Preparation method of ibuprofen-containing composition and its products and applications

Abstract

The present application belongs to the field of pharmaceutical preparations, and provides a method for preparing a composition containing ibuprofen and its corresponding products and applications, the method comprising: (1) mixing ibuprofen and a matrix in the presence of an organic solvent; (2) adding the mixed product of step (1) to water in the presence of an emulsifier and then sealing; (3) blowing the sealed product of step (2). The ibuprofen-containing composition prepared by the method can not only be released quickly to achieve a rapid onset effect, but also last for a long time to achieve a longer duration of drug effect, while providing better drug absorption.

Description

[0001] This application is a divisional application of the Chinese patent application with application date of September 12, 2024, application number 202411273300.7, and invention name “Preparation method of drug-containing composition, its product and application”. The contents recorded in the parent application are incorporated into this application. Field of the Invention

[0002] The present application belongs to the field of pharmaceutical preparations. Specifically, the present application provides a preparation method of an ibuprofen-containing composition and a product and application thereof. Background Art

[0003] In the prior art, many pharmaceutical preparations have limitations in drug release speed and cannot meet the needs of quick release and sustained release at the same time. Taking ibuprofen as an example, ibuprofen is considered to be the safest non-steroidal anti-inflammatory drug, mainly composed of equal amounts of levulo-ibuprofen and dextro-ibuprofen, which inhibits cyclooxygenase, reduces the synthesis of prostaglandins, and produces analgesic and anti-inflammatory effects. It is used to relieve mild to moderate pain such as headache, arthralgia, migraine, toothache, myalgia, neuralgia, and dysmenorrhea. It is also used for the fever caused by the common cold or influenza. A kind of ibuprofen sustained-release microsphere disclosed in CN113133971A, although its release lasts for a long time, it needs a long time to be released to the required amount, to achieve the effect of pain relief. Another kind of ibuprofen rapid-release medicine can quickly release ibuprofen, the effect of pain relief achieved quickly, but the duration is short, and it is necessary to take medicine repeatedly in a short time to achieve both pain relief and side effects. Summary of the invention

[0004] In one aspect, the present application provides a method for preparing a drug-containing composition, the method comprising:

[0005] (1) mixing the drug and the matrix in the presence of an organic solvent;

[0006] (2) adding the mixed product of step (1) into water in the presence of an emulsifier and then sealing the water;

[0007] (3) blowing the sealed product of step (2);

[0008] Wherein, the matrix is ​​selected from at least one of polyacrylic acid resin RS100, ethyl cellulose, gelatin, sodium alginate, chitosan, glycolide-lactide copolymer 7525 and glycolide-lactide copolymer 5050;

[0009] The drug is a fat-soluble drug;

[0010] The sealing conditions include: temperature of 0-15°C and time of 0.1-1h;

[0011] The conditions for blowing air include: temperature of 20-35°C, time of 0.1-2h, wind speed of 1-10m 3 / min.

[0012] Further, the weight ratio of the drug to the matrix is ​​1:0.1-10;

[0013] And / or, the drug is acetaminophen, diclofenac sodium, cobotide, oxycodone hydrochloride, tramadol, codeine, aspirin, ibuprofen, indomethacin, naproxen, acetaminophen, rofecoxib, dextromethorphan hydrobromide, pentoxyverine, guaifenesin, acetylcysteine, ambromide, bromhexine, ramelteon, zolpidem tartrate, zopiclone, eszopiclone, zaleplon, spironolactone, hydrochlorothiazide, metoprolol, bisoprolol, amlodipine, nifedipine, enalapril One of the following: metformin, ramipril, captopril, valsartan, losartan, candesartan, irbesartan, metformin, acarbose, gliclazide, glibenclamide, voglibose, carbidopa, levodopa, pramipexole, selegiline, bromocriptine, piribedil, amantadine, entacapone, sodium valproate, ethosuximide, carbamazepine, phenytoin, phenobarbital, primidone, galantamine hydrobromide, quetiapine fumarate, rivastigmine, donepezil, methylphenidate, guanfacine, and risperidone.

[0014] Further, the content of the drug in the mixed system is 2-60% by weight;

[0015] And / or, the glycolide-lactide copolymer 7525 and the glycolide-lactide copolymer 5050 have a weight average molecular weight of 10,000-50,000 and a viscosity of 0.1-0.5 dl / g.

