CN105078903A - Medicine sildenafil citrate composition dry suspension for treating male impotence - Google Patents
Medicine sildenafil citrate composition dry suspension for treating male impotence Download PDFInfo
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- CN105078903A CN105078903A CN201510629839.6A CN201510629839A CN105078903A CN 105078903 A CN105078903 A CN 105078903A CN 201510629839 A CN201510629839 A CN 201510629839A CN 105078903 A CN105078903 A CN 105078903A
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- sildenafil citrate
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Abstract
The invention discloses a medicine sildenafil citrate composition dry suspension for treating male impotence, and belongs to the technical field of medicines. The composition dry suspension is prepared from sildenafil citrate, cane sugar, sodium carboxymethyl starch, xanthan gum, sodium stearate and 95% ethanol. Sildenafil citrate is a new crystalline form composition, and an X-ray powder diffraction pattern of sildenafil citrate shown in Figure 1 is obtained through Cu-Kalpha radioactive measurement. Sildenafil citrate provided by the invention is different from sildenafil citrate reported in the prior art. Experiments show that the composition with the new crystalline form is improved in hygroscopicity, high in stability and very low in impurity content. The dry suspension prepared from the sildenafil citrate composition with the new crystalline form is high in stability, very low in moisture and impurity content and high in bioavailability, and improves the safety during clinical application.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine sildenafil citrate compositions dry suspension 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 compound of this novel crystal forms structure has the hygroscopicity of improvement, good stability, and impurity content is low, dry suspension good stability prepared by this sildenafil citrate crystal compound, moisture and impurity content low, bioavailability is high, 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 sildenafil citrate compositions dry suspension for the treatment of impotence.
In order to complete object of the present invention, the technical scheme of employing is:
Treat a medicine sildenafil citrate compositions dry suspension for impotence, described compositions dry suspension is made up of sildenafil citrate, sucrose, carboxymethylstach sodium, xanthan gum, sodium stearate, 95% ethanol; 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.
As preferably, described compositions dry suspension is made up of the sildenafil citrate of 10 weight portions, the sucrose of 14.0-14.8 weight portion, the carboxymethylstach sodium of 4.2-4.4 weight portion, the xanthan gum of 3.0-3.2 weight portion, the sodium stearate of 0.3-0.5 weight portion, 95% ethanol of 11-13 weight portion.
As preferably, described compositions dry suspension is made up of the sildenafil citrate of 10 weight portions, the sucrose of 14.4 weight portions, the carboxymethylstach sodium of 4.3 weight portions, the xanthan gum of 3.1 weight portions, the sodium stearate of 0.4 weight portion, 95% ethanol of 12 weight portions.
As preferably, the preparation method of described compositions dry suspension comprises the following steps:
(1) supplementary material process: sieve sildenafil citrate 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: sildenafil citrate, sucrose, carboxymethylstach sodium, xanthan gum, sodium stearate are added in wet mixing pelletizer, are dry mixed 10 minutes, 95% ethanol is joined wet mixing pelletizer wet mixing cutting, select 18 orders granulation soft material processed;
(4) dry granulate: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4 hours, by material 24 order granulate after drying;
(5) mix: granule after granulate is dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 15 minutes are set;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
As preferably, the preparation method of the sildenafil citrate crystal in the present composition comprises the following steps:
(1) be dissolved in by sildenafil citrate in the mixed solvent of acetone and water, the solvent load that needs of every gram of sildenafil citrate is 100ml, and the volume ratio of acetone and water is 2:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains sildenafil citrate crystal.
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 compound of this novel crystal forms structure has the hygroscopicity of improvement, good stability, impurity content is low, dry suspension good stability prepared by this sildenafil citrate crystal compound, moisture and impurity content low, bioavailability is high, improves 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
(1) be dissolved in by sildenafil citrate in the mixed solvent of acetone and water, the solvent load that needs of every gram of sildenafil citrate is 100ml, and the volume ratio of acetone and water is 2:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains sildenafil citrate crystal.
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 dry suspension
Prescription: sildenafil citrate crystal-form compound, the sucrose of 14.0 weight portions, the carboxymethylstach sodium of 4.2 weight portions, the xanthan gum of 3.0 weight portions, the sodium stearate of 0.3 weight portion, 95% ethanol of 11 weight portions that the embodiment 1 of 10 weight portions is obtained.
Preparation method:
(1) supplementary material process: sieve sildenafil citrate 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: sildenafil citrate, sucrose, carboxymethylstach sodium, xanthan gum, sodium stearate are added in wet mixing pelletizer, are dry mixed 10 minutes, 95% ethanol is joined wet mixing pelletizer wet mixing cutting, select 18 orders granulation soft material processed;
(4) dry granulate: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4 hours, by material 24 order granulate after drying;
(5) mix: granule after granulate is dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 15 minutes are set;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 3:the preparation of sildenafil citrate dry suspension
Prescription: sildenafil citrate crystal-form compound, the sucrose of 14.4 weight portions, the carboxymethylstach sodium of 4.3 weight portions, the xanthan gum of 3.1 weight portions, the sodium stearate of 0.4 weight portion, 95% ethanol of 12 weight portions that the embodiment 1 of 10 weight portions is obtained.
