CN102499909B - Itraconazole dispersible tablets and preparation method thereof - Google Patents
Itraconazole dispersible tablets and preparation method thereof Download PDFInfo
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- CN102499909B CN102499909B CN 201110443219 CN201110443219A CN102499909B CN 102499909 B CN102499909 B CN 102499909B CN 201110443219 CN201110443219 CN 201110443219 CN 201110443219 A CN201110443219 A CN 201110443219A CN 102499909 B CN102499909 B CN 102499909B
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Abstract
The invention relates to itraconazole dispersible tablets with improved dissolubility and a preparation method thereof. The method comprises the following steps of: mixing itraconazole, hydroxypropyl methyl cellulose, crosslinking povidone and dichloromethane in a weight ratio of 1:(1-5):(1-5):(10-20) uniformly, dissolving fully, and controlling the temperature to be between 40 and 80 DEG C; mixing cyclodextrin, lauryl sodium sulfate, polyethyleneglycol 4000 and ethanol in a weight ratio of 1:(0.1-1):(0.1-2):(3-6) uniformly, dissolving fully, and controlling the temperature to be between 40 and 60 DEG C; mixing the mixture uniformly until the itraconazole is dissolved completely, drying, and granulating to obtain itraconazole composite powder; and mixing the composite powder and pharmaceutic adjuvants uniformly, and tabletting to obtain the itraconazole dispersible tablets. The itraconazole dispersible tablets are high in water solubility, easy to disperse and high in dissolution, and the problems of low water solubility and low bioavailability of the itraconazole are solved.
Description
Technical field
The present invention relates to itraconazole, particularly relate to a kind of deliquescent itraconazole dispersible tablet of improvement and preparation method thereof that has.
Background technology
Itraconazole is the antifungal drug in triazole class that is insoluble in water, and deep fungal and superficial fungi are had antifungic action, because it has activity by force, and has a broad antifungal spectrum, characteristics such as cure rate height are widely used.Its structural formula is as follows:
Studies show that the itraconazole poorly water-soluble, tablet disperses the difficulty height, and process in leaching is the working difficult point of itraconazole dispersible tablet.Because its water solublity lower (1 μ g/ml is following) is so exist the low-down problem of bioavailability when oral administration.
For the water solublity that improves itraconazole to improve its bioavailability, it is 0.5-10 μ m that patent ZL98806999.7 discloses a kind of diameter, the itraconazole granule of amorphous form.But after this itraconazole granule and pharmaceutical excipient made tablet, can not disperse the short time, have the problem of difficulties in dispersion.
Patent ZL200610065136.6 discloses the compositions that a kind of oral administration contains itraconazole, described compositions contains the 40-69.9wt% solid dispersion, the infiltration derivant of 0.1-30wt%, the disintegrating agent of 0.1-30wt%, described solid dispersion are dispersed in by the itraconazole with 1 weight portion in the absorption enhancer mixture of the hydroxypropyl emthylcellulose of 0.1-10 weight portion and 0.01-5 weight portion and prepare with amorphism.The preparation method of said composition needs earlier itraconazole to be prepared into the itraconazole dispersion, again with this dispersion and other adjuvant mixing granulations, tabletting, and the addition for each dispersion, infiltration derivant, disintegrating agent etc. in the compositions is carried out strictness control, to reach preferable dissolution and bioavailability, complicated process of preparation.
Patent ZL200910076988.9 discloses a kind of Itraconazole composite powder and preparation method thereof, be dissolved in the itraconazole medicine in the organic solvent earlier, the aqueous solution that adds hydrophilicity condiment, be settled out the suspension of itraconazole granule, obtain powder body after the drying, diameter of particle is 0.5-15 μ m, and it is 100nm-1 μ m that powder body is dispersed in the itraconazole particle grain size that obtains in the water.This composite granule has higher dissolution, but is hydrophilic carrier with the polyvinylpyrrolidone, has higher cost.
Patent ZL200910305827.2 discloses a kind of Itraconazole composition and preparation method thereof, said composition is made up of itraconazole, starch, mannitol, sucrose, steviosin, preparation technology is simple, used pharmaceutic adjuvant safety, do not contain harmful organic solvent, cost is lower, good stability, but dissolution will reach more than 85%, need more than 100 minute time, dissolution rate is still waiting to improve.
