CN105193749A - Medicinal tadalafil composition tablets for treating urological diseases - Google Patents
Medicinal tadalafil composition tablets for treating urological diseases Download PDFInfo
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- CN105193749A CN105193749A CN201510572578.9A CN201510572578A CN105193749A CN 105193749 A CN105193749 A CN 105193749A CN 201510572578 A CN201510572578 A CN 201510572578A CN 105193749 A CN105193749 A CN 105193749A
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- tadanafil
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- tadalafil
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Abstract
The invention relates to medicinal tadalafil composition tablets for treating urological diseases, and belongs to the technical field of medicine. The tablets are prepared from an internally added original accessory, an adhesive and a lubricant, wherein the internally added original accessory consists of tadalafil, sodium starch glycolate, starch, lactose and microcrystalline cellulose; the adhesive is prepared from sodium dodecyl sulfate and purified water; the lubricant is magnesium stearate. The tadalafil is a compound of a novel crystal form, an X-ray powder diffraction pattern measured by Cu-K alpha rays is shown in picture 1, the tadalafil is different from that reported in the prior art, and a test shows that the compound of the novel crystal form has obviously improved water solubility, low impurity content and high stability; compared with the prior art, the tablets prepared from the tadalafil compound of the novel crystal form are high in dissolubility and stability and low in impurity content, and safety in clinical application is improved.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine tadanafil composition tablet for the treatment of Urology Surgery class disease.
Background technology
Tadanafil is sold as Cialis at present.Cialis is EliLilly development, is used for the treatment of sexual impotence.At this aspect of performance, according to reports, tadanafil works by suppressing cyclic guanylic acid (cGMP)-specific PDE5 type (PDE5).The suppression of PDE5 probably causes smooth muscle loosening by the amount improving cGMP and increases blood flow and alleviate sexual impotence.
, that is, there is different crystal forms in polytropism, is the characteristic of some molecules and molecular complex.Single molecule, as tadanafil, may produce many crystal forms, they have different crystal structures and physical property, as fusing point, X-ray diffractogram, INFRARED ABSORPTION fingerprint and solid state NMR spectroscopy.A kind of crystal form may produce the hot model of action being different from other crystal form.Hot model of action can test Indoor measurement by the technology of such as capillary melting point, thermogravimetric analysis (" TGA ") and differential scanning calorimetry (" DSC "), and these methods are for distinguishing the form of polycrystalline.
The difference of different crystal form physical properties comes from orientation and the intermolecular interaction of molecule adjacent in blocks of solid or coordination compound.Correspondingly, compared with the crystal form of other same compound or coordination compound, polymorph is shared same molecular formula and has the distinct solids of different beneficial physical performances.
A most important physical property of medical compounds is its dissolubility in aqueous, particularly its dissolubility in patient's gastric juice.Such as, when absorbing slow by gastrointestinal, often wishing to dissolve at the stomach of patient or the drug slow of enteral conditional instability, thus not accumulating in harmful environment.The different crystal forms of same medicine compound or polymorph may and it is reported that weighing-appliance has different water solubilities.
Tadanafil is considered to substantially water insoluble and is only slightly soluble in the solid of some organic solvent such as methanol, ethanol and acetone.U.S. Patent No. 6,841,167 report tadanafil have the water solubility of about 2 μ g/ml water at 25 DEG C.
Tadanafil is insoluble drug, and bioavailability is lower, and the ineffective dose therefore taken is larger, and can produce multiple bad putting and answer, non-rational use of drug can cause vision impairment or forfeiture.Pharmaceutical preparation for tadanafil is improving the bioavailability of medicine, reduces the research of the generation of untoward reaction, is widely used in treatment male sexual disorder clinically particularly important for tadanafil.
Prior art application diverse ways overcomes the obviously bad water-soluble of tadanafil.Disclosed international patent application WO01/08686 seems to disclose the pharmaceutical preparation containing tadanafil with " free drug " type mixed with diluent, lubricant, hydrophilic bonding agent and disintegrating agent.
