The pharmaceutical composition for nasal administration is characterized by comprising, by weight, 1-100 parts of glibenclamide, 100-1000 parts of a surfactant, 50-800 parts of an oil phase and 10-1000 parts of an aqueous phase.
- A pharmaceutical composition of nasally administrable glibenclamide according to claim 1, characterized in that it comprises, in parts by weight, 1-50 parts of glibenclamide; preferably, 2-20 parts of glibenclamide are contained.
- A pharmaceutical composition of nasally administered glibenclamide according to claim 1, characterized in that the surfactant is selected from one or more of diethylene glycol monoethyl ether, tween, polyoxyethylene ether-35 castor oil, polyoxyethylene ether-40 hydrogenated castor oil, caprylic acid capric acid polyethylene glycol glyceride, stearoyl polyoxyethylene glyceride, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene sorbitan fatty acid ester, phospholipid, polyethylene glycol-15 hydroxystearate, coconut oil C8/C10 polyethylene glycol glyceride, vitamin E polyethylene glycol succinate; preferably, the surfactant is selected from one or more of diethylene glycol monoethyl ether, tween, polyoxyethylene ether-35 castor oil, polyoxyethylene ether-40 hydrogenated castor oil, caprylic/capric polyethylene glycol glyceride, stearoyl polyoxyethylene glyceride and polyoxyethylene-polyoxypropylene copolymer; more preferably, the surfactant is selected from one or more of diethylene glycol monoethyl ether, tween, polyoxyethylene ether-35 castor oil, polyoxyethylene ether-40 hydrogenated castor oil and caprylic/capric polyethylene glycol glyceride; the medicine composition comprises 200-900 parts by weight of surfactant; preferably, the surfactant is contained in an amount of 250 to 700 parts.
- A pharmaceutical composition of nasally administered glibenclamide according to claim 1, characterized in that the oil phase is selected from one or more of propylene glycol monocaprylate, oleoyl polyoxyethylene glyceride, caprylic capric monodiglyceride, monolinoleate, medium chain triglycerides, triacetin, propylene glycol dicaprylic caprate, dipalmitoyl glyceryl stearate, glyceryl monostearate, glyceryl distearate, propylene glycol monolaurate, polyglycerol oleate, stearyl, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, corn oil, soybean oil, olive oil, oleic acid, linoleic acid; preferably, the oil phase is selected from one or more of propylene glycol monocaprylate, oleic acid, oleoyl polyoxyethylene glyceride, caprylic capric acid mono-diglyceride, glyceryl distearate, propylene glycol monolaurate, polyglycerol oleate, stearyl, glyceryl monooleate, isopropyl myristate and isopropyl palmitate; more preferably, the oil phase is selected from one or more of propylene glycol monocaprylate, oleic acid, oleoyl polyoxyethylene glyceride, caprylic capric acid mono-diglyceride.
- A pharmaceutical composition of nasally administered glibenclamide according to claim 1, characterized in that it comprises, in parts by weight, 100-500 parts of an oily phase; preferably, it comprises 130-400 parts of oil phase; the pharmaceutical composition comprises, in parts by weight, 50-800 parts of an aqueous phase, preferably 100-350 parts of an aqueous phase.
- A pharmaceutical composition of nasally administered glibenclamide according to claim 1, characterized in that it further comprises a combination of one or more cosurfactants, stabilizers.
- A pharmaceutical composition of nasally administered glibenclamide according to claim 6, characterized in that said cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, glycerol, ethanol, isopropanol, propylene glycol monolaurate, polyglycerol oleate, diethylene glycol monoethyl ether, propylene glycol monocaprylate; preferably, the cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, glycerol, ethanol, isopropanol, diethylene glycol monoethyl ether and propylene glycol monocaprylate; more preferably, the cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, propylene glycol monocaprylate; preferably, the cosurfactant is used in an amount of 10-800 parts by weight; more preferably, the cosurfactant is used in an amount of 50-600 parts; further preferably, the cosurfactant is used in an amount of 80-300 parts.
- A pharmaceutical composition of nasally administrable glibenclamide according to claim 6, characterized in that the stabilizer is selected from one or more of povidone, gelatin, xanthan gum, acacia, tragacanth, dextran, sodium alginate, sodium carboxymethyl cellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, carbomer, polyvinyl alcohol; preferably, the stabilizer is selected from one or more of povidone, gelatin, xanthan gum, sodium carboxymethylcellulose and hydroxypropyl cellulose; more preferably, the stabilizer is selected from one or more of povidone, sodium carboxymethyl cellulose and hydroxypropyl cellulose; preferably, the pharmaceutical composition comprises 10-200 parts of stabilizer in parts by weight; more preferably, the pharmaceutical composition comprises 50-150 parts of a stabilizer; further preferably, the pharmaceutical composition comprises 80-120 parts of stabilizer.
- A method for preparing a pharmaceutical composition according to any one of claims 1-8, wherein the surfactant and the oil phase are mixed uniformly according to the prescribed amount, glibenclamide is added for ultrasonic dissolution, and water phase is added for uniform mixing; preferably, the preparation method of the pharmaceutical composition further comprises the step of adding one or more of cosurfactants and stabilizers.
- Use of a pharmaceutical composition of a nasally administered glibenclamide according to any one of claims 1 to 8 for the treatment of neurological diseases; preferably, the pharmaceutical composition of the glibenclamide which is administrated through nose is used for treating apoplexy and cerebral contusion.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020112844872 | 2020-11-17 | ||
| CN202011284487 | 2020-11-17 | ||
| PCT/CN2021/130724 WO2022105720A1 (en) | 2020-11-17 | 2021-11-15 | Glibenclamide pharmaceutical composition and preparation method therefor |
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| Publication Number | Publication Date |
|---|---|
| CN116600814A true CN116600814A (en) | 2023-08-15 |
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| CN202180076960.4A Pending CN116600814A (en) | 2020-11-17 | 2021-11-15 | Pharmaceutical composition of glibenclamide and preparation method thereof |
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| Country | Link |
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| CN (1) | CN116600814A (en) |
| WO (1) | WO2022105720A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006041922A2 (en) * | 2004-10-08 | 2006-04-20 | Dara Biosciences, Inc. | Agents and methods for administration to the central nervous system |
| CN108078999B (en) * | 2017-12-22 | 2020-08-14 | 沈阳药科大学 | Pharmaceutical composition for preventing and treating cerebral arterial thrombosis and preparation method and application thereof |
| CN108310387A (en) * | 2018-03-23 | 2018-07-24 | 昆药集团股份有限公司 | A kind of combination product and its application for preventing and/or treating cerebral ischemia |
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- 2021-11-15 CN CN202180076960.4A patent/CN116600814A/en active Pending
- 2021-11-15 WO PCT/CN2021/130724 patent/WO2022105720A1/en active Application Filing
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| WO2022105720A1 (en) | 2022-05-27 |
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