CN102499909A - Itraconazole dispersible tablets and preparation method thereof - Google Patents
Itraconazole dispersible tablets and preparation method thereof Download PDFInfo
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- CN102499909A CN102499909A CN2011104432195A CN201110443219A CN102499909A CN 102499909 A CN102499909 A CN 102499909A CN 2011104432195 A CN2011104432195 A CN 2011104432195A CN 201110443219 A CN201110443219 A CN 201110443219A CN 102499909 A CN102499909 A CN 102499909A
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- itraconazole
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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 all had antifungic action, because of it has activity by force, and has a broad antifungal spectrum, characteristics such as cure rate height are widely used.Its structural formula is following:
Research shows the itraconazole poorly water-soluble, and tablet disperses difficulty high, and process in leaching is the working difficult point of itraconazole dispersible tablet.Because its water solublity lower (below the 1 μ g/ml) 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 processed 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; Said compositions contains the 40-69.9wt% solid dispersion; The infiltration derivant of 0.1-30wt%; The disintegrating agent of 0.1-30wt%, said solid dispersion are dispersed in through the itraconazole with 1 weight portion in the absorption enhancer mixture of hydroxypropyl emthylcellulose and 0.01-5 weight portion of 0.1-10 weight portion and prepare with amorphism.The method for preparing 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; Add the aqueous solution of hydrophilicity condiment, be settled out the particulate suspension of itraconazole, 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, and said composition is made up of itraconazole, starch, mannitol, sucrose, steviosin, and 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 that the present invention will solve provides the method for preparing of simple, the lower-cost itraconazole dispersible tablet of a kind of technology, and the itraconazole dispersible tablet that obtains of method thus, and this dispersible tablet has the dissolution height, is easy to dispersive characteristics.
For reaching above-mentioned purpose, the method for preparing 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 said step (1), (2) is obtained respectively dissolves fully, drying, and pelletize obtains Itraconazole composite powder;
(4) composite granule and the pharmaceutic adjuvant mix homogeneously that step (3) are obtained, tabletting promptly gets.
The method for preparing of itraconazole dispersible tablet of the present invention, in the wherein preferred said step (3), dry dry with spray dryer, inlet temperature is 170-190 ℃, outlet temperature is 70-90 ℃.
The method for preparing of itraconazole dispersible tablet of the present invention, in the wherein preferred said 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 method for preparing of itraconazole dispersible tablet of the present invention, in the wherein preferred said step (3), the fluidised bed granulator pelletize is used in pelletize, and the inlet temperature of fluidised bed granulator is 85-95 ℃, and outlet temperature is 45-55 ℃.
The method for preparing of itraconazole dispersible tablet of the present invention, medicinal adjuvant is the conventional pharmaceutic adjuvant in this area 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.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 more preferably said 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, it has the dissolution height, is easy to dispersive characteristics, and its dissolution is 80-90%, and the fully decentralized time is 1-3 minute.
The inventive method; Through itraconazole being dissolved in the organic solvent (polyvinylpolypyrrolidone, dichloromethane, Macrogol 4000 (Haidian, Beijing fellow member of an association or organization's fine chemistry industry company), ethanol etc.) and adding 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, Itraconazole composite powder is mixed with a certain proportion of disintegrating agent (carboxymethyl starch sodium), fluidizer (magnesium stearate), filler (Lactis Anhydrous (the happy company of German U.S. agent)) etc., carry out tabletting and obtain 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, and cost is lower, the itraconazole dispersible tablet that obtains; Good water solubility, be easy to disperse, dissolution is high, be easy to suitability for industrialized production, has 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, do more detailed explanation with other technical characterictic and advantage to 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).Raw materials mix is even, and the control solution temperature is 40 ℃, lets 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.Raw materials mix is even, and the control solution temperature is 40 ℃, lets solid such as cyclodextrin be dissolved in the liquid ethanol.
Above-mentioned two kinds of solution mix homogeneously to itraconazoles are dissolved fully, and dry with spray dryer, dryer inlet temperature is 170 ℃, and outlet temperature is 70 ℃; Dry back is with the pelletize of centrifugal granulator machine, and 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, this raw materials mix is even, press 100 with tablet machine, promptly get the itraconazole dispersible tablet.
