CN105418512B - Monocrystalline, preparation method and its pharmaceutical composition of ingavirin - Google Patents
Monocrystalline, preparation method and its pharmaceutical composition of ingavirin Download PDFInfo
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- CN105418512B CN105418512B CN201410483627.7A CN201410483627A CN105418512B CN 105418512 B CN105418512 B CN 105418512B CN 201410483627 A CN201410483627 A CN 201410483627A CN 105418512 B CN105418512 B CN 105418512B
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Abstract
The present invention relates to the monocrystalline of ingavirin, preparation method and pharmaceutical composition, the monocrystalline is monoclinic system, its crystallographic axis：
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular it relates to the monocrystalline and its drug regimen of ingavirin
Thing.
Background field
Ingavirin (Ingavirin), chemistry are entitled：5- { [2- (1H- imidazol-4 yls) ethyl] amino } -5- carbonyls penta
Acid；Molecular formula is：C10H15N3O3；Chemical structural formula is：
Ingavirin is team's research and development of Russian military virologist, chief therapist Alexandria academician,
The Valenta companies of one of drugmaker by Russia's maximum release the novel antiviral product of listing, its popularity flu
(H3N2 hypotypes, Influenza A H1N1, H5N1), Type B virus, adenovirus have compared with high antiviral curative effect.Its mechanism of action is suppression
The viral core duplicate stage of system, different from present antiviral drugs mechanism of action, ingavirin suppresses the virus N P eggs newly synthesized
Migration from cytoplasm to nucleus in vain, this is the important stage of virus infection host.
Ingavirin not yet lists in China at present, also without import application for registration, the only sharp medicine company Limited Liability in Sichuan hundred
Company proposes the application for registration of capsule in January, 2012.
Ingavirin and its synthetic method are refer in the patent application of Application No. WO9901103 first, contains them
Pharmaceutical composition and anti-viral uses, but the problem of do not tell about crystal form.Ingavirin currently on the market is capsule preparations,
Capsule is one of widely used oral dosage form of field of medicaments, since medicine is directly filled in powder or graininess
In softgel shell, the influence for the factor such as be not stressed, therefore rapid scattered, dissolution and absorption in the gastrointestinal tract, there is higher biology
Availability.
The crystalline forms of compound can influence stability, water solubility, storage stability, the preparation easiness of pharmaceutical preparation
Deng.When being considered key in terms of the easiness, stability, water solubility and the excellent pharmacokinetics that such as prepare in some aspects,
A kind of crystal form may be due to another crystal form.Ingavirin viscosity is larger, and stability is poor, in view of the compound
Pharmacy value, it is critically important to obtain high purity, stability height, the product with definite crystal form.Here we are with regard to ingavirin
Monocrystalline configuration studied, it is found that it is better than the prior art in terms of stability and dissolution rate.
The content of the invention
It is an object of the invention to by selecting suitable solvent to provide a kind of ingavirin monocrystalline configuration, it is a kind of
The good crystal form of high, the more uniform size distribution of purity, it is more more stable than unformed powder.The monocrystalline is monoclinic system, its crystallographic axis： Interplanar angle α=90.00 °, β=109.050
(4) °, γ=90.00 °, see attached drawing 1.
It is a further object to provide a kind of preparation method of above-mentioned ingavirin monocrystalline, it is characterised in that：
By ingavirin, dissolved clarification, afterwards addition low polar solvent concussion shake up in highly polar solvent, and sealing places one section
Time, obtains crystal.
Wherein described highly polar solvent is C1-3Alcohols, organic base or its mixed liquor, wherein alcohols are preferably methanol, ethanol；
The preferred triethylamine of organic bases, N, N- diisopropylethylamine.
The highly polar solvent volume (ml) is with ingavirin quality (g) than being 1:10-100.
When the highly polar solvent is mixed liquor, wherein the volume ratio of alcohols and organic base is 2-20:1.
The low polar solvent is C6-8Alkane solvents, preferably alkane solvents are n-hexane.
A period of time is placed in the sealing, is 2~10 days.
Ingavirin crystal form purity height (up to more than 99.9%) made from the method, single contaminant are less than 1 ‰, to Gao Pin is made
The medicine of matter is particularly important.
Another object of the present invention is to provide the pharmaceutical composition containing this ingavirin monocrystalline and its in anti-current
Application on Influenza Virus.
The pharmaceutical composition of ingavirin monocrystalline of the present invention and its preparation are as follows：Pharmaceutical composition is by ingavirin
The pharmaceutically acceptable auxiliary material such as monocrystalline and filler, lubricant forms and is prepared into preparation.
