CN105106139A - Medicine of tadalafil composition particles for treating urinary surgery diseases - Google Patents
Medicine of tadalafil composition particles for treating urinary surgery diseases Download PDFInfo
- Publication number
- CN105106139A CN105106139A CN201510639150.1A CN201510639150A CN105106139A CN 105106139 A CN105106139 A CN 105106139A CN 201510639150 A CN201510639150 A CN 201510639150A CN 105106139 A CN105106139 A CN 105106139A
- Authority
- CN
- China
- Prior art keywords
- tadanafil
- medicine
- weight
- tadalafil
- sucrose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Abstract
The invention belongs to the technical field of medicine, and relates to medicine of tadalafil composition particles for treating urinary surgery diseases. The composition is prepared from the tadalafil, sucrose, calcium glycerophosphate, dextran sulfate sodium and 95-percent ethanol. The tadalafil is a novel crystal form compound; an X-ray powder diffraction pattern obtained through Cu-Ka ray measurement is shown as a Figure 1; the medicine belongs to the tadalafil different from that reported in the prior art. Experiments show that the novel crystal form compound has obviously improved water solubility, low impurity content and good stability; the particles prepared from the tadalafil novel crystal form compound have good stability, low impurity content and high bioavailability; the clinical application safety is improved.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine tadanafil composition granule 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.
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, 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, granule good stability prepared by this tadanafil crystal compound, impurity content is low, and 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 tadanafil composition granule 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 granule for the treatment of Urology Surgery class disease, described compositions is made up of tadanafil, sucrose, calcium glycerophosphate, dextran sulfate sodium, 95% ethanol; 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.
As preferably, with parts by weight, described compositions is made up of the tadanafil of 2 weight portions, the sucrose of 23-25 weight portion, the calcium glycerophosphate of 1-2 weight portion, the dextran sulfate sodium of 4-5 weight portion, 95% ethanol of 5.5-5.9 weight portion.
As preferably, with parts by weight, described compositions is made up of the tadanafil of 2 weight portions, the sucrose of 24 weight portions, the calcium glycerophosphate of 1.5 weight portions, the dextran sulfate sodium of 4.5 weight portions, 95% ethanol of 5.7 weight portions.
As preferably, the preparation method of described composition granule comprises the following steps:
(1) supplementary material process: tadanafil is pulverized 80 orders;
(2) weigh: weigh according to prescription;
(3) granulate: tadanafil, sucrose, calcium glycerophosphate, dextran sulfate sodium 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) drying and screening: 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 2-3 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
The preparation method of the tadanafil crystal in the present composition comprises the following steps:
Volume tadanafil being dissolved in 40 DEG C is in the methanol of 9 times of tadanafil weight and the mixed solvent of acetonitrile, the volume ratio of methanol and acetonitrile is 3:2, after having dissolved, adds the dichloromethane solvent that volume is 8 times of tadanafil weight, room temperature is reduced the temperature in 1.5 hours, keep 3 hours in room temperature, then, then be cooled to-5 DEG C further, then, place 2 hours at-5 DEG C, crystallize out, namely obtains tadanafil 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 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, granule good stability prepared by this tadanafil crystal compound, impurity content is low, bioavailability is high, 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
Volume tadanafil being dissolved in 40 DEG C is in the methanol of 9 times of tadanafil weight and the mixed solvent of acetonitrile, the volume ratio of methanol and acetonitrile is 3:2, after having dissolved, adds the dichloromethane solvent that volume is 8 times of tadanafil weight, room temperature is reduced the temperature in 1.5 hours, keep 3 hours in room temperature, then, then be cooled to-5 DEG C further, then, place 2 hours at-5 DEG C, crystallize out, namely obtains tadanafil crystal.
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 tadanafil granule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: tadanafil is pulverized 80 orders;
(2) weigh: weigh according to prescription;
(3) granulate: tadanafil, sucrose, calcium glycerophosphate, dextran sulfate sodium 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) drying and screening: 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 2-3 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 3:the preparation of tadanafil granule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: tadanafil is pulverized 80 orders;
(2) weigh: weigh according to prescription;
(3) granulate: tadanafil, sucrose, calcium glycerophosphate, dextran sulfate sodium 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) drying and screening: 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 2-3 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 4:the preparation of tadanafil granule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: tadanafil is pulverized 80 orders;
(2) weigh: weigh according to prescription;
(3) granulate: tadanafil, sucrose, calcium glycerophosphate, dextran sulfate sodium 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) drying and screening: 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 2-3 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
test example 1:soluble test
The dissolubility performance of this test example to the tadanafil compound crystal of embodiment 1 carries out analysis of experiments.Concrete test 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 the embodiment of the present invention 1 under table 1 room temperature
From upper table analysis, the water solublity of tadanafil crystalline compounds provided by the invention is 2.4 times, commercially available prod.
test example 2:stability test
This test example carries out accelerated test to embodiment 3, 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 2 by stability high spot reviews project.
The stability test of table 2 tadanafil preparation
Conclusion: carry out accelerated test 6 months by preparing sample to experimental example 3, every inspection target and detect results contrast in 0 month, be showed no significant change, and impurity content is low.
Identical test is carried out to other embodiments, has obtained similar test result.
Claims (5)
1. treat a medicine tadanafil composition granule for Urology Surgery class disease, it is characterized in that: described compositions is made up of tadanafil, sucrose, calcium glycerophosphate, dextran sulfate sodium, 95% ethanol; 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 granule for the treatment of Urology Surgery class disease according to claim 1, it is characterized in that: with parts by weight, described compositions is made up of the tadanafil of 2 weight portions, the sucrose of 23-25 weight portion, the calcium glycerophosphate of 1-2 weight portion, the dextran sulfate sodium of 4-5 weight portion, 95% ethanol of 5.5-5.9 weight portion.
