CN104940154A - Sildenafil citrate composition tablet as medicine for treating urological diseases - Google Patents
Sildenafil citrate composition tablet as medicine for treating urological diseases Download PDFInfo
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- CN104940154A CN104940154A CN201510436552.1A CN201510436552A CN104940154A CN 104940154 A CN104940154 A CN 104940154A CN 201510436552 A CN201510436552 A CN 201510436552A CN 104940154 A CN104940154 A CN 104940154A
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Abstract
The invention discloses a sildenafil citrate composition tablet as a medicine for treating urological diseases. The tablet is prepared from internally-added raw auxiliary materials, a binder and externally-added auxiliary materials, wherein the internally-added raw auxiliary materials comprise sildenafil citrate, sodium carbonate, starch, dextrin, cane sugar and crospovidone; the binder is prepared from povidone K30 and purified water; the externally-added auxiliary materials comprises carboxymethyl starch sodium and magnesium stearate. According to the invention, the sildenafil citrate is a compound with a new crystal form, X-ray powder diffraction pattern, measured by using a Cu-K alpha ray, of the sildenafil citrate is shown in the graph 1 (in the description), and the sildenafil citrate provided by the invention is different from the sildenafil citrate reported in the prior art; experiment results prove that the compound with the new crystal structure has improved hygroscopicity; compared with the prior art, the tablet prepared from the sildenafil citrate compound with the new crystal form has the advantages that the dissolution rate is high, the stability is good, the water content and impurity content are low, and the safety of clinical application is improved.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine sildenafil citrate composition tablet for the treatment of urological diseases.
Background technology
Sldenafil is the medicine of the Erectile Dysfunction disease that the objective and subjective reason of a kind of effective treatment causes, in March, 1997 goes on the market in the U.S. as prescription drugs through FDA approval, sldenafil is high selectivity PDE5 (PDE5) inhibitor, PDE5 expresses at cavernous body of penis camber, and in other tissue, (comprising platelet, blood vessel and visceral smooth muscle, skeletal muscle), expression is low.Sldenafil, by Selective depression PDE5, strengthens nitric oxide (NO)-cGMP approach, raises cGMP level and causes corpus cavernosum smooth muscle to relax, making patients with erectile dysfunction produce natural erectile response to sexual stimulus.Erectile response generally with sldenafil dosage and plasma concentration increase and strengthen.
Sildenafil citrate hygroscopicity is strong, easy moisture absorption under normality and going bad, and therefore the height of water content to the stability influence of medicine comparatively greatly, needs strictly to control product quality, bring larger difficulty to the preparation of preparation.Therefore, the sildenafil citrate compound that a kind of performance improvement is provided is necessary.
The present inventor starts with from the research of sildenafil citrate solid chemical material existence, a kind of sildenafil citrate crystalline compounds has been prepared through a large amount of tests, surprisingly find through overtesting, the compound of this novel crystal forms structure has the hygroscopicity of improvement, the tablet prepared of this sildenafil citrate crystal compound comparatively prior art to compare dissolution high, good stability, moisture and impurity content low, improve the safety of clinical practice.
Summary of the invention
The object of the present invention is to provide a kind of medicine sildenafil citrate composition tablet for the treatment of urological diseases.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine sildenafil citrate composition tablet for the treatment of urological diseases, it is characterized in that, described composition tablet is made up of interior supplementary material, binding agent and the additional adjuvant of adding; Add supplementary material in described to be made up of the sildenafil citrate of 1 weight portion, the sodium carbonate of 0.36 weight portion, the starch of 0.80 weight portion, the dextrin of 0.50 weight portion, the sucrose of 0.50 weight portion, the polyvinylpolypyrrolidone of 0.40 weight portion; Described sildenafil citrate is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
Preferably, described binding agent is dissolved in the purified water of 1.6 weight portions by the PVP K30 of 0.10 weight portion to make.
Preferably, described additional adjuvant is made up of the carboxymethylstach sodium of 0.20 weight portion, the magnesium stearate of 0.02 weight portion.