Should be used for improving another technology deliquescent to comprise and use " coprecipitate " of tadanafil to prepare preparation, wherein tadanafil and carrier " thing of combining closely " in the easy mixed solvent of non-aqueous water and (optionally) water, use wherein carrier be substantially undissolved aqueous " co-precipitation medium " from " thing of combining closely ", co-precipitation is out.See U.S. Patent No. 5,985,326, some of them clearly information or non-existent.
The present inventor starts with from the research of tadanafil solid chemical material existence, a kind of tadanafil crystalline compounds has been prepared through a large amount of tests, surprisingly find through overtesting, the water solublity that the compound tool of this novel crystal forms structure has clear improvement, impurity content is low, good stability, the tablet prepared of this tadanafil crystal compound comparatively prior art to compare dissolution high, good stability, impurity content is low, improves the safety of clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine tadanafil composition tablet for the treatment of Urology Surgery class disease.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine tadanafil composition tablet for the treatment of Urology Surgery class disease, described composition tablet by interiorly adding supplementary material, binding agent is made; Add supplementary material in described and comprise tadanafil, tadanafil is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
As preferably, with parts by weight, add supplementary material in described and be made up of the tadanafil of 2 weight portions, the carboxymethylstach sodium of 4.3 weight portions, the starch of 3.5 weight portions, the lactose of 21 weight portions, the microcrystalline Cellulose of 4 weight portions.
As preferably, with parts by weight, described binding agent is made up of the sodium lauryl sulphate of 0.1 weight portion and the purified water of 16 weight portions.
As preferably, with parts by weight, described lubricant is be the magnesium stearate of 0.2 weight portion.
As preferably, the preparation method of described composition tablet comprises the following steps:
(1) supplementary material process: lactose is crossed 80 mesh sieves with shaking screen, crosses 40 mesh sieves by microcrystalline Cellulose;
(2) weigh: weigh each supplementary material according to recipe quantity;
(3) supplementary material premixing: after manual for the ratio of the tadanafil of recipe quantity and the lactose of 2/7 premix, to put in pulverizer 100 orders together and pulverizes;
(4) binding agent preparation: the sodium lauryl sulphate of recipe quantity is joined in purified water and makes binding agent;
(5) granulate: add in high-speed mixing granulating machine by adding adjuvant in the tadanafil pulverized and lactose mixed powder (1:3) and remaining lactose and other, open stirring motor low speed (I speed) mixing 10 minutes, add the binding agent prepared, low speed (I speed) wet mixing 120-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
(6) dry: boiling drier inlet temperature to be controlled at 50 DEG C-60 DEG C, wet granular is placed in boiling drier, notes checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reaching uniform drying, bag is trembled 1 time, dry 120-150 minute every 30 minutes;
(7) always mix: granule after drying and magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
(8) tabletting: select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-8kgf;
(9) pack.
The preparation method of the tadanafil crystal in the present composition comprises the following steps:
Be dissolved in by tadanafil in the mixed solvent of dimethyl sulfoxine that 35 DEG C of volumes are 5 times of tadanafil weight, 3-picoline, the volume ratio of dimethyl sulfoxine and 3-picoline is 3:1; First add the water of 9 times that volume total amount is tadanafil weight and the mixed solvent A of oxolane with the speed of 25ml/min, the volume ratio of water and oxolane is 4:1.5, and limit edged stirs, control temperature 35 DEG C, growing the grain 1 hour; And then add the water of 12 times that volume total amount is tadanafil weight and the mixed solvent B of oxolane with the speed of 15ml/min, the volume ratio of water and oxolane is 3:1, growing the grain is after 2.5 hours, be cooled to-5 DEG C with the speed of 20 DEG C/h, then keep mixing speed 260 revs/min of stirring and crystallizing, growing the grain 2 hours; Filter, 45 DEG C, drying under reduced pressure obtains tadanafil crystalline compounds.