In the pharmaceutical composition of ingavirin monocrystalline of the present invention, ingavirin monocrystalline dosage is 45~180mg, into
One step ingavirin content be preferably 90mg；Filler is lactose, microcrystalline cellulose or mannitol, is preferably mannitol, its
The weight ratio of middle ingavirin and filler is 3:1~1:3；The preferred magnesium stearate of the lubricant and/or superfine silica gel powder, lubrication
The content of agent is the 1%~2% of the sum of ingavirin and mannitol weight.
Pharmaceutical composition of the present invention is oral formulations, can be tablet or capsule, is preferably capsule.
The preparation method of pharmaceutical composition of the present invention is：Weigh the ingavirin and auxiliary material of recipe quantity, and crossed 50 or
60 mesh sieves, afterwards progressively increase ingavirin and lactose equivalent uniformly mixed, add water and carry out wet granulation as wetting agent, afterwards
Dried at a temperature of 50 DEG C~80 DEG C, 20 mesh whole grains；The lubricant of recipe quantity is added, is uniformly mixed, detects ingavirin particle
Intermediates content；Loading amount is adjusted, it is filling into capsule；7/plate of aluminium-plastic bubble plate packing.
Brief description of the drawings
Fig. 1：Ingavirin monocrystalline space structure figure of the present invention
Embodiment
Embodiment is only that the present invention is further explained and described, and is not necessarily to be construed as any limit to the present invention
System.
Embodiment 1:The preparation method of ingavirin monocrystalline
Ingavirin 0.2g is weighed, adds 2ml methanol, then room temperature dissolved clarification is slowly added into appropriate n-hexane, concussion is shaken
Even, static layering, sealing is placed 10 days, obtains colourless bulk crystals, is filtered.
Embodiment 2:The preparation method of ingavirin monocrystalline
Ingavirin 0.2g is weighed, adds 20ml methanol, then room temperature dissolved clarification is slowly added into appropriate n-hexane, concussion is shaken
Even, static layering, sealing is placed 5 days, obtains colourless bulk crystals, is filtered.
Embodiment 3：The preparation method of ingavirin monocrystalline
Weigh ingavirin 0.2g, add 2ml methanol and 1ml triethylamines, room temperature dissolved clarification, be then slowly added into it is appropriate just oneself
Alkane, concussion shake up, static layering, and sealing is placed 2 days, obtains colourless bulk crystals, filter.
Embodiment 4：The preparation method of ingavirin monocrystalline
Ingavirin 0.2g is weighed, adds 10ml methanol and 1ml triethylamines, room temperature dissolved clarification, is then slowly added into right amount just
Hexane, concussion shake up, static layering, and sealing is placed 2 days, obtains colourless bulk crystals, filter.
Embodiment 5：The preparation method of ingavirin monocrystalline
Ingavirin 0.2g is weighed, adds 20ml methanol and 1ml triethylamines, room temperature dissolved clarification, is then slowly added into right amount just
Hexane, concussion shake up, static layering, and sealing is placed 3 days, obtains colourless bulk crystals, filter.
Embodiment 6：The pharmaceutical composition of ingavirin monocrystalline
Ingavirin monocrystalline 90mg
Mannitol 90mg
Superfine silica gel powder 1.8mg
Magnesium stearate 1.8mg
Technique：Ingavirin is placed in wet granulator with mannitol and is uniformly mixed；By the material after mixing with No. 10
The piece that hardness is 100~150 is made in punching press；The piece pressed is placed in oscillating granulator with 24 mesh sieve whole grains；After whole grain
Grain mixes together with superfine silica gel powder, magnesium stearate in three-dimensional motion mixer；Filling capsule.
After testing, its dissolution rate is：
| Time (min) | 5 | 10 | 15 | 20 | 30 | 45 | 60 |
| Embodiment 3 | 68.18 | 98.69 | 99.99 | 99.64 | 100.01 | 100.10 | 100.29 |
| Commercially available production 170213 | 54.99 | 92.11 | 97.38 | 97.90 | 97.88 | 97.92 | 97.71 |
The result shows that product dissolution rate of the present invention is very fast, external uniformity is preferable.
