CN105106132A - Pharmic tadalafil composition granules for treating urological diseases - Google Patents
Pharmic tadalafil composition granules for treating urological diseases Download PDFInfo
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- CN105106132A CN105106132A CN201510594344.4A CN201510594344A CN105106132A CN 105106132 A CN105106132 A CN 105106132A CN 201510594344 A CN201510594344 A CN 201510594344A CN 105106132 A CN105106132 A CN 105106132A
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- tadanafil
- granule
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- urological diseases
- tadalafil
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Abstract
The invention discloses pharmic tadalafil composition granules for treating urological diseases, and belongs to the technical field of medicament. A composition is prepared from tadalafil, saccharose, glucose, glycine, polyethylene glycol and purified water. The tadalafil is a novel crystal-type compound, an X-ray powder diffraction pattern measured through a Cu-K alpha-ray is shown in graph 1, and the tadalafil is different from that reported in the prior art; according to experiments, it is found that the compound with the novel crystal-type structure has significantly improved water solubility and is low in impurity content and good in stability; the granules prepared from the novel crystal-type tadalafil compound is good in stability, low in impurity content and high in bioavailability, and the safety of clinical applications is improved.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine tadanafil composition granule for the treatment of urological diseases.
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, 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, some of them clearly information or non-existent.
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, surprisingly 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 urological diseases.
In order to complete object of the present invention, the technical scheme of employing is:
Treat a medicine tadanafil composition granule for urological diseases, described compositions is made up of tadanafil, sucrose, glucose, glycine, Polyethylene Glycol, purified water; 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 22-24 weight portion, the glucose of 10-11 weight portion, the glycine of 0.25-0.35 weight portion, the Polyethylene Glycol of 2-4 weight portion, the purified water of 5.5-6 weight portion.
As preferably, with parts by weight, described compositions is made up of the tadanafil of 2 weight portions, the sucrose of 23 weight portions, the glucose of 10.5 weight portions, the glycine of 0.3 weight portion, the Polyethylene Glycol of 3 weight portions, the purified water of 5.7 weight portions.
As preferably, the preparation method of described compositions comprises the following steps:
1) supplementary material process: tadanafil is crossed 40 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to recipe quantity;
3) granulate: the tadanafil of recipe quantity, sucrose, glucose, glycine, Polyethylene Glycol are joined in high-speed mixing granulating machine, open stirring motor mixed on low speed 15 minutes, add the purified water of recipe quantity, low speed wet mixing 220 ~ 250 seconds soft materials processed, select 18 order nylon wires to be arranged in oscillating granulator and granulate;
4) drying and screening: boiling drier inlet temperature is 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, reach uniform drying, bag is trembled 1 time every 30 minutes, be dried to moisture≤3.0%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
5) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
The preparation method of the tadanafil crystal in described compositions comprises the following steps:
Get tadanafil crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the dimethyl sulfoxine of tadanafil weight 7 times, carbon tetrachloride, dimethyl sulfoxine, carbon tetrachloride volume ratio are 3:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 0.9T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is tadanafil weight 6 times of dichloromethane, diisopropyl ether, the volume ratio of dichloromethane, diisopropyl ether is 4:1; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described 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
Get tadanafil crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the dimethyl sulfoxine of tadanafil weight 7 times, carbon tetrachloride, dimethyl sulfoxine, carbon tetrachloride volume ratio are 3:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 0.9T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is tadanafil weight 6 times of dichloromethane, diisopropyl ether, the volume ratio of dichloromethane, diisopropyl ether is 4:1; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described 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 as table 1
Table 1 tadanafil composition prescription
Preparation method:
1) supplementary material process: tadanafil is crossed 40 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to recipe quantity;
3) granulate: the tadanafil of recipe quantity, sucrose, glucose, glycine, Polyethylene Glycol are joined in high-speed mixing granulating machine, open stirring motor mixed on low speed 15 minutes, add the purified water of recipe quantity, low speed wet mixing 220-250 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
4) drying and screening: boiling drier inlet temperature is 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, reach uniform drying, bag is trembled 1 time every 30 minutes, be dried to moisture≤3.0%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
5) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 3:the preparation of tadanafil granule:
Prescription: with parts by weight as table 2
Table 2 tadanafil composition prescription
Preparation method:
1) supplementary material process: tadanafil is crossed 40 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to recipe quantity;
3) granulate: the tadanafil of recipe quantity, sucrose, glucose, glycine, Polyethylene Glycol are joined in high-speed mixing granulating machine, open stirring motor mixed on low speed 15 minutes, add the purified water of recipe quantity, low speed wet mixing 220-250 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
4) drying and screening: boiling drier inlet temperature is 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, reach uniform drying, bag is trembled 1 time every 30 minutes, be dried to moisture≤3.0%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
5) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 4:the preparation of tadanafil granule:
Prescription: with parts by weight as table 3
Table 3 tadanafil composition prescription
Preparation method:
1) supplementary material process: tadanafil is crossed 40 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to recipe quantity;
3) granulate: the tadanafil of recipe quantity, sucrose, glucose, glycine, Polyethylene Glycol are joined in high-speed mixing granulating machine, open stirring motor mixed on low speed 15 minutes, add the purified water of recipe quantity, low speed wet mixing 220-250 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
4) drying and screening: boiling drier inlet temperature is 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, reach uniform drying, bag is trembled 1 time every 30 minutes, be dried to moisture≤3.0%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
5) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
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 4 by HPLC.
The dissolubility of tadanafil crystalline compounds in water of embodiment of the present invention 1-3 under table 4 room temperature
From upper table analysis, the water solublity of tadanafil crystalline compounds provided by the invention is that commercially available prod is more than 2 times.
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 5 by stability high spot reviews project.
The stability test of table 5 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.
Claims (5)
1. treat a medicine tadanafil composition granule for urological diseases, it is characterized in that: described compositions is made up of tadanafil, sucrose, glucose, glycine, Polyethylene Glycol, purified water; 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 urological diseases according to claim 1, is characterized in that: described compositions is made up of the tadanafil of 2 weight portions, the sucrose of 22-24 weight portion, the glucose of 10-11 weight portion, the glycine of 0.25-0.35 weight portion, the Polyethylene Glycol of 2-4 weight portion, the purified water of 5.5-6 weight portion.
3. the medicine tadanafil composition granule for the treatment of urological diseases according to claim 2, is characterized in that: described compositions is made up of the tadanafil of 2 weight portions, the sucrose of 23 weight portions, the glucose of 10.5 weight portions, the glycine of 0.3 weight portion, the Polyethylene Glycol of 3 weight portions, the purified water of 5.7 weight portions.
4., according to the medicine tadanafil composition granule of the arbitrary described treatment urological diseases 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 crossed 40 mesh sieves with shaking screen;
2) weigh: weigh each supplementary material according to recipe quantity;
3) granulate: the tadanafil of recipe quantity, sucrose, glucose, glycine, Polyethylene Glycol are joined in high-speed mixing granulating machine, open stirring motor mixed on low speed 15 minutes, add the purified water of recipe quantity, low speed wet mixing 220-250 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
4) drying and screening: boiling drier inlet temperature is 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, reach uniform drying, bag is trembled 1 time every 30 minutes, be dried to moisture≤3.0%, granule shaking screen after drying sieved the granule got between 16 order-32 orders;
5) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
5. the medicine tadanafil composition granule for the treatment of urological diseases according to claim 1, it is characterized in that, the preparation method of the crystal of described tadanafil comprises the following steps:
Get tadanafil crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the dimethyl sulfoxine of tadanafil weight 7 times, carbon tetrachloride, dimethyl sulfoxine, carbon tetrachloride volume ratio are 3:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 0.9T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is tadanafil weight 6 times of dichloromethane, diisopropyl ether, the volume ratio of dichloromethane, diisopropyl ether is 4:1; After being added dropwise to complete, be cooled to-5 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described tadanafil crystal.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432281A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Preparation method of pharmaceutical ceftazidime crystal compound for treating surgical infection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432281A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Preparation method of pharmaceutical ceftazidime crystal compound for treating surgical infection |
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Application publication date: 20151202 |