[0016] Further, the weight ratio of the emulsifier to water is 1:10-1000;

[0017] And / or, the mixing conditions include: temperature of 0-30° C. and time of 0.1-3 h.

[0018] Further, the organic solvent is selected from at least one of ethanol, acetone, ethyl acetate, dichloromethane and methyl acetate;

[0019] And / or, the emulsifier is selected from at least one of sucrose fatty acid esters, polyoxyl (40) stearate, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, polyoxypropylene polyoxyethylene copolymer and sodium lauryl sulfate.

[0020] Furthermore, the method also includes performing solid-liquid separation on the product obtained in step (3).

[0021] On the other hand, the present application provides a drug-containing composition prepared according to the above method.

[0022] Further, the composition consists of a matrix and a drug dispersed in the matrix;

[0023] and / or, the weight ratio of the drug to the matrix in the drug-containing composition is 1:0.1-10;

[0024] And / or, the drug-containing composition is a microsphere, and the particle size of the microsphere is 100-700 μm;

[0025] On the other hand, the present application provides the use of the above composition in preparing a pharmaceutical preparation.

[0026] Furthermore, the pharmaceutical preparation is a dry suspension, tablet, capsule, dispersible tablet or orodisintegrating tablet.

[0027] The blowing mentioned in the present invention is transverse blowing, that is, the blowing direction is substantially parallel to the liquid surface of the sealed product. Due to the airflow diffusion angle provided by the blowing instrument and the spontaneous diffusion behavior of the airflow, the blowing direction being completely parallel to the liquid surface is only an ideal state. In actual operation, the "substantially parallel" means that the angle between the axial direction of the blown air and the liquid surface does not exceed a certain angle, such as 30°, 20°, 10°, 5°, etc.

[0028] In the present invention, in order to allow the drug in the obtained composition to be released quickly and continuously, the weight ratio of the drug to the matrix is ​​1:0.1-10, and can be 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 or a range formed by any two of the above values ​​and a value in the range.

[0029] In the present invention, the content of the drug in the mixed system is 2-60% by weight, which can be 2% by weight, 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight or a range formed by any two of the above values ​​and the value of the range.

[0030] In addition to the above-listed types, in the present invention, the drug can be a fat-soluble drug selected from analgesics, non-steroidal anti-inflammatory drugs, antitussives, hypnotics, antihypertensives, hypoglycemics, anti-Parkinson's disease drugs, anti-epileptic drugs and psychotropic drugs.

[0031] In the present invention, the analgesic is one of acetaminophen, diclofenac sodium, cobotide, oxycodone hydrochloride, tramadol and codeine.

[0032] In the present invention, the non-steroidal anti-inflammatory drug is one of aspirin, ibuprofen, indomethacin, naproxen, acetaminophen and rofecoxib.

[0033] In the present invention, the antitussive is one of dextromethorphan hydrobromide, pentoxyverine, guaifenesin, acetylcysteine, ambromide and bromhexine.

[0034] In the present invention, the hypnotic drug is one of ramelteon, zolpidem tartrate, zopiclone, s-zopiclone and zaleplon.

[0035] In the present invention, the antihypertensive drug is one of spironolactone, hydrochlorothiazide, metoprolol, bisoprolol, amlodipine, nifedipine, enalapril, ramipril, captopril, valsartan, losartan, candesartan and irbesartan.

[0036] In the present invention, the hypoglycemic drug is one of metformin, acarbose, gliclazide, glibenclamide and voglibose.

[0037] In the present invention, the anti-Parkinson's disease drug is one of carbidopa, levodopa, pramipexole, selegiline, bromocriptine, piribedil, amantadine and entacapone.

[0038] In the present invention, the antiepileptic drug is one of sodium valproate, ethosuximide, carbamazepine, phenytoin sodium, phenobarbital and primidone.

[0039] In the present invention, the psychotropic drug is one of galantamine hydrobromide, quetiapine fumarate, rivastigmine, donepezil, methylphenidate, guanfacine and risperidone.

[0040] In the present invention, the PLGA (co-glycolide lactide) 7525 is a glycolide lactide copolymer having a glycolide to lactide molar ratio of 3:1; the PLGA (co-glycolide lactide) 5050 is a glycolide lactide copolymer having a glycolide to lactide molar ratio of 1:1. In the present invention, the weight average molecular weight of the glycolide lactide copolymer is 10000-50000, and can be 10000, 20000, 30000, 40000, 50000 or a range formed by any two of the above values ​​and a value within the range, and the viscosity is 0.1-0.5dl / g, and can be 0.1dl / g, 0.2dl / g, 0.3dl / g, 0.4dl / g, 0.5dl / g or a range formed by any two of the above values ​​and a value within the range.