Summary of the invention
The technical problem to be solved in the present invention provides the preparation method of simple, the lower-cost itraconazole dispersible tablet of a kind of technology, and the itraconazole dispersible tablet that obtains of method thus, the characteristics that this dispersible tablet has the dissolution height, is easy to disperse.
For reaching above-mentioned purpose, the preparation method of a kind of itraconazole dispersible tablet of the present invention may further comprise the steps:
(1) with itraconazole, hydroxypropyl emthylcellulose, polyvinylpolypyrrolidone (cross-linking polyethylene pyrrolidone, Crosslinking polyvingypyrrolidone, PVPP) and dichloromethane by weight 1: (1-5): (1-5): (10-20) mix homogeneously, fully dissolving, temperature is controlled at 40-80 ℃;
(2) with cyclodextrin, sodium lauryl sulphate, Macrogol 4000 and dehydrated alcohol by weight 1: (0.1-1): (0.1-2): (3-6) mix homogeneously, fully dissolving, temperature is controlled at 40-60 ℃;
(3) mixture mix homogeneously to the itraconazole that described step (1), (2) are obtained respectively dissolves fully, drying, and pelletize obtains Itraconazole composite powder;
(4) composite granule and the pharmaceutic adjuvant mix homogeneously that step (3) is obtained, tabletting, namely.
The preparation method of itraconazole dispersible tablet of the present invention, wherein in the preferred described step (3), it is 170-190 ℃ that drying is used spray dryer drying, inlet temperature, outlet temperature is 70-90 ℃.
The preparation method of itraconazole dispersible tablet of the present invention, wherein in the preferred described step (3), pelletize is with the pelletize of centrifugal granulator machine, and the rotating speed of centrifugal granulator machine is 350-450rpm, and inlet temperature is 70-90 ℃, and outlet temperature is 45-55 ℃.
The preparation method of itraconazole dispersible tablet of the present invention, wherein in the preferred described step (3), pelletize fluidised bed granulator pelletize, the inlet temperature of fluidised bed granulator is 85-95 ℃, outlet temperature is 45-55 ℃.
The preparation method of itraconazole dispersible tablet of the present invention, medicinal adjuvant is the pharmaceutic adjuvant of this area routine in the wherein said step (4), belongs to the commercially available prod, its specification meets national pharmaceutic adjuvant standard and gets final product.Preferably contain lactose, carboxymethyl starch sodium (Carboxymethyl starch sodium, CMS-Na), hydroxypropyl cellulose (Hydroxypropyl cellulose) and magnesium stearate.More preferably the weight ratio of composite granule and lactose, carboxymethyl starch sodium (YingKou AODA Pharmaceutical CO.,LTD), hydroxypropyl cellulose (Huzhou Zhanwang Pharmaceutical Co., Ltd.) and magnesium stearate (YingKou AODA Pharmaceutical CO.,LTD) is 1 in the described step (4): (0.15-0.25): (0.15-0.25): (0.10-0.15): (0.0025-0.01).
The itraconazole dispersible tablet that the present invention is obtained by said method, the characteristics that it has the dissolution height, is easy to disperse, its dissolution is 80-90%, the fully decentralized time is 1-3 minute.
The inventive method, by itraconazole being dissolved in organic solvent (polyvinylpolypyrrolidone, dichloromethane, Macrogol 4000 (Haidian, Beijing fellow member of an association or organization's fine chemistry industry company), ethanol etc.) in and add surfactant (sodium lauryl sulphate), itraconazole solution is imported water solublity preferably in the hydroxyl inclusion complex in solution and stir, evenly medicinal liquid is carried out spray drying or lyophilization, obtain Itraconazole composite powder, with Itraconazole composite powder and a certain proportion of disintegrating agent (carboxymethyl starch sodium), fluidizer (magnesium stearate), filler mixing such as (Lactis Anhydrous (the happy companies of German U.S. agent)) is carried out tabletting and is obtained the itraconazole dispersible tablet.In addition, can also contain silicon dioxide (Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong), microcrystalline Cellulose this areas such as (Japanese Asahi Kasei Corporations) adjuvant commonly used about pharmaceutic adjuvant, the inventive method technology is simple, cost is lower, the itraconazole dispersible tablet that obtains, good water solubility, be easy to dispersion, dissolution height, be easy to suitability for industrialized production, solved the difficult problem that itraconazole is not soluble in water, bioavailability is low.