The preparation method of described composition tablet comprises the following steps:
(1) supplementary material process: sodium carbonate, dextrin, sucrose, sildenafil citrate are crossed 100 mesh sieves with shaking screen;
(2) weigh: weigh each supplementary material according to recipe quantity;
(3) binding agent is prepared: be dissolved in purified water by the PVP K30 of recipe quantity, be made into PVP K30 aqueous solution;
(4) granulate: by interiorly adding supplementary material sildenafil citrate, sodium carbonate, starch, dextrin, sucrose, polyvinylpolypyrrolidone add in high-speed mixing granulating machine, open stirring motor low speed (I speed) mixing 10 minutes, add PVP K30 aqueous solution, low speed (I speed) wet mixing 90 ~ 120 seconds soft materials processed, select 18 order nylon wires to be arranged in oscillating granulator and granulate;
(5) dry: boiling drier inlet temperature to be controlled at 55 DEG C ~ 60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reaching uniform drying;
(6) always mix: granule after drying and carboxymethylstach sodium, magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 10 minutes;
(7) tabletting: select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-8kgf;
(8) pack.
The preparation method of the sildenafil citrate crystal in the present composition comprises the following steps:
(1) added by sildenafil citrate solid in the mixed solvent of 2, the 4-lutidines of 45 DEG C, ether, the volume of mixed solvent is 10 times of sildenafil citrate weight, and the volume ratio of 2,4-lutidines, ether is 5:1.5;
(2) control temperature is under the condition of 45 DEG C, adds the mixed solvent of ethanol and methyl salicylate in the solution that step (1) obtains, and the volume of mixed solvent is 12 times of sildenafil citrate weight, and the volume ratio of ethanol and methyl salicylate is 3:1;
(3) after adding the mixed solvent of ethanol and methyl salicylate, be that 6.5 DEG C/min is cooled to-10-DEG C with speed, leave standstill 5 hours, crystallize out at-10-DEG C, filter, washing, obtains sildenafil citrate compound after vacuum drying.
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 sildenafil citrate novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this sildenafil citrate crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, the hygroscopicity that the compound tool of this novel crystal forms structure has clear improvement, the tablet prepared of this sildenafil citrate crystal compound comparatively prior art to compare dissolution high, good stability, moisture and impurity content low, improve the safety of clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of sildenafil citrate crystal prepared by the embodiment of the present invention 1.
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 sildenafil citrate crystal
(1) added by sildenafil citrate solid in the mixed solvent of 2, the 4-lutidines of 45 DEG C, ether, the volume of mixed solvent is 10 times of sildenafil citrate weight, and the volume ratio of 2,4-lutidines, ether is 5:1.5;
(2) control temperature is under the condition of 45 DEG C, adds the mixed solvent of ethanol and methyl salicylate in the solution that step (1) obtains, and the volume of mixed solvent is 12 times of sildenafil citrate weight, and the volume ratio of ethanol and methyl salicylate is 3:1;
(3) after adding the mixed solvent of ethanol and methyl salicylate, be that 6.5 DEG C/min is cooled to-10-DEG C with speed, leave standstill 5 hours, crystallize out at-10-DEG C, filter, washing, obtains sildenafil citrate compound after vacuum drying.
The X-ray powder diffraction pattern that the sildenafil citrate crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of sildenafil citrate composition tablet:
Prescription: with parts by weight as table 1
Table 1 sildenafil citrate composition prescription
(1) supplementary material process: sodium carbonate, dextrin, sucrose, sildenafil citrate are crossed 100 mesh sieves with shaking screen;
(2) weigh: weigh each supplementary material according to recipe quantity;
(3) binding agent is prepared: be dissolved in purified water by the PVP K30 of recipe quantity, be made into polyvidone k30 aqueous solution;
(4) granulate: by interiorly adding supplementary material sildenafil citrate, sodium carbonate, starch, dextrin, sucrose, polyvinylpolypyrrolidone add in high-speed mixing granulating machine, open stirring motor low speed (I speed) mixing 10 minutes, add PVP K30 aqueous solution, low speed (I speed) wet mixing 90 ~ 120 seconds soft materials processed, select 18 order nylon wires to be arranged in oscillating granulator and granulate;
(5) dry: boiling drier inlet temperature to be controlled at 55 DEG C ~ 60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reaching uniform drying;
(6) always mix: granule after drying and carboxymethylstach sodium, magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 10 minutes;
(7) tabletting: select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-8kgf;
(8) pack.
test example 1:wettability test
This test example compares the hygroscopicity of the sildenafil citrate of sildenafil citrate compound provided by the invention and prior art.