[0041] In the present invention, the weight ratio of the emulsifier to water is 1:10-1000, and can be 1:10, 1:50, 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, 1:1000 or a range formed by any two of the above values ​​and a value in that range.

[0042] In the present invention, the mixing conditions include: a temperature of 0-30°C, which can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C or a range formed by any two of the above values ​​and a value in the range; a time of 0.1-3h, which can be 0.1h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h or a range formed by any two of the above values ​​and a value in the range.

[0043] In the present invention, in order to allow the drug in the obtained composition to be released quickly and continuously, the sealing conditions include: a temperature of 0-15°C, which can be 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C or a range formed by any two of the above values ​​and a value in the range; a time of 0.1-1h, which can be 0.1h, 0.2h, 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h or a range formed by any two of the above values ​​and a value in the range.

[0044] In the present invention, in order to allow the drug in the obtained composition to be released quickly and continuously, the blowing conditions include: a temperature of 20-35°C, which can be 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 33°C, 35°C or a range formed by any two of the above values ​​and a value in the range; a time of 0.1-2h, which can be 0.1h, 0.2h, 0.4h, 0.6h, 0.8h, 1h, 1.2h, 1.4h, 1.6h, 1.8h, 2h or a range formed by any two of the above values ​​and a value in the range; a wind speed of 1-10m 3 / min, can be 1m 3 / min、2m 3 / min、3m 3 / min、4m 3 / min、5m 3 / min、6m 3 / min、7m 3 / min、8m 3 / min、9m 3 / min、10m 3 / min or the range formed by any two of the above values ​​and the value of the range.

[0045] In the present invention, the organic solvent is not limited as long as it can dissolve the drug and the matrix and is volatile. Preferably, the organic solvent is selected from at least one of ethanol, acetone, ethyl acetate, dichloromethane and methyl acetate.

[0046] In the present invention, the emulsifier is not limited and is an emulsifier commonly used by those skilled in the art. The emulsifier is selected from at least one of sucrose fatty acid esters, polyoxyl (40) stearate, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, polyoxypropylene polyoxyethylene copolymer and sodium lauryl sulfate.

[0047] In the present invention, stirring may be performed during the mixing process.

[0048] In the present invention, in order to obtain the composition, the method further comprises performing solid-liquid separation on the product obtained in step (3).

[0049] In the present invention, the method further comprises washing the solid obtained by solid-liquid separation.

[0050] On the other hand, the present application also provides a drug-containing composition prepared using the above preparation method.

[0051] Furthermore, the drug-containing composition consists of a matrix and the drug dispersed in the matrix.

[0052] In the present invention, the weight ratio of the drug to the matrix in the composition is 1:0.1-10, and can be 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 or a range formed by any two of the above values ​​and a value in the range.

[0053] In the present invention, the drug-containing composition is a microsphere, and the particle size of the microsphere is 100-700 μm, which can be 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm or a range formed by any two of the above values ​​and a value within the range.

[0054] In the present invention, the auxiliary materials are auxiliary materials commonly used in preparing medicines and can be added according to different preparations.

[0055] The drug-containing composition prepared by the method of the present invention can not only be released quickly to achieve a rapid effect, but also last for a long time to achieve a longer duration of drug effect. More preferably, the drug absorption degree is also higher, so it can not only take effect quickly, but also take effect continuously, reduce the number of medications and side effects. In addition, the preparation process of the method of the present invention is simple and controllable, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 is a transmission microscope photograph of the microspheres of Example 1-1;

[0057] Figure 2 is a transmission microscope photograph of the microspheres of Example 1-2;

[0058] Figure 3 This is a transmission microscope photo of the microspheres in Comparative Example 1-1;

[0059] Figure 4 This is a transmission microscope photo of the microspheres in Comparative Example 1-2;

[0060] Figure 5 is the change of blood drug concentration in rats of each group given ibuprofen;

[0061] Figure 6 is the change of blood drug concentration in each group of rats treated with metformin;

[0062] Figure 7 is the body temperature changes of rats in each group. DETAILED DESCRIPTION

[0063] In the following embodiments:

[0064] Ibuprofen Source: Hubei Hendi Pharmaceutical Co., Ltd.;

[0065] Polyacrylic acid resin RS100 Source: Evonik Specialty Chemicals (Shanghai) Co., Ltd.;

[0066] Sucrose fatty acid esters Source: Zhejiang Hetang Technology Co., Ltd.;

[0067] Stearic acid polyoxyl (40) ester Source: Nanjing Well Pharmaceutical Technology Co., Ltd.;

[0068] Polyvinyl alcohol source: Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd.;

[0069] Commercially available ibuprofen immediate release (suspension) Source: Shanghai Johnson & Johnson Pharmaceutical Co., Ltd.;

[0070] Commercially available ibuprofen sustained-release (capsules) Source: Sino-US Tianjin SmithKline Pharmaceutical Co., Ltd.;

[0071] Source of commercially available metformin tablets: Beijing Jingfeng Pharmaceutical Group;

[0072] Source of commercially available metformin extended-release tablets: Merck Pharmaceuticals (Jiangsu) Co., Ltd.;

[0073] Commercially available spironolactone tablets source: Pfizer Labs;

[0074] Commercially available dextromethorphan hydrobromide sustained-release tablets Source: Shanghai Modern Pharmaceutical Co., Ltd.;

[0075] Commercially available card levodopa sustained-release tablets Source: MSD Sharp & Dohme GmbH;

[0076] Commercially available sodium valproate sustained-release tablets source: Sanofi (Hangzhou) Pharmaceutical Co., Ltd.;

[0077] Commercially available quetiapine fumarate extended-release tablets source: AstraZeneca Pharmaceuticals Ltd.

[0078] Example 1: Preparation of ibuprofen microspheres.

[0079] Example 1-1:

[0080] (1) dissolving ibuprofen and polyacrylic acid resin RS100 in anhydrous ethanol at a weight ratio of 1:0.25 to form an oil phase, wherein the content of ibuprofen is 45% by weight, the temperature is 10-20° C., and the time is 1 hour;

[0081] (2) In a reaction kettle, sucrose fatty acid ester and water are mixed at a weight ratio of 1:400 to form an aqueous phase. Under stirring, the oil phase is added to the aqueous phase, and then the reaction kettle is immediately covered with a lid to seal the reaction kettle. The sealing temperature is 0-5° C. and the sealing time is 0.5 h.

[0082] (3) Open the lid and blow air horizontally at a temperature of 25-30°C for 1.5 hours at a wind speed of 2.5 m / s. 3 / min;

[0083] (4) subjecting the product obtained in step (3) to solid-liquid separation;

[0084] (5) Washing the solid obtained in step (4) to obtain microspheres of 100-700 μm.

[0085] The microspheres were shown by transmission microscopy. Figure 1 .

[0086] Embodiment 1-2:

[0087] (1) dissolving ibuprofen and polyacrylic acid resin RS100 in a mixed solvent of dichloromethane and anhydrous ethanol (weight ratio 10:1) at a weight ratio of 1:4 to form an oil phase, wherein the content of ibuprofen is 5% by weight, the temperature is 5-10° C., and the time is 2 h;

[0088] (2) In a reaction kettle, polyoxyl (40) stearate and water are mixed at a weight ratio of 1:1000 to form an aqueous phase, and the oil phase is added to the aqueous phase under stirring, and then the reaction kettle is immediately covered with a lid to seal the reaction kettle at a sealing temperature of 5-10° C. for 0.3 h;

[0089] (3) Open the lid and blow air horizontally at a temperature of 20-25°C for 1 hour at a wind speed of 5 m / s. 3 / min;

[0090] (4) subjecting the product obtained in step (3) to solid-liquid separation;

[0091] (5) Washing the solid obtained in step (4) to obtain microspheres of 100-700 μm.

[0092] The microspheres were shown by transmission microscopy. Figure 2 .

[0093] Embodiment 1-3:

[0094] (1) dissolving ibuprofen and polyacrylic acid resin RS100 in a mixed solvent of ethyl acetate and anhydrous ethanol (weight ratio of 15:1) at a weight ratio of 1:9 to form an oil phase, wherein the content of ibuprofen is 2.5% by weight, the temperature is 0-5°C, and the time is 3 hours;

[0095] (2) In a reaction kettle, polyvinyl alcohol and water are mixed at a weight ratio of 1:20 to form an aqueous phase. Under stirring, the oil phase is added to the aqueous phase, and then the reaction kettle is immediately covered with a lid for sealing. The sealing temperature is 10-15° C. and the sealing time is 0.75 h.