Embodiment 2 to 9, and is as shown in table 1: operating procedure is with embodiment 1, and difference is that the addition of each component is different.In addition; For the process conditions in the method for preparing of the present invention (like the gateway temperature of the solution temperature of described each step of aforementioned summary of the invention, exsiccator gateway temperature, granulator; The selection type of comminutor etc.); Be simply to adjust according to the amount or the practical operation situation of adding component, do not have influence basically for the performance of the itraconazole dispersible tablet that obtains.
Each components selection and weight proportion thereof in the method for preparing 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; Promptly the weight ratio when itraconazole, hydroxypropyl emthylcellulose, polyvinylpolypyrrolidone and dichloromethane meets 1: (1-5): (1-5): scope (10-20); Cyclodextrin, sodium lauryl sulphate, Macrogol 4000 and alcoholic acid weight ratio meet 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
In embodiment 1, remove hydroxypropyl emthylcellulose, 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
In embodiment 1, remove polyvinylpolypyrrolidone, 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
In embodiment 1, remove sodium lauryl sulphate, 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 cyclodextrin, sodium lauryl sulphate, Macrogol 4000 and alcoholic acid weight ratio 1: 0.08: 0.1: 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
In embodiment 1, remove Macrogol 4000, 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 cyclodextrin, sodium lauryl sulphate, Macrogol 4000 and alcoholic acid weight ratio 1: 0.1: 0.08: 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 a lactose, carboxymethyl starch sodium; Hydroxy propyl cellulose and magnesium stearate; Also can be added with this areas such as microcrystalline Cellulose, silicon dioxide pharmaceutic adjuvant commonly used in this external other specific embodiment, the weight ratio between each composition is the common ratio in this area, is not limited to weight proportion of the present invention; The weight ratio of composite granule that obtains like embodiment in this Comparative Examples 1 and lactose, carboxymethyl starch sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline Cellulose, silicon dioxide is 1: 0.1: 0.1: 0.05: 0.002: 0.05: 0.05; Detecting dissolution behind the tabletting is 80.6%, and conclusion is that selection and the proportioning thereof of pharmaceutic adjuvant is not very big to the dispersibility influence of itraconazole sheet of the present invention, when selecting the conventional adjuvant in this area 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
In embodiment 1, remove carboxymethyl starch sodium, other conditions are constant, and it is qualified basically to detect dispersing uniformity behind the tabletting, and dissolution is 81.1%.
Comparative Examples 7
In embodiment 1, remove hydroxypropyl cellulose, other conditions are constant, and it is qualified basically to detect dispersing uniformity behind the tabletting, and dissolution is 80.7%.
Test Example
Experimental apparatus: D800-LS intellectual drug digestion instrument, Tianda Tianfa Science and Technology Co. Ltd., the result of this Test Example sees table 1.
Dissolution: 1000ml is a 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.)
These article of getting, according to dissolution method, 1000ml is a dissolution medium with hydrochloric acid solution (4 → 1000), rotating speed is that per minute 50 changes; Operation in accordance with the law in the time of 45 minutes, is got solution 10ml; Filter, precision is measured subsequent filtrate 2ml, places the 10ml measuring bottle; Be 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, adds 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; Add hydrochloric acid solution (4 → 1000) and be diluted to scale, shake up, as reference substance solution.Get above-mentioned two kinds of solution, measure, measure trap respectively, calculate every stripping quantity in the wavelength of 254nm with ultraviolet visible spectrophotometry.
Above-described embodiment describes 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 (9)
1. the method for preparing 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 said step (1), (2) is obtained respectively dissolves fully, drying, and pelletize obtains Itraconazole composite powder;
(4) composite granule and the pharmaceutic adjuvant mix homogeneously that step (3) are obtained, tabletting promptly gets.
2. method according to claim 1 is characterized in that: in the said step (3), said dry dry with spray dryer, inlet temperature is 170-190 ℃, and outlet temperature is 70-90 ℃.
3. method according to claim 1 is characterized in that: in the said step (3), said 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 said step (3), the fluidised bed granulator pelletize is used in said pelletize, and inlet temperature is 85-95 ℃, and outlet temperature is 45-55 ℃.
5. method according to claim 1 is characterized in that: the pharmaceutic adjuvant in the said 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 in the said step (4): (0.15-0.25): (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 is characterized in that: its dissolution is 80-90%.
9. itraconazole dispersible tablet according to claim 7 is characterized in that: its fully decentralized time is 1-3 minute.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| 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 |
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2011
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Patent Citations (5)
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| 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 |
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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 |
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