Preparation method:
(1) supplementary material process: sieve sildenafil citrate 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: sildenafil citrate, sucrose, carboxymethylstach sodium, xanthan gum, sodium stearate are added in wet mixing pelletizer, are dry mixed 10 minutes, 95% ethanol is joined wet mixing pelletizer wet mixing cutting, select 18 orders granulation soft material processed;
(4) dry granulate: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4 hours, by material 24 order granulate after drying;
(5) mix: granule after granulate is dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 15 minutes are set;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 4:the preparation of sildenafil citrate dry suspension
Prescription: sildenafil citrate crystal-form compound, the sucrose of 14.8 weight portions, the carboxymethylstach sodium of 4.4 weight portions, the xanthan gum of 3.2 weight portions, the sodium stearate of 0.5 weight portion, 95% ethanol of 13 weight portions that the embodiment 1 of 10 weight portions is obtained.
Preparation method:
(1) supplementary material process: sieve sildenafil citrate 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: sildenafil citrate, sucrose, carboxymethylstach sodium, xanthan gum, sodium stearate are added in wet mixing pelletizer, are dry mixed 10 minutes, 95% ethanol is joined wet mixing pelletizer wet mixing cutting, select 18 orders granulation soft material processed;
(4) dry granulate: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4 hours, by material 24 order granulate after drying;
(5) mix: granule after granulate is dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 15 minutes are set;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
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 1.
Table 1 sample hygroscopicity measurement result
Wherein:
Sample 1: the obtained sildenafil citrate of the embodiment of the present invention 1 first;
Sample 2: the sildenafil citrate second batch that the embodiment of the present invention 1 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 (PfizerIrelandPharmaceuticals).
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:stability test
1, accelerated test
The sildenafil citrate dry suspension that Example 3 is obtained, under high temperature 40 DEG C, relative humidity 75% ± 5% condition 6 months, carries out accelerated test investigation, the results are shown in Table 2:
Table 2 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 dry suspension 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 dry suspension good stability of gained of the present invention, moisture, impurity content are low.
Identical test is carried out to other embodiments, has obtained similar result of the test.
Claims (5)
1. treat a medicine sildenafil citrate compositions dry suspension for impotence, it is characterized in that: described compositions dry suspension is made up of sildenafil citrate, sucrose, carboxymethylstach sodium, xanthan gum, sodium stearate, 95% ethanol; 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 compositions dry suspension for the treatment of impotence according to claim 1, is characterized in that: described compositions dry suspension is made up of the sildenafil citrate of 10 weight portions, the sucrose of 14.0-14.8 weight portion, the carboxymethylstach sodium of 4.2-4.4 weight portion, the xanthan gum of 3.0-3.2 weight portion, the sodium stearate of 0.3-0.5 weight portion, 95% ethanol of 11-13 weight portion.
3. the medicine sildenafil citrate compositions dry suspension for the treatment of impotence according to claim 2, is characterized in that: described compositions dry suspension is made up of the sildenafil citrate of 10 weight portions, the sucrose of 14.4 weight portions, the carboxymethylstach sodium of 4.3 weight portions, the xanthan gum of 3.1 weight portions, the sodium stearate of 0.4 weight portion, 95% ethanol of 12 weight portions.
4. the medicine sildenafil citrate compositions dry suspension of the treatment impotence according to any one of claim 1-3, it is characterized in that, the preparation method of described compositions dry suspension comprises the following steps:
(1) supplementary material process: sieve sildenafil citrate 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: sildenafil citrate, sucrose, carboxymethylstach sodium, xanthan gum, sodium stearate are added in wet mixing pelletizer, are dry mixed 10 minutes, 95% ethanol is joined wet mixing pelletizer wet mixing cutting, select 18 orders granulation soft material processed;
(4) dry granulate: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4 hours, by material 24 order granulate after drying;
(5) mix: granule after granulate is dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 15 minutes are set;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
5. the medicine sildenafil citrate compositions dry suspension for the treatment of impotence according to claim 1, it is characterized in that, the preparation method of the crystal of described sildenafil citrate comprises the following steps:
(1) be dissolved in by sildenafil citrate in the mixed solvent of acetone and water, the solvent load that needs of every gram of sildenafil citrate is 100ml, and the volume ratio of acetone and water is 2:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains sildenafil citrate crystal.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510629839.6A CN105078903A (en) | 2015-09-29 | 2015-09-29 | Medicine sildenafil citrate composition dry suspension for treating male impotence |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510629839.6A CN105078903A (en) | 2015-09-29 | 2015-09-29 | Medicine sildenafil citrate composition dry suspension for treating male impotence |
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| CN105078903A true CN105078903A (en) | 2015-11-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510629839.6A Withdrawn CN105078903A (en) | 2015-09-29 | 2015-09-29 | Medicine sildenafil citrate composition dry suspension for treating male impotence |
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Application publication date: 20151125 |
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