[0096] (3) Open the lid and blow air horizontally at a temperature of 30-35°C for 2 hours at a wind speed of 10 m / s. 3 / min;

[0097] (4) subjecting the product obtained in step (3) to solid-liquid separation;

[0098] (5) Washing the solid obtained in step (4) to obtain microspheres of 100-700 μm.

[0099] Embodiment 1-4:

[0100] The method of Example 1-1 was followed, except that the polyacrylic acid resin RS100 was replaced with ethyl cellulose.

[0101] Embodiment 1-5:

[0102] The method of Example 1-1 was followed, except that the polyacrylic acid resin RS100 was replaced with a lactide-glycolide copolymer (the molar ratio of glycolide to lactide was 1:1; the weight average molecular weight was 30,000, and the viscosity was 0.3 dl / g).

[0103] Embodiment 1-6:

[0104] The method of Example 1-1 is followed, except that the polyacrylic acid resin RS100 is replaced with gelatin. Comparative Example 1-1:

[0105] The method of Example 1-1 is followed, except that no sealing is performed in step (2), to obtain microspheres of 100-700 μm.

[0106] The microspheres were shown by transmission microscopy. Figure 3 .

[0107] Comparative Example 1-2:

[0108] The method of Example 1-1 is followed, except that in step (3), only the lid is opened, and no air blowing is performed to increase the temperature, and the wind speed is 0.5 m / s. 3 / min, the temperature is 0-5°C, and microspheres of 100-700 μm are obtained. The obtained microspheres are shown by transmission microscopy. Figure 4 .

[0109] Example 2: Preparation of metformin microspheres.

[0110] Examples 2-1, 2-2, 2-3, 2-4, 2-5, 2-6 and Comparative Examples 2-1, 2-2 are respectively carried out according to the methods of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and Comparative Examples 1-1, 1-2, except that ibuprofen is replaced with metformin.

[0111] Example 3: Preparation of spironolactone microspheres.

[0112] Examples 3-1, 3-2, 3-3, 3-4, 3-5, 3-6 and Comparative Examples 3-1 and 3-2 were prepared in accordance with the methods of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and Comparative Examples 1-1 and 1-2, except that ibuprofen was replaced with spironolactone. Results The results obtained by transmission microscopy and in vitro dissolution analysis were consistent with the above.

[0113] Example 4: Preparation of dextromethorphan hydrobromide microspheres.

[0114] Examples 4-1, 4-2, 4-3, 4-4, 4-5, 4-6 and Comparative Examples 4-1 and 4-2 were prepared according to the methods of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and Comparative Examples 1-1 and 1-2, except that ibuprofen was replaced with dextromethorphan hydrobromide.

[0115] Example 5: Preparation of levodopa microspheres.

[0116] Examples 5-1, 5-2, 5-3, 5-4, 5-5, 5-6 and Comparative Examples 5-1 and 5-2 are prepared according to the methods of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and Comparative Examples 1-1 and 1-2, except that ibuprofen is replaced with levodopa.

[0117] Example 6: Preparation of ramelteon microspheres.

[0118] Examples 6-1, 6-2, 6-3, 6-4, 6-5, 6-6 and Comparative Examples 6-1 and 6-2 are prepared according to the methods of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and Comparative Examples 1-1 and 1-2, except that ibuprofen is replaced with ramelteon.

[0119] Example 7: Preparation of sodium valproate microspheres.

[0120] Examples 7-1, 7-2, 7-3, 7-4, 7-5, 7-6 and Comparative Examples 7-1 and 7-2 are prepared according to the methods of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and Comparative Examples 1-1 and 1-2, except that ibuprofen is replaced with sodium valproate.

[0121] Example 8: Preparation of quetiapine fumarate microspheres.

[0122] Examples 8-1, 8-2, 8-3, 8-4, 8-5, 8-6 and Comparative Examples 8-1 and 8-2 are prepared according to the methods of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6 and Comparative Examples 1-1 and 1-2, except that ibuprofen is replaced with quetiapine fumarate.

[0123] Example 9: Test experimental results.

