CN104940166A - Sildenafil citrate composition capsule as medicine for treating male impotence - Google Patents
Sildenafil citrate composition capsule as medicine for treating male impotence Download PDFInfo
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- CN104940166A CN104940166A CN201510436551.7A CN201510436551A CN104940166A CN 104940166 A CN104940166 A CN 104940166A CN 201510436551 A CN201510436551 A CN 201510436551A CN 104940166 A CN104940166 A CN 104940166A
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Abstract
The invention discloses a sildenafil citrate composition capsule as a medicine for treating male impotence, and belongs to the technical field of medicines. The composition capsule is prepared from internally-added raw auxiliary materials, a binder and a lubricant, wherein the internally-added raw auxiliary materials comprise sildenafil citrate, sodium carbonate, starch, cane sugar and CMS-Na; the binder is prepared from povidone K30 and purified water; the lubricant is 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; the capsule 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 capsule for the treatment of impotence.
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 hygroscopicity that the compound tool of this novel crystal forms structure has clear improvement, capsule dissolubility prepared by this sildenafil citrate crystal compound is 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 capsule for the treatment of impotence.
In order to realize object of the present invention, the technical scheme of employing is:
Treat a medicine sildenafil citrate composition capsule for impotence, it is characterized in that, described compositions is made up of interior supplementary material, binding agent and the lubricant 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 0.9 weight portion, the sucrose of 0.7 weight portion, the sodium starch glycol of 0.4 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 made up of the PVP K30 of 0.08 weight portion and the purified water of 1 weight portion.
Preferably, described lubricant is the magnesium stearate of 0.02 weight portion.
The preparation method of present composition capsule comprises the following steps:
(1) supplementary material process: sodium carbonate, sucrose, sodium starch glycol, 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, sucrose, sodium starch glycol 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 magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
(7) capsule-filling: select Autocapsulefillingmachine fill, regulates content uniformity to meet inner quality standard;
(8) pack.
The preparation method of the sildenafil citrate crystal in the present composition comprises the following steps:
Get sildenafil citrate crude drug, the volume adding 30 DEG C is that in the mixed solvent of the triethanolamine of sildenafil citrate weight 8 times, carbon tetrachloride, triethanolamine and carbon tetrachloride volume ratio are 6:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 0.3T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent that volume is sildenafil citrate weight 6 times of dichloromethane, acetone, the volume ratio of dichloromethane and acetone is 3.5:2; After being added dropwise to complete, be cooled to 0 DEG C with the speed of 7 DEG C/min, leave standstill 4 hours, filter, washing, vacuum drying, obtains described sildenafil citrate compound.
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, capsule dissolubility prepared by this sildenafil citrate crystal compound is 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 that the sildenafil citrate 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 sildenafil citrate crystal
Get sildenafil citrate crude drug, the volume adding 30 DEG C is that in the mixed solvent of the triethanolamine of sildenafil citrate weight 8 times, carbon tetrachloride, triethanolamine and carbon tetrachloride volume ratio are 6:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 0.3T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent that volume is sildenafil citrate weight 6 times of dichloromethane, acetone, the volume ratio of dichloromethane and acetone is 3.5:2; After being added dropwise to complete, be cooled to 0 DEG C with the speed of 7 DEG C/min, leave standstill 4 hours, filter, washing, vacuum drying, obtains described sildenafil citrate compound.
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 capsule:
Prescription: with parts by weight as table 1
Table 1 sildenafil citrate composition prescription
(1) supplementary material process: sodium carbonate, sucrose, sodium starch glycol, 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, sucrose, sodium starch glycol 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 magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
(7) capsule-filling: select Autocapsulefillingmachine fill, regulates content uniformity to meet inner quality standard;
(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, the results are shown in Table 3
Table 3 dissolution determination result
As seen from the experiment, the dissolution of capsule of the present invention is significantly higher than Imported Tablet.
test example 3: stability test
The sildenafil citrate capsule that Example 2 is obtained, 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 capsule stability that the present invention obtains is good, and moisture, impurity content are low.
Claims (5)
1. treat a medicine sildenafil citrate composition capsule for impotence, it is characterized in that: described compositions is made up of interior supplementary material, binding agent and the lubricant 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. the medicine sildenafil citrate composition capsule for the treatment of impotence according to claim 1, is characterized in that: 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 0.9 weight portion, the sucrose of 0.7 weight portion, the sodium starch glycol of 0.4 weight portion.
3. the medicine sildenafil citrate composition capsule for the treatment of impotence according to claim 1, is characterized in that: described binding agent is made up of the PVP K30 of 0.08 weight portion and the purified water of 1 weight portion.
4. the medicine sildenafil citrate composition capsule for the treatment of impotence according to claim 1, is characterized in that: described lubricant is the magnesium stearate of 0.02 weight portion.
5. the medicine sildenafil citrate composition capsule for the treatment of impotence according to claim 1, it is characterized in that, the preparation method of described composition capsule comprises the following steps:
(1) supplementary material process: sodium carbonate, sucrose, sodium starch glycol, 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, sucrose, sodium starch glycol add in high-speed mixing granulating machine, open stirring motor I speed, mix 10 minutes, add PVP K30 aqueous solution, motor I speed wet mixing 90-120 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
(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 magnesium stearate are placed in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
(7) capsule-filling: select Autocapsulefillingmachine fill, regulates content uniformity to meet inner quality standard;
(8) pack.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115837013A (en) * | 2022-12-28 | 2023-03-24 | 北京悦康科创医药科技股份有限公司 | Aidenafil citrate capsule and preparation method and application thereof |
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 CN201510436551.7A patent/CN104940166A/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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115837013A (en) * | 2022-12-28 | 2023-03-24 | 北京悦康科创医药科技股份有限公司 | Aidenafil citrate capsule and preparation method and application thereof |
| CN115837013B (en) * | 2022-12-28 | 2024-05-10 | 北京悦康科创医药科技股份有限公司 | Aidenafil citrate capsule and preparation method and application thereof |
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Application publication date: 20150930 |