3. the medicine tadanafil composition granule for the treatment of Urology Surgery class disease according to claim 2, it is characterized in that: with parts by weight, described compositions is made up of the tadanafil of 2 weight portions, the sucrose of 24 weight portions, the calcium glycerophosphate of 1.5 weight portions, the dextran sulfate sodium of 4.5 weight portions, 95% ethanol of 5.7 weight portions.
4. the medicine tadanafil composition granule of the treatment Urology Surgery class disease according to any one of claim 1-3, it is characterized in that, the preparation method of described composition granule comprises the following steps:
(1) supplementary material process: tadanafil is pulverized 80 orders;
(2) weigh: weigh according to prescription;
(3) granulate: tadanafil, sucrose, calcium glycerophosphate, dextran sulfate sodium 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) drying and screening: 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 2-3 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
5. the medicine tadanafil composition granule for the treatment of Urology Surgery class disease according to claim 1, it is characterized in that, the preparation method of the crystal of described tadanafil comprises the following steps:
Volume tadanafil being dissolved in 40 DEG C is in the methanol of 9 times of tadanafil weight and the mixed solvent of acetonitrile, the volume ratio of methanol and acetonitrile is 3:2, after having dissolved, adds the dichloromethane solvent that volume is 8 times of tadanafil weight, room temperature is reduced the temperature in 1.5 hours, keep 3 hours in room temperature, then, then be cooled to-5 DEG C further, then, place 2 hours at-5 DEG C, crystallize out, namely obtains tadanafil crystal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510639150.1A CN105106139A (en) | 2015-10-08 | 2015-10-08 | Medicine of tadalafil composition particles for treating urinary surgery diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510639150.1A CN105106139A (en) | 2015-10-08 | 2015-10-08 | Medicine of tadalafil composition particles for treating urinary surgery diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105106139A true CN105106139A (en) | 2015-12-02 |
Family
ID=54654427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510639150.1A Withdrawn CN105106139A (en) | 2015-10-08 | 2015-10-08 | Medicine of tadalafil composition particles for treating urinary surgery diseases |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105106139A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106821991A (en) * | 2017-03-21 | 2017-06-13 | 南京正科医药股份有限公司 | A kind of preparation method of particulate footpath Tadalafei |
| CN107854545A (en) * | 2017-11-01 | 2018-03-30 | 武汉草根生物医药科技有限公司 | A kind of broad-spectrum antiseptic, antiviral Chinese herbal granules and preparation method thereof |
-
2015
- 2015-10-08 CN CN201510639150.1A patent/CN105106139A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106821991A (en) * | 2017-03-21 | 2017-06-13 | 南京正科医药股份有限公司 | A kind of preparation method of particulate footpath Tadalafei |
| CN107854545A (en) * | 2017-11-01 | 2018-03-30 | 武汉草根生物医药科技有限公司 | A kind of broad-spectrum antiseptic, antiviral Chinese herbal granules and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10519176B2 (en) | Crystalline forms | |
| JP7253491B2 (en) | Crystal Polymorph of Kinase Inhibitor Compound, Pharmaceutical Composition Containing Same, and Method for Producing and Application of Same | |
| CN103304476B (en) | Preparation method of ibuprofen-nicotinamide eutectic crystals | |
| KR101490329B1 (en) | Fimasartan Potassium Monohydrate Crystal, Preparation Thereof And Pharmaceutical Composition Comprising Them | |
| CN105358553A (en) | Novel crystalline hydrates of 1-([beta]-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene | |
| JP2017526699A (en) | Composition of (6S) -5-methyltetrahydrofolic acid or its salt and its preparation and application | |
| CN105753904A (en) | Refining method for tedizolid phosphate | |
| Budiman et al. | Enhancement of solubility and dissolution rate of glibenclamide by cocrystal approach with solvent drop grinding method | |
| JP6957807B2 (en) | Type 2 crystals of right-handed oxyracetam, preparation method and application | |
| WO2017001991A1 (en) | Cocrystals of trigonelline | |
| CN105106139A (en) | Medicine of tadalafil composition particles for treating urinary surgery diseases | |
| CN105193749A (en) | Medicinal tadalafil composition tablets for treating urological diseases | |
| WO2021227146A1 (en) | N-[8-(2-hydroxybenzoyl)amino]monopotassium octanoate crystal compound, and preparation method therefor and use thereof | |
| CN103145735B (en) | Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof | |
| CN106543124A (en) | dapagliflozin compound | |
| CN105106132A (en) | Pharmic tadalafil composition granules for treating urological diseases | |
| CN103509001B (en) | A kind of esomeprazole magnesium trihydrate and preparation method thereof | |
| CN105106216A (en) | Drug tadalafil composition capsules for treating impotence of males | |
| CN108516966A (en) | Crystal form of Dapagliflozin and its preparation method and application | |
| CN105055418A (en) | Tadalafil medicine composition dry suspension for treating male impotence | |
| CN105193728A (en) | Medicine tadalafil composition dry suspension for treating male erectile dysfunction | |
| CN105106170A (en) | Tadalafil composition capsules for treating impotence | |
| CN105232483A (en) | Pharmaceutical tadalafil composition tablet for treating urological diseases | |
| CN105055411A (en) | Pantoprazole sodium composition for treating gastric ulcer | |
| CN105061427A (en) | Tadalafil drug compound for treating male erectile dysfunction |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20151202 |