Embodiment 7：The pharmaceutical composition of ingavirin monocrystalline
Ingavirin monocrystalline 90mg
Mannitol 125.6mg
Superfine silica gel powder 2.2mg
Magnesium stearate 2.2mg
Technique：Preparation process：The ingavirin and auxiliary material of recipe quantity are weighed, and is crossed 50 or 60 mesh sieves, afterwards by English
Jia Weilin and mannitol equivalent progressively increase it is uniformly mixed, add water as wetting agent progress wet granulation, after 50 DEG C~80 DEG C
At a temperature of dry, 20 mesh whole grains；The lubricant of recipe quantity is added, is uniformly mixed, detects the intermediates content of ingavirin particle；
Loading amount is adjusted, it is filling into capsule；7/plate of aluminium-plastic bubble plate packing.
After testing, its dissolution rate is：
| Time (min) | 5 | 10 | 15 | 20 | 30 | 45 | 60 |
| Embodiment 4 | 57.66 | 98.00 | 101.68 | 100.63 | 101.50 | 102.25 | 102.02 |
| Commercially available production 170213 | 54.99 | 92.11 | 97.38 | 97.90 | 97.88 | 97.92 | 97.71 |
The result shows that product dissolution rate of the present invention is very fast, external uniformity is preferable.
Embodiment 8：Ingavirin monocrystalline stability experiment
Claims (7)
1. a kind of ingavirin monocrystalline, its feature are represented with following parameters：Crystallographic system, space group, lattice parameter, elementary cell area
(VElementary cell), the molecular number (Z) in elementary cell, density (d),
A kind of 2. preparation method of ingavirin monocrystalline as claimed in claim 1, it is characterised in that：By ingavirin in high pole
Property solvent in dissolved clarification, afterwards add low polar solvent concussion shakes up, sealing place 2-10 days, crystal is obtained, wherein the high pole
Property solvent is selected from C1-3Alcohols, C1-3The mixed liquor of alcohols and organic base, the low polar solvent are C6-8Alkane solvents.
3. the preparation method of ingavirin monocrystalline as claimed in claim 2, wherein alcohols are selected from methanol, ethanol；Organic bases
Selected from triethylamine, N, N- diisopropylethylamine.
4. the preparation method of ingavirin monocrystalline as claimed in claim 2, wherein the highly polar solvent volume (ml) and English
Jia Weilin mass (g) is than being 1:10-100.
5. the preparation method of ingavirin monocrystalline as claimed in claim 2, wherein alcohols and organic base in the mixed liquor
Volume ratio be 2-20：1.
6. the preparation method of ingavirin monocrystalline as claimed in claim 2, wherein the low polar solvent is n-hexane.
7. a kind of pharmaceutical composition, it is characterised in that including the ingavirin monocrystalline described in claim 1, and can pharmaceutically connect
The carrier received.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410483627.7A CN105418512B (en) | 2014-09-19 | 2014-09-19 | Monocrystalline, preparation method and its pharmaceutical composition of ingavirin |
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| CN201410483627.7A CN105418512B (en) | 2014-09-19 | 2014-09-19 | Monocrystalline, preparation method and its pharmaceutical composition of ingavirin |
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| CN105418512A CN105418512A (en) | 2016-03-23 |
| CN105418512B true CN105418512B (en) | 2018-05-01 |
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| WO2023204729A1 (en) * | 2022-04-19 | 2023-10-26 | Общество с ограниченной ответственностью "Гелеспон" | Pharmaceutical compositions based on a novel substance of 4-[2-(1н-imidazol-4-yl)-ethylcarbamoyl]-butanoic acid and method for producing said substance |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757388A (en) * | 2012-07-04 | 2012-10-31 | 四川百利药业有限责任公司 | Preparation method of high-purity etravirine |
| CN103288742A (en) * | 2013-06-04 | 2013-09-11 | 四川百利药业有限责任公司 | Preparation method for high-purity ingavirin raw material |
| CN103382179A (en) * | 2013-06-05 | 2013-11-06 | 四川百利药业有限责任公司 | Ingavirin polymorph and its preparation method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2141483C1 (en) * | 1997-07-04 | 1999-11-20 | Небольсин Владимир Евгеньевич | Peptide derivatives or their pharmaceutically acceptable salts, method of their synthesis, use and pharmaceutical composition |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757388A (en) * | 2012-07-04 | 2012-10-31 | 四川百利药业有限责任公司 | Preparation method of high-purity etravirine |
| CN103288742A (en) * | 2013-06-04 | 2013-09-11 | 四川百利药业有限责任公司 | Preparation method for high-purity ingavirin raw material |
| CN103382179A (en) * | 2013-06-05 | 2013-11-06 | 四川百利药业有限责任公司 | Ingavirin polymorph and