Below technical scheme of the present invention is made further explanation:
The present invention is by the precise controlling to crystallization condition, and prepared a kind of tadanafil novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this tadanafil crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, the water solublity that the compound tool of this novel crystal forms structure has clear improvement, impurity content is low, good stability, the tablet prepared of this tadanafil crystal compound comparatively prior art to compare dissolution high, good stability, impurity content is low, improves the safety of clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the tadanafil crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of tadanafil crystal
Be dissolved in by tadanafil in the mixed solvent of dimethyl sulfoxine that 35 DEG C of volumes are 5 times of tadanafil weight, 3-picoline, the volume ratio of dimethyl sulfoxine and 3-picoline is 3:1; First add the water of 9 times that volume total amount is tadanafil weight and the mixed solvent A of oxolane with the speed of 25ml/min, the volume ratio of water and oxolane is 4:1.5, and limit edged stirs, control temperature 35 DEG C, growing the grain 1 hour; And then add the water of 12 times that volume total amount is tadanafil weight and the mixed solvent B of oxolane with the speed of 15ml/min, the volume ratio of water and oxolane is 3:1, growing the grain is after 2.5 hours, be cooled to-5 DEG C with the speed of 20 DEG C/h, then keep mixing speed 260 revs/min of stirring and crystallizing, growing the grain 2 hours; Filter, 45 DEG C, drying under reduced pressure obtains tadanafil crystalline compounds.
The X-ray powder diffraction pattern that the tadanafil crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of tadalafil tablet:
Prescription: with parts by weight, the tadanafil crystal-form compound 2 parts that embodiment 1 is obtained, carboxymethylstach sodium 4.3 parts, starch 3.5 parts, lactose 21 parts, microcrystalline Cellulose 4 parts, sodium lauryl sulphate 0.1 part, purified water 16 parts, magnesium stearate 0.2 part.
Preparation method:
(1) supplementary material process: lactose is crossed 80 mesh sieves with shaking screen, crosses 40 mesh sieves by microcrystalline Cellulose;
(2) weigh: weigh each supplementary material according to recipe quantity;
(3) supplementary material premixing: after manual for the ratio of the tadanafil of recipe quantity and the lactose of 2/7 premix, to put in pulverizer 100 orders together and pulverizes;
(4) binding agent preparation: the sodium lauryl sulphate of recipe quantity is joined in purified water and makes binding agent;
(5) granulate: add in high-speed mixing granulating machine by adding adjuvant in the tadanafil pulverized and lactose mixed powder (1:3) and remaining lactose and other, open stirring motor low speed (I speed) mixing 10 minutes, add the binding agent prepared, low speed (I speed) wet mixing 120-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
(6) dry: boiling drier inlet temperature to be controlled at 50 DEG C-60 DEG C, wet granular is placed in boiling drier, notes checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reaching uniform drying, bag is trembled 1 time, dry 120-150 minute every 30 minutes;
(7) always mix: granule after drying and magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
(8) tabletting: select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-8kgf;
(9) pack.
test example 1:soluble test
The dissolubility performance of this experimental example to the tadanafil compound crystal of embodiment 1 carries out analysis of experiments.Specific experiment method is: in the low capacity bottle of constant temperature jacket, add appropriate distilled water, tadanafil is added to no longer dissolving at 25 DEG C, start magnetic stirrer, Keep agitation under constant temperature, in experimentation, system is in the state of two-phase coexistent all the time, after 70 minutes system liquid phase in tadanafil concentration be dissolubility at this temperature.Carry out sample analysis after 2 hours, get the close meansigma methods of adjacent two times result as measured value of experiment, before sampling, in order to make solid-liquid fully be separated, after stopping stirring, not molten tadanafil is deposited to the bottom of low capacity bottle, a small amount of upper clear supernate is extracted with syringe, with the filter paper filtering of 0.45 micron, sample thief from filtrate, the content of tadanafil is measured, specifically in table 1 by HPLC.