Test method: respectively under the condition of humidity 60% and 90%, room temperature, each sample thief 1g is placed on electronic balance, and time recording weight, to detect moisture absorption degree, the results are shown in Table 2.
Table 2 sample hygroscopicity measurement result
Wherein:
Sample 1: the sildenafil citrate that the embodiment of the present invention 1 is obtained;
Sample 2: the sildenafil citrate that the embodiment of the present invention 2 is obtained;
Sample 3: according to " sildenafil citrate improvement in synthesis " [Xiang Honglin, Hu Gaoyun, etc. sildenafil citrate improvement in synthesis, Hunan Medical college journal, 2000,2(1): 47-48] the obtained sildenafil citrate compound of method;
Sample 4, sildenafil citrate crude drug imported product (Pfizer Ireland Pharmaceuticals).
As can be seen from above-mentioned result of the test, compared with the sildenafil citrate of prior art, the hygroscopicity that sildenafil citrate tool provided by the present invention has clear improvement.
test example 2: Dissolution Rate Testing
Comparative example 1: viagra (Pfizer factory)
According to the dissolubility of this product raw material, and with reference to Sildenafil citrate tablets national drug registered standard WS
1method in-(X-010)-2010Z quality standard under dissolution test item, measures the dissolution of this product with ultraviolet visible spectrophotometry.
Get this product, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC, first method), with the hydrochloric acid solution 900ml of 0.01mol/L for solvent, rotating speed is 100 turns per minute, operates in accordance with the law.Through 15 minutes time, get solution and filter, get subsequent filtrate as need testing solution (specification: 25mg); Or it is appropriate to get subsequent filtrate, make every 1ml about containing sldenafil 27 μ g(specification: 50mg with the dilution of 0.01mol/L hydrochloric acid solution) or 22 μ g(specification: 100mg) solution, as need testing solution; Separately get sildenafil citrate reference substance appropriate, accurately weighed, be diluted to every 1ml about containing sldenafil 27 μ g(specification with 0.01mol/L dissolve with hydrochloric acid solution: 25mg, 50mg) or 22 μ g(specification: 100mg) solution product solution in contrast.Get above-mentioned need testing solution and reference substance solution, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IVA), measure absorbance respectively at 290nm place, calculate the stripping quantity of every sheet, the results are shown in Table 3
Table 3 dissolution determination result
As seen from the experiment, the dissolution of tablet of the present invention is significantly higher than imported product.
test example 3: stability test
The Sildenafil citrate tablets that Example 2 is obtained and viagra (Pfizer factory), under high temperature 40 DEG C, relative humidity 75% ± 5% condition 6 months, carry out accelerated test investigation, result was as table 4:
Table 4 accelerated test investigates result
From accelerated test result, viagra all has significant change through 6 months accelerated test moisture, content, related substances, and product of the present invention has no significant change through 6 months accelerated test character, moisture, content, related substances, and moisture and its related substances are all well below imported product viagra, as can be seen here, the Sildenafil citrate tablets good stability of gained of the present invention, moisture, impurity content are low.
2, long term test
Sample thief, by commercially available back, place 24 months under long term test (temperature 30 DEG C ± 2 DEG C, relative humidity 65% ± 5%) condition, every quality index inspection has no significant change, and moisture all controls below 1.0%, and its related substances is all below 0.15%, well below imported product viagra, as can be seen here, the Sildenafil citrate tablets good stability of gained of the present invention, moisture, impurity content are low.
Claims (5)
1. treat a medicine sildenafil citrate composition tablet for Urology Surgery class disease, it is characterized in that, described composition tablet is made up of interior supplementary material, binding agent and the additional adjuvant of adding; Described sildenafil citrate 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. composition tablet according to claim 1, it is characterized in that, with parts by weight, add supplementary material in described and be made up of the sildenafil citrate of 1 weight portion, the sodium carbonate of 0.36 weight portion, the starch of 0.80 weight portion, the dextrin of 0.50 weight portion, the sucrose of 0.50 weight portion, the polyvinylpolypyrrolidone of 0.40 weight portion.
