CN105193728A - Medicine tadalafil composition dry suspension for treating male erectile dysfunction - Google Patents

Abstract

The invention discloses a medicine tadalafil composition dry suspension for treating male erectile dysfunction. The composition dry suspension is prepared from tadalafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose and aerosol. Tadalafil is a new crystal form compound, the X-ray powder diffraction pattern obtained by conducting measurement through Cu-K alpha rays is shown in the figure 1, tadalafil is different from tadalafil reported in the prior art, tests show that the composition of the new crystal form structure has obviously-improved water solubility and is low impurity content and high in stability, the dry suspension prepared from the tadalafil new crystal form compound is high in stability, low in impurity content and high in bioavailability, and the safety of clinical application is improved.

Description

A kind of medicine tadanafil compositions dry suspension for the treatment of impotence

Technical field

The invention belongs to medical art, relate to a kind of medicine tadanafil compositions dry suspension for the treatment of impotence.

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.

, namely 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, can produce multiple untoward reaction, and 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.

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, the water solublity that the compound tool of this novel crystal forms structure has clear improvement is found through overtesting, impurity content is low, good stability, dry suspension good stability prepared by this tadanafil crystal compound, impurity content is 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 tadanafil 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 tadanafil compositions dry suspension for impotence, described compositions is made up of tadanafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose, micropowder silica gel; 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 tadanafil compositions is made up of the tadanafil of 2 weight portions, the sorbitol of 100-110 weight portion, the tragacanth of 5-6 weight portion, the aluminium-magnesium silicate of 3.0-3.8 weight portion, the sucralose of 4-6 weight portion, the micropowder silica gel of 3.0-3.2 weight portion.

As preferably, with parts by weight, described tadanafil compositions is made up of the tadanafil of 2 weight portions, the sorbitol of 105 weight portions, the tragacanth of 5.5 weight portions, the aluminium-magnesium silicate of 3.4 weight portions, the sucralose of 5 weight portions, the micropowder silica gel of 3.1 weight portions.

As preferably, the preparation method of described tadanafil compositions dry suspension comprises the following steps:

(1) supplementary material process: sieve tadanafil 80 orders;

(2) weigh: weigh according to technology preparation;

(3) mix: tadanafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose, micropowder silica gel are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 30 minutes are set;

(4) 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 tadanafil crystal in the present composition comprises the following steps:

(1) be dissolved in by tadanafil in the mixed solvent of dimethyl sulfoxide and water, the solvent load that needs of every gram of tadanafil is 75ml, and the volume ratio of dimethyl sulfoxide and water is 5:1;

(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-15 DEG C, filters, dry, collects crystal and 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, dry suspension 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

(1) be dissolved in by tadanafil in the mixed solvent of dimethyl sulfoxide and water, the solvent load that needs of every gram of tadanafil is 75ml, and the volume ratio of dimethyl sulfoxide and water is 5:1;

(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-15 DEG C, filters, dry, collects crystal and 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 dry suspension

Prescription: the obtained tadanafil crystal-form compound of the embodiment 1 of 2 weight portions, the sorbitol of 100 weight portions, the tragacanth of 5 weight portions, the aluminium-magnesium silicate of 3.0 weight portions, the sucralose of 4 weight portions, the micropowder silica gel of 3.0 weight portions.

Preparation method:

(1) supplementary material process: sieve tadanafil 80 orders;

(2) weigh: weigh according to technology preparation;

(3) mix: tadanafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose, micropowder silica gel are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 30 minutes are set;

(4) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.

embodiment 3:the preparation of tadanafil dry suspension

Prescription: the obtained tadanafil crystal-form compound of the embodiment 1 of 2 weight portions, the sorbitol of 105 weight portions, the tragacanth of 5.5 weight portions, the aluminium-magnesium silicate of 3.4 weight portions, the sucralose of 5 weight portions, the micropowder silica gel of 3.1 weight portions.

Preparation method:

(1) supplementary material process: sieve tadanafil 80 orders;

(2) weigh: weigh according to technology preparation;

(3) mix: tadanafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose, micropowder silica gel are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 30 minutes are set;

(4) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.

embodiment 4:the preparation of tadanafil dry suspension

Prescription: the obtained tadanafil crystal-form compound of the embodiment 1 of 2 weight portions, the sorbitol of 110 weight portions, the tragacanth of 6 weight portions, the aluminium-magnesium silicate of 3.8 weight portions, the sucralose of 6 weight portions, the micropowder silica gel of 3.2 weight portions.

Preparation method:

(1) supplementary material process: sieve tadanafil 80 orders;

(2) weigh: weigh according to technology preparation;

(3) mix: tadanafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose, micropowder silica gel are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 30 minutes are set;

(4) 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 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 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 2.3 times, commercially available prod.

test example 2: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 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 2, 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 compositions dry suspension for impotence, it is characterized in that: described compositions is made up of tadanafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose, micropowder silica gel; 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 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 tadanafil of 2 weight portions, the sorbitol of 100-110 weight portion, the tragacanth of 5-6 weight portion, the aluminium-magnesium silicate of 3.0-3.8 weight portion, the sucralose of 4-6 weight portion, the micropowder silica gel of 3.0-3.2 weight portion.

3. the medicine tadanafil 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 tadanafil of 2 weight portions, the sorbitol of 105 weight portions, the tragacanth of 5.5 weight portions, the aluminium-magnesium silicate of 3.4 weight portions, the sucralose of 5 weight portions, the micropowder silica gel of 3.1 weight portions.

4. the medicine tadanafil compositions dry suspension of the treatment impotence according to any one of claim 1-3, is characterized in that, the preparation method of described tadanafil compositions dry suspension comprises the following steps:

(1) supplementary material process: sieve tadanafil 80 orders;

(2) weigh: weigh according to technology preparation;

(3) mix: tadanafil, sorbitol, tragacanth, aluminium-magnesium silicate, sucralose, micropowder silica gel are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 30 minutes are set;

(4) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.

5. the medicine tadanafil 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 tadanafil comprises the following steps:

(1) be dissolved in by tadanafil in the mixed solvent of dimethyl sulfoxide and water, the solvent load that needs of every gram of tadanafil is 75ml, and the volume ratio of dimethyl sulfoxide and water is 5:1;

(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-15 DEG C, filters, dry, collects crystal and namely obtains tadanafil crystal.