The dissolubility of tadanafil crystalline compounds in water of embodiment of the present invention 1-3 under table 1 room temperature
From upper table analysis, the water solublity of tadanafil crystalline compounds provided by the invention is that commercially available prod is more than 2 times.
test example 2:dissolution Rate Testing
This experimental example be to the embodiment of the present invention 2 prepare tadanafil tablet with use commercially available tadanafil be prepared into tablet, disintegrating tablet, chewable tablet (comparative example 1,2,3) dissolving out capability experiment Analysis.Except the difference that crude drug uses, comparative example 1,2,3 adopts prescription and the preparation method of embodiment 2.Sample measures dissolution according to " Chinese Pharmacopoeia " 2005 editions second annex XC first method respectively, solvent uses the hac buffer of PH4.5 as dissolution fluid, and measured the stripping quantity determination dissolution of tadanafil by efficient liquid phase chromatographic analysis, experimental result reference table 2.
The In Vitro Dissolution result of the test of table 2 tadanafil preparation
As can be seen from Table 2, tadanafil tablet of the present invention stripping is very fast, and cumulative concentration reaches almost stripping completely after more than 95%, 45min very soon, apparently higher than commercially available prod.
test example 3:stability test
This experimental example carries out accelerated test to embodiment 2, temperature 40 DEG C ± 2 DEG C, carries out accelerated test under the condition of relative humidity 75% ± 5%, investigate 6 months, respectively at the 1st, 2,3, sampling in June, investigate, see table 3 by stability high spot reviews project.
The stability test of table 3 tadanafil preparation
Conclusion: carry out accelerated test 6 months by preparing sample to experimental example 2, every inspection target and detect results contrast in 0 month, be showed no significant change, and impurity content is low.
Claims (6)
1. treat a medicine tadanafil composition tablet for Urology Surgery class disease, it is characterized in that: described composition tablet by interiorly adding supplementary material, binding agent is made; Add supplementary material in described and comprise tadanafil, described tadanafil is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine tadanafil composition tablet for the treatment of Urology Surgery class disease according to claim 1, it is characterized in that: with parts by weight, add supplementary material in described and be made up of the tadanafil of 2 weight portions, the carboxymethylstach sodium of 4.3 weight portions, the starch of 3.5 weight portions, the lactose of 21 weight portions, the microcrystalline Cellulose of 4 weight portions.
3. the medicine tadanafil composition tablet for the treatment of Urology Surgery class disease according to claim 1, is characterized in that: with parts by weight, and described binding agent is made by the sodium lauryl sulphate of 0.1 weight portion and the purified water of 16 weight portions.
4. the medicine tadanafil composition tablet for the treatment of Urology Surgery class disease according to claim 1, it is characterized in that: with parts by weight, described lubricant is the magnesium stearate of 0.2 weight portion.
5. prepare a method for the medicine tadanafil composition tablet for the treatment of Urology Surgery class disease as claimed in claim 1, it is characterized in that comprising the following steps:
(1) supplementary material process: lactose is crossed 80 mesh sieves with shaking screen, crosses 40 mesh sieves by microcrystalline Cellulose;
(2) weigh: weigh each supplementary material according to recipe quantity;
(3) supplementary material premixing: after manual for the ratio of the tadanafil of recipe quantity and the lactose of 2/7 premix, to put in pulverizer 100 orders together and pulverizes;
(4) binding agent preparation: the sodium lauryl sulphate of recipe quantity is joined in purified water and makes binding agent;
(5) granulate: add in high-speed mixing granulating machine by adding adjuvant in the tadanafil pulverized and lactose 1:3 mixed powder and remaining lactose and other, open stirring motor mixed on low speed 10 minutes, add the binding agent prepared, low speed wet mixing 120-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
(6) dry: boiling drier inlet temperature to be controlled at 50 DEG C-60 DEG C, wet granular is placed in boiling drier, notes checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reaching uniform drying, bag is trembled 1 time, dry 120-150 minute every 30 minutes;
(7) always mix: granule after drying and magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
(8) tabletting: select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-8kgf;
(9) pack.
6. the medicine tadanafil composition tablet for the treatment of Urology Surgery class disease according to claim 1, it is characterized in that, the preparation method of described tadanafil crystal comprises the following steps:
Be dissolved in by tadanafil in the mixed solvent of dimethyl sulfoxine that 35 DEG C of volumes are 5 times of tadanafil weight, 3-picoline, the volume ratio of dimethyl sulfoxine and 3-picoline is 3:1; First add the water of 9 times that volume total amount is tadanafil weight and the mixed solvent A of oxolane with the speed of 25ml/min, the volume ratio of water and oxolane is 4:1.5, and limit edged stirs, control temperature 35 DEG C, growing the grain 1 hour; And then add the water of 12 times that volume total amount is tadanafil weight and the mixed solvent B of oxolane with the speed of 15ml/min, the volume ratio of water and oxolane is 3:1, growing the grain is after 2.5 hours, be cooled to-5 DEG C with the speed of 20 DEG C/h, then keep mixing speed 260 revs/min of stirring and crystallizing, growing the grain 2 hours; Filter, 45 DEG C, drying under reduced pressure obtains tadanafil crystalline compounds.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510572578.9A CN105193749A (en) | 2015-09-10 | 2015-09-10 | Medicinal tadalafil composition tablets for treating urological diseases |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510572578.9A CN105193749A (en) | 2015-09-10 | 2015-09-10 | Medicinal tadalafil composition tablets for treating urological diseases |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110638770A (en) * | 2019-10-25 | 2020-01-03 | 株洲千金药业股份有限公司 | Tadalafil tablet preparation method and tablet prepared by same |
| CN110664766A (en) * | 2019-10-10 | 2020-01-10 | 甘肃普安制药股份有限公司 | Tadalafil tablet and preparation method thereof |
| CN117505021A (en) * | 2023-11-28 | 2024-02-06 | 诺泽流体科技(上海)有限公司 | Air flow crushing method applied to tadalafil bulk drug |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010163425A (en) * | 2008-12-18 | 2010-07-29 | Daiichi Sankyo Healthcare Co Ltd | Medicinal composition containing phosphodiesterase-5 inhibitor and pantethine |
| WO2011048553A2 (en) * | 2009-10-22 | 2011-04-28 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical compositions of pde-5 inhibitors and dapoxetine |
| CN102180876A (en) * | 2011-05-28 | 2011-09-14 | 浙江华海药业股份有限公司 | New preparation method for Tadalafei crystal form I |
| CN104844600A (en) * | 2015-05-13 | 2015-08-19 | 山东罗欣药业集团股份有限公司 | Tadalafil compound and composition thereof |
-
2015
- 2015-09-10 CN CN201510572578.9A patent/CN105193749A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010163425A (en) * | 2008-12-18 | 2010-07-29 | Daiichi Sankyo Healthcare Co Ltd | Medicinal composition containing phosphodiesterase-5 inhibitor and pantethine |
| WO2011048553A2 (en) * | 2009-10-22 | 2011-04-28 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical compositions of pde-5 inhibitors and dapoxetine |
| CN102180876A (en) * | 2011-05-28 | 2011-09-14 | 浙江华海药业股份有限公司 | New preparation method for Tadalafei crystal form I |
| CN104844600A (en) * | 2015-05-13 | 2015-08-19 | 山东罗欣药业集团股份有限公司 | Tadalafil compound and composition thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110664766A (en) * | 2019-10-10 | 2020-01-10 | 甘肃普安制药股份有限公司 | Tadalafil tablet and preparation method thereof |
| CN110638770A (en) * | 2019-10-25 | 2020-01-03 | 株洲千金药业股份有限公司 | Tadalafil tablet preparation method and tablet prepared by same |
| CN110638770B (en) * | 2019-10-25 | 2022-04-05 | 株洲千金药业股份有限公司 | Tadalafil tablet preparation method and tablet prepared by same |
| CN117505021A (en) * | 2023-11-28 | 2024-02-06 | 诺泽流体科技(上海)有限公司 | Air flow crushing method applied to tadalafil bulk drug |
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Application publication date: 20151230 |