The specific embodiment
Below in conjunction with embodiment and test data, be described in more detail with other technical characterictic and advantage the present invention is above-mentioned.
Embodiment 1
The accurate following raw material of weighing:
Itraconazole 100g (Shandong Shouguang Fukang Pharmaceutical Co., Ltd.), hydroxypropyl emthylcellulose 100g (mountains and rivers, Anhui pharmaceutic adjuvant company), polyvinylpolypyrrolidone (available from BASF AG) 100g, dichloromethane 1000g (Tianjin good fortune chemical reagent in morning factory).With the raw material mix homogeneously, the control solution temperature is 40 ℃, allows solid such as itraconazole be dissolved in the liquid dichloromethane.
The accurate following raw material of weighing:
Cyclodextrin 100g, sodium lauryl sulphate 10g, Macrogol 4000 10g, dehydrated alcohol 300g.With the raw material mix homogeneously, the control solution temperature is 40 ℃, allows solid such as cyclodextrin be dissolved in the liquid ethanol.
Above-mentioned two kinds of solution mix homogeneously to itraconazoles are dissolved fully, use the spray dryer drying, dryer inlet temperature is 170 ℃, and outlet temperature is 70 ℃; The centrifugal granulator machine pelletize of dry back, the comminutor rotating speed is 350rpm, and inlet temperature is 70 ℃, and outlet temperature is 45 ℃, obtains Itraconazole composite powder.
The accurate following raw material of weighing:
The Itraconazole composite powder 420g that above-mentioned steps obtains, lactose 63g, carboxymethyl starch sodium 63g, hydroxy propyl cellulose 42g, magnesium stearate 1.05g with this raw material mix homogeneously, presses 100 with tablet machine, namely gets the itraconazole dispersible tablet.
Embodiment 2 to 9, and is as shown in table 1: operating procedure is with embodiment 1, and difference is the addition difference of each component.In addition; for (the gateway temperature of the solution temperature of described each step of summary of the invention, exsiccator gateway temperature, granulator as described above of the process conditions in the preparation method of the present invention; the selection type of comminutor etc.); be simply to adjust according to amount or the practical operation situation of adding component, do not have influence substantially for the performance of the itraconazole dispersible tablet that obtains.
Each components selection and weight proportion thereof in the preparation method of itraconazole dispersible tablet of the present invention, be that the inventor advanced to consult the preferable value range that a large amount of documents and test many times obtain, namely work as itraconazole, hydroxypropyl emthylcellulose, the weight ratio of polyvinylpolypyrrolidone and dichloromethane meets 1: (1-5): (1-5): scope (10-20), cyclodextrin, sodium lauryl sulphate, the weight ratio of Macrogol 4000 and ethanol meets 1: (0.1-1): (0.1-2): during (3-6) value range, can make the dissolution of the itraconazole sheet that obtains better, can reach 80-90%, jitter time is shorter, is 1-3 minute.Remove a certain component or its content in the above-mentioned raw materials component not in above-mentioned scope, then dissolution reduces, and dispersing uniformity is relatively poor, and jitter time also prolongs, and only lifts following Comparative Examples explanation.
Comparative Examples 1
Remove hydroxypropyl emthylcellulose in embodiment 1, other conditions are constant, and detecting dissolution behind the tabletting is 43%, and conclusion is whether the use of hydroxypropyl emthylcellulose can directly influence its dissolution.(weight ratio that is itraconazole, hydroxypropyl emthylcellulose, polyvinylpolypyrrolidone and dichloromethane is 1: 0.1: 1: 10), detecting dissolution behind the tabletting is 67.7%, and dissolution reduces than embodiment 1 when the addition of hydroxypropyl emthylcellulose is reduced to 50g.
Comparative Examples 2
Remove polyvinylpolypyrrolidone in embodiment 1, other conditions are constant, and it is defective to detect dispersing uniformity behind the tabletting, and conclusion is whether the use of polyvinylpolypyrrolidone can directly influence dispersing uniformity.(weight ratio that is itraconazole, hydroxypropyl emthylcellulose, polyvinylpolypyrrolidone and dichloromethane is 1: 1: 0.1: 10), detecting dissolution behind the tabletting is 81.6%, and dissolution reduces than embodiment 1 when the addition of polyvinylpolypyrrolidone is reduced to 50g.