[0124] 1. In vitro dissolution:

[0125] Method: The above examples and comparative examples were measured according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 General Rules 0931 Second Method). Dissolution conditions: 900 ml of pH 6.0 phosphate buffer (accurately weigh about 6.805 g of potassium dihydrogen phosphate and about 0.224 g of sodium hydroxide, put into 1 L of water, stir to dissolve, and obtain) was used as the dissolution medium, the speed was 75 revolutions per minute, and the operation was carried out according to the law. The in vitro dissolution data of Examples 1-8 are shown in Tables 1-8.

[0126] Table 1: In vitro dissolution data of Example 1

[0127]

[0128] Note: The unit is %.

[0129] Table 2: In vitro dissolution data of Example 2

[0130]

[0131] Note: The unit is %.

[0132] Table 3: In vitro dissolution data of Example 3

[0133]

[0134] Note: The unit is %.

[0135] Table 4: In vitro dissolution data of Example 4

[0136]

[0137] Note: The unit is %.

[0138] Table 5: In vitro dissolution data of Example 5

[0139]

[0140] Note: The unit is %.

[0141] Table 6: In vitro dissolution data of Example 6

[0142] Example 0.5h 1h 2h 4h 6h 8h Example 6-1 36.2 43.7 56.6 71.4 87.6 98.5 Example 6-2 35.6 42.9 55.6 70.2 86.1 97.8 Example 6-3 36.0 43.4 56.2 71.0 87.1 98.9 Example 6-4 35.4 42.7 55.3 69.8 85.6 96.3 Example 6-5 37.0 44.6 57.8 72.9 89.5 100.6 Example 6-6 36.6 44.2 57.3 72.3 88.7 99.7 Comparative Example 6-1 53.5 74.2 86.3 98.7 100.1 100.6 Comparative Example 6-2 18.4 25.7 38.9 52.4 67.9 78.3

[0143] Note: The unit is %.

[0144] Table 7: In vitro dissolution data of Example 7

[0145]

[0146] Note: The unit is %.

[0147] Table 8: In vitro dissolution data of Example 8

[0148]

[0149] From the above data, it can be seen that compared with the comparative example, the advantages of rapid release and sustained release are combined, and it can dissolve quickly and continuously, so that the dissolution rate is fast at first and then slow, which can take effect quickly and last for a long time.

[0150] 2. Pharmacokinetics experiment:

[0151] Method: Six beagle dogs were randomly divided into two groups using each drug, and the preparations of the above embodiments and comparative examples or commercially available control preparations (immediate release, sustained release) were orally administered, and cross-administered. The dosage of ibuprofen was 0.015 g / kg, the dosage of metformin was 50 mg / kg, the dosage of spironolactone was 5 mg / kg, the dosage of dextromethorphan hydrobromide was 6 mg / kg, the dosage of levodopa was 20 mg / kg, and the dosage of quetiapine fumarate was 5 mg / kg. Fasting for 12 hours before administration, food was provided 4 hours after administration on the day of the test, and water was not forbidden during the test. The preparation of the present invention and the commercially available preparation were administered once, and the total dosage of the commercially available rapid-release preparation was the same as that of the present invention and the commercially available preparation. The administration was divided into two times (6 hours apart), and blood was collected from the beagle dogs at different time points after administration; 2 mL of blood was collected from the veins of the four limbs and placed in EDTA-K 2In the vacuum blood collection tube, gently invert and mix 5 to 8 times to mix the blood and anticoagulant and then wait for centrifugation. Within 1 hour after blood sample collection, centrifuge at 1700g for 10 minutes at 4°C to separate the upper plasma. The separated plasma sample is stored in a refrigerator below -60°C; or temporarily stored in a refrigerator at -20°C and transferred to a refrigerator below -60°C within 24 hours. The blood sample should be collected and placed in the refrigerator within 2 hours.

[0152] Biological sample analysis: The drug content in plasma was detected using a validated LC-MS / MS method. The results are shown in Tables 9-14 and Figure 5-6 .

[0153] Data processing: WinNonlin software was used to calculate pharmacokinetic parameters. The results are shown in Tables 15-20. max It indicates the time required to reach the peak concentration of the drug after administration. This parameter reflects the speed at which the drug enters the body. The faster the absorption rate, the shorter the peak time. The unit is h; C max It indicates the highest blood drug concentration after administration. This parameter is an important indicator of the absorption rate and degree of the drug in the body. The unit is ng / mL. AUClast represents the area of ​​the blood drug concentration curve from the start of administration to the last point on the time axis, which is used to evaluate the degree of drug absorption. The unit is h×ng / mL. AUCINF_obs represents the area of ​​the blood drug concentration curve on the time axis from 0 to infinity, which is used to predict the degree of drug absorption. The unit is h×ng / mL. T 1 / 2 It represents the terminal elimination half-life, which is the time required for the blood drug concentration in the terminal phase to drop by half. It directly reflects the elimination rate of the drug from the body, and the unit is h.

[0154] Table 9: Plasma drug content in the pharmacokinetic experiment of Example 1

[0155]

[0156] Note: The unit is ng / mL.

[0157] Table 10: Plasma drug content in the pharmacokinetic experiment of Example 2

[0158]

[0159] Note: The unit is ng / mL.

[0160] Table 11: Plasma drug content in pharmacokinetic experiments of Example 3

[0161]

[0162] Note: The unit is ng / mL.

[0163] Table 12: Plasma drug content in pharmacokinetic experiments of Example 4

[0164]

[0165] Note: The unit is ng / mL.

[0166] Table 13: Plasma drug content in pharmacokinetic experiments of Example 5

[0167]

[0168] Note: The unit is ng / mL.

[0169] Table 14: Plasma drug content in pharmacokinetic experiments of Example 8

[0170]

[0171] Note: The unit is ng / mL.

[0172] Table 15: Pharmacokinetic parameter experimental results of Example 1

[0173]

[0174] According to Table 15, the ibuprofen pharmaceutical composition obtained by the method of the present invention has a similar peak time and peak concentration as the commercially available immediate-release preparation, indicating that the ibuprofen pharmaceutical composition of the present invention can take effect quickly and has good absorption. 1 / 2 Both are higher than those of commercially available rapid-release and sustained-release drugs, indicating that the elimination rate of the ibuprofen pharmaceutical composition of the present invention from the body is slower than that of commercially available rapid-release and sustained-release drugs, and the duration of drug effect is longer.

[0175] Table 16: Pharmacokinetic parameter experimental results of Example 2

[0176]

[0177] According to Table 16, the metformin pharmaceutical composition obtained by the method of the present invention has a similar peak time and peak concentration as the commercially available immediate-release preparation, indicating that the metformin pharmaceutical composition of the present invention can take effect quickly. 1 / 2 Both are higher than those of commercially available rapid-release and sustained-release drugs, indicating that the elimination rate of the metformin pharmaceutical composition of the present invention from the body is slower than that of commercially available rapid-release and sustained-release drugs, and the drug effect lasts longer.

[0178] Table 17: Pharmacokinetic parameter experimental results of Example 3

[0179] Example <![CDATA[T max ]]> <![CDATA[C max ]]> AUClast AUCINF_obs <![CDATA[T 1 / 2 ]]> Example 3-1 1.5 110.8 168.4 170.6 5.8 Example 3-2 1.5 118.6 160.4 162.5 5.8 Comparative Example 3-1 1.5 121.2 153.6 155.7 5.6 Comparative Example 3-2 2 68.4 91.2 92.4 2.5 Spironolactone tablets available on the market 2.6 53.6 80.8 81.9 2.4

[0180] According to Table 17, the spironolactone pharmaceutical composition obtained by the method of the present invention has a shorter peak time, and the peak concentration, AUClast, AUCINF_obs and T 1 / 2 Both are higher than those on the market, indicating that the spironolactone pharmaceutical composition of the present invention can not only take effect quickly, but also be better absorbed and have a longer duration of efficacy.

[0181] Table 18: Pharmacokinetic parameter experimental results of Example 4

[0182]

[0183] According to Table 18, the dextromethorphan pharmaceutical composition obtained by the method of the present invention is compared with the commercially available dextromethorphan. The dextromethorphan pharmaceutical composition of the present invention has a shorter peak time, and its peak concentration, AUClast and AUCINF_obs are all higher than those of the commercially available dextromethorphan. 1 / 2 This indicates that the dextromethorphan pharmaceutical composition of the present invention can not only take effect quickly, but also be better absorbed, and the duration of drug effect is not shortened.

[0184] Table 19: Pharmacokinetic parameter experimental results of Example 5

[0185]

[0186] According to Table 19, the carbendazim pharmaceutical composition obtained by the method of the present invention has a shorter peak time than the commercially available carbendazim pharmaceutical composition, and its peak concentration, AUClast and AUCINF_obs are similar to those of the commercially available carbendazim. 1 / 2 This indicates that the carboplatin-levodopa pharmaceutical composition of the present invention can not only take effect quickly but also have a longer duration of efficacy.

[0187] Table 20: Pharmacokinetic parameter experimental results of Example 8

[0188]

[0189] According to Table 20, the quetiapine fumarate pharmaceutical composition obtained by the method of the present invention has a shorter peak time, and the peak concentration, AUClast, AUCINF_obs and T 1 / 2 All of them are higher than those on the market, indicating that the quetiapine fumarate pharmaceutical composition of the present invention can not only quickly take effect, but also has a longer duration of drug effect and a better drug absorption degree.

[0190] The results show that the pharmaceutical composition prepared by the method of the present invention can not only take effect quickly, but also has a longer duration of efficacy and a higher degree of drug absorption.

[0191] 3. Efficacy experiment:

[0192] The model was established by inducing fever in rats with dry yeast. The initial body temperature of the model group was high, and no drug intervention was performed subsequently. The initial body temperature of the blank group was normal, and no drug intervention was performed subsequently. The initial body temperature of the experimental group was high, and drug intervention was performed subsequently. The commercially available rapid-release preparation of ibuprofen (ibuprofen suspension), the commercially available sustained-release preparation of ibuprofen (ibuprofen sustained-release capsules), and Example 1 of the present invention were used to intervene, and the therapeutic effect on the fever model in rats was investigated. The body temperature of rats in different groups was tested to observe the changes in the body temperature of rats in different time periods. The results are shown in Figure 7 .

[0193] It can be seen from the above results that within 1 hour after administration, the drug of the present invention has the best effect. The drug group of the present invention is better than the other two groups at 6 hours and 8 hours after administration, with significant differences (P<0.05). At 12 hours after administration, the drug of the present invention is the best, followed by the ibuprofen rapid-release preparation group and the ibuprofen sustained-release preparation group.

[0194] It can be seen from this that the product of the present invention can both take effect quickly and have a long-lasting effect.

[0195] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing a composition containing ibuprofen, characterized in that: The method comprises: (1) mixing ibuprofen and a base in the presence of an organic solvent; (2) adding the mixed product of step (1) into water in the presence of an emulsifier and then sealing the water; (3) blowing the sealed product of step (2); Wherein, the matrix is ​​selected from at least one of polyacrylic acid resin RS100, ethyl cellulose, gelatin, sodium alginate, chitosan, glycolide-lactide copolymer 75-25 and glycolide-lactide copolymer 50-50; The sealing conditions include: temperature of 0-15°C and time of 0.1-1h; The blowing conditions include: temperature of 20-35°C, time of 0.1-2h, wind speed of 1-10m 3 / min; The weight ratio of the emulsifier to water is 1:10-1000; The mixing conditions include: temperature of 0-30°C and time of 0.1-3h; The organic solvent is selected from at least one of ethanol, acetone, ethyl acetate, dichloromethane and methyl acetate; The emulsifier is selected from at least one of sucrose fatty acid esters, polyoxyl (40) stearate, polyvinyl alcohol, polyoxyethylene sorbitan monooleate, polyoxypropylene polyoxyethylene copolymer and sodium lauryl sulfate.

2. The method according to claim 1, wherein: The weight ratio of the ibuprofen to the matrix is ​​1:0.1-10.

3. The method according to claim 1 or 2, wherein: The content of ibuprofen in the mixed system is 2-60% by weight; And / or, the glycolide-lactide copolymer 75-25 and the glycolide-lactide copolymer 50-50 have a weight average molecular weight of 10,000-50,000 and a viscosity of 0.1-0.5 dl / g.

4. The method according to claim 1 or 2, wherein: The method further comprises performing solid-liquid separation on the product obtained in step (3).

5. The ibuprofen-containing composition prepared by the method described in any one of claims 1 to 4.

6. The ibuprofen-containing composition according to claim 5, wherein: The ibuprofen-containing composition is composed of a matrix and ibuprofen dispersed in the matrix; and / or, the weight ratio of ibuprofen to matrix in the ibuprofen-containing composition is 1:0.1-10; And / or, the ibuprofen-containing composition is microspheres, and the particle size of the microspheres is 100-700 μm.

7. Use of the ibuprofen-containing composition according to claim 5 or 6 in the preparation of an ibuprofen preparation.

8. The use according to claim 7, wherein: The ibuprofen preparation is in the form of a dry suspension, tablet or capsule.

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