3. composition tablet according to claim 1, is characterized in that, with parts by weight, described binding agent is dissolved in the purified water of 1.6 weight portions by the PVP K30 of 0.10 weight portion to make.
4. composition tablet according to claim 1, is characterized in that, with parts by weight, described additional adjuvant is made up of the carboxymethylstach sodium of 0.20 weight portion, the magnesium stearate of 0.02 weight portion.
5. composition tablet according to claim 1, is characterized in that, the preparation method of described composition tablet comprises the following steps:
(1) supplementary material process: sodium carbonate, dextrin, sucrose, sildenafil citrate are crossed 100 mesh sieves with shaking screen;
(2) weigh: weigh each supplementary material according to recipe quantity;
(3) binding agent is prepared: be dissolved in purified water by the PVP K30 of recipe quantity, be made into polyvidone k30 aqueous solution;
(4) granulate: by interiorly adding supplementary material sildenafil citrate, sodium carbonate, starch, dextrin, sucrose, polyvinylpolypyrrolidone add in high-speed mixing granulating machine, open stirring motor low speed (I speed) mixing 10 minutes, add PVP K30 aqueous solution, low speed (I speed) wet mixing 90 ~ 120 seconds soft materials processed, select 18 order nylon wires to be arranged in oscillating granulator and granulate;
(5) dry: boiling drier inlet temperature to be controlled at 55 DEG C ~ 60 DEG C, wet granular is placed in boiling drier, note checking exsiccator upper-lower seal situation and granule boiling situation time dry and double granule, reaching uniform drying;
(6) always mix: granule after drying and carboxymethylstach sodium, magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 10 minutes;
(7) tabletting: select high speed tablet press tabletting, regulate pressure to make the molding of slice, thin piece energy and hardness at 5-8kgf;
(8) pack.
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| CN201510436552.1A CN104940154A (en) | 2015-07-23 | 2015-07-23 | Sildenafil citrate composition tablet as medicine for treating urological diseases |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240134A (en) * | 1998-06-22 | 2000-01-05 | 辉瑞研究及发展公司 | Nose added medicinal preparation for curing sexual function disturbance |
| WO2004072079A1 (en) * | 2003-02-11 | 2004-08-26 | Pfizer Limited | Hydrated and anhydrous sildenafil hemi-citrate compound |
| WO2007080362A1 (en) * | 2006-01-14 | 2007-07-19 | Pliva Hrvatska D.O.O. | Pharmaceutically acceptable co-crystalline forms of sildenafil |
| WO2007110559A1 (en) * | 2006-03-29 | 2007-10-04 | Pliva Hrvatska D.O.O. | Pharmaceutically acceptable salts and polymorphic forms of sildenafil |
| CN102497857A (en) * | 2009-06-19 | 2012-06-13 | 纳米模型匈牙利有限公司 | Nanostructured sildenafil base, its pharmaceutically acceptable salts and co-crystals, compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
| CN103664961A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Synthetic process of sildenafil |
-
2015
- 2015-07-23 CN CN201510436552.1A patent/CN104940154A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240134A (en) * | 1998-06-22 | 2000-01-05 | 辉瑞研究及发展公司 | Nose added medicinal preparation for curing sexual function disturbance |
| WO2004072079A1 (en) * | 2003-02-11 | 2004-08-26 | Pfizer Limited | Hydrated and anhydrous sildenafil hemi-citrate compound |
| WO2007080362A1 (en) * | 2006-01-14 | 2007-07-19 | Pliva Hrvatska D.O.O. | Pharmaceutically acceptable co-crystalline forms of sildenafil |
| WO2007110559A1 (en) * | 2006-03-29 | 2007-10-04 | Pliva Hrvatska D.O.O. | Pharmaceutically acceptable salts and polymorphic forms of sildenafil |
| CN102497857A (en) * | 2009-06-19 | 2012-06-13 | 纳米模型匈牙利有限公司 | Nanostructured sildenafil base, its pharmaceutically acceptable salts and co-crystals, compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
| CN103664961A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Synthetic process of sildenafil |
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Application publication date: 20150930 |