Comparative Examples 3
Remove sodium lauryl sulphate in embodiment 1, other conditions are constant, and detecting dissolution behind the tabletting is 61%, and conclusion is whether the use of sodium lauryl sulphate can directly influence its dissolution.(be the weight ratio 1: 0.08: 0.1 of cyclodextrin, sodium lauryl sulphate, Macrogol 4000 and ethanol: 3), detecting dissolution behind the tabletting is 69.4%, and dissolution reduces than embodiment 1 when the addition of sodium lauryl sulphate is reduced to 8g.
Comparative Examples 4
Remove Macrogol 4000 in embodiment 1, other conditions are constant, and detecting dissolution behind the tabletting is 27%, and conclusion is whether the use of Macrogol 4000 can directly influence its dissolution.(be the weight ratio 1: 0.1: 0.08 of cyclodextrin, sodium lauryl sulphate, Macrogol 4000 and ethanol: 3), detecting dissolution behind the tabletting is 53.6%, and dissolution reduces than embodiment 1 when the addition of Macrogol 4000 is reduced to 8g.
Comparative Examples 5
In embodiment 1, the main component of pharmaceutic adjuvant is lactose, carboxymethyl starch sodium, hydroxy propyl cellulose and magnesium stearate, also can be added with microcrystalline Cellulose in this external other specific embodiment, the pharmaceutic adjuvant that this areas such as silicon dioxide are commonly used, weight ratio between each composition is the common ratio in this area, be not limited to weight proportion of the present invention, the composite granule and the lactose that obtain as embodiment in this Comparative Examples 1, carboxymethyl starch sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline Cellulose, the weight ratio of silicon dioxide is 1: 0.1: 0.1: 0.05: 0.002: 0.05: 0.05, detecting dissolution behind the tabletting is 80.6%, conclusion is the selection of pharmaceutic adjuvant and proportioning thereof to the dispersibility influence of itraconazole sheet of the present invention is not very big, when selecting this area routine adjuvant for use, the itraconazole sheet also can reach dissolution (more than 80%) preferably, but when adopting pharmaceutic adjuvant of the present invention, itraconazole sheet dispersibility of the present invention is better, shown in data in the table 1.
Comparative Examples 6
Remove carboxymethyl starch sodium in embodiment 1, other conditions are constant, and it is qualified substantially to detect dispersing uniformity behind the tabletting, and dissolution is 81.1%.
Comparative Examples 7
Remove hydroxypropyl cellulose in embodiment 1, other conditions are constant, and it is qualified substantially to detect dispersing uniformity behind the tabletting, and dissolution is 80.7%.
The test example
Experimental apparatus: D800-LS intellectual drug digestion instrument, Tianda Tianfa Science and Technology Co. Ltd., what this test was routine the results are shown in Table 1.
Dissolution: 1000ml is dissolution medium with hydrochloric acid solution (4 → 1000), and rotating speed is that per minute 50 changes, and (2010 editions pharmacopeia are defined as: 9 → 1000 hydrochloric acid, rotating speed are 75 commentaries on classics.Compare two kinds of methods, experimental condition of the present invention is harsher.)
Get this product, according to dissolution method, 1000ml is dissolution medium with hydrochloric acid solution (4 → 1000), rotating speed is that per minute 50 changes, operation in the time of 45 minutes, is got solution 10ml in accordance with the law, filter, precision is measured subsequent filtrate 2ml, places the 10ml measuring bottle, is diluted to scale with 5% (v/v) methanol-hydrochloric acid solution (4 → 1000), shake up, as need testing solution; Other gets the about 10mg of itraconazole reference substance, and accurate the title decides, and puts in the 100ml measuring bottle, add methanol 20ml, ultrasonicly in 40 ℃ of water-baths make dissolving, put coldly, reuse hydrochloric acid solution (4 → 1000) is diluted to scale, shake up, precision is measured 2ml, places the 10ml measuring bottle, adds hydrochloric acid solution (4 → 1000) and is diluted to scale, shake up, in contrast product solution.Get above-mentioned two kinds of solution, measure with ultraviolet visible spectrophotometry, measure trap respectively at the wavelength place of 254nm, calculate every stripping quantity.
Above-described embodiment is described preferred implementation of the present invention; be not that scope of the present invention is limited; design under the prerequisite of spirit not breaking away from the present invention; various distortion and improvement that those of ordinary skills make technical scheme of the present invention all should fall in the definite protection domain of claims of the present invention.
Claims (8)
1. the preparation method of an itraconazole dispersible tablet is characterized in that, may further comprise the steps:
(1) with itraconazole, hydroxypropyl emthylcellulose, polyvinylpolypyrrolidone and dichloromethane by weight 1:(1-5): (1-5): (10-20) mix homogeneously, fully dissolving, temperature is controlled at 40-80 ℃;
(2) with cyclodextrin, sodium lauryl sulphate, Macrogol 4000 and dehydrated alcohol by weight 1:(0.1-1): (0.1-2): (3-6) mix homogeneously, fully dissolving, temperature is controlled at 40-60 ℃;
(3) mixture mix homogeneously to the itraconazole that described step (1), (2) are obtained respectively dissolves fully, drying, and pelletize obtains Itraconazole composite powder;
(4) composite granule and the pharmaceutic adjuvant mix homogeneously that step (3) is obtained, tabletting, namely.
2. method according to claim 1 is characterized in that: in the described step (3), and described drying spray dryer drying, inlet temperature is 170-190 ℃, outlet temperature is 70-90 ℃.
3. method according to claim 1 is characterized in that: in the described step (3), described pelletize is with the pelletize of centrifugal granulator machine, and rotating speed is 350-450rpm, and inlet temperature is 70-90 ℃, and outlet temperature is 45-55 ℃.
4. method according to claim 1 is characterized in that: in the described step (3), and described pelletize fluidised bed granulator pelletize, inlet temperature is 85-95 ℃, outlet temperature is 45-55 ℃.
5. method according to claim 1, it is characterized in that: the pharmaceutic adjuvant in the described step (4) comprises lactose, carboxymethyl starch sodium, hydroxypropyl cellulose and magnesium stearate.
6. method according to claim 5 is characterized in that: the weight ratio of composite granule and lactose, carboxymethyl starch sodium, hydroxypropyl cellulose and magnesium stearate is 1:(0.15-0.25 in the described step (4)): (0.15-0.25): (0.10-0.15): (0.0025-0.01).
7. the itraconazole dispersible tablet that obtains of each described method of claim 1-6.
8. itraconazole dispersible tablet according to claim 7, it is characterized in that: its dissolution is 80-90%.
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| CN109172532A (en) * | 2018-10-24 | 2019-01-11 | 北京哈三联科技有限责任公司 | A kind of itraconazole dispersible tablets and its preparation method and application |
| CN110898015A (en) * | 2019-12-31 | 2020-03-24 | 上海汉维生物医药科技有限公司 | Preparation method of itraconazole preparation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985002767A1 (en) * | 1983-12-21 | 1985-07-04 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
| US4764604A (en) * | 1985-03-15 | 1988-08-16 | Janssen Pharmaceutica N.V. | Derivatives of gamma-cyclodextrin |
| CN1615870A (en) * | 2004-09-17 | 2005-05-18 | 北京博尔达生物技术开发有限公司 | Itraconazole freeze-dried powder injection and preparing method |
| CN102100678A (en) * | 2011-02-18 | 2011-06-22 | 天津力生制药股份有限公司 | Itraconazole sulfate capsules and method for preparing same |
-
2011
- 2011-12-27 CN CN 201110443219 patent/CN102499909B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985002767A1 (en) * | 1983-12-21 | 1985-07-04 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
| US4764604A (en) * | 1985-03-15 | 1988-08-16 | Janssen Pharmaceutica N.V. | Derivatives of gamma-cyclodextrin |
| US4764604B1 (en) * | 1985-03-15 | 1990-06-12 | Janssen Pharmaceutica Nv | |
| CN1615870A (en) * | 2004-09-17 | 2005-05-18 | 北京博尔达生物技术开发有限公司 | Itraconazole freeze-dried powder injection and preparing method |
| CN102100678A (en) * | 2011-02-18 | 2011-06-22 | 天津力生制药股份有限公司 | Itraconazole sulfate capsules and method for preparing same |
Non-Patent Citations (1)
| Title |
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| 于波涛等，.伊曲康唑_2_羟丙基环糊精共熔物及其分散片的制备与体外释药考察.《中国医院药学杂质》.2005,第25卷(第12期),第1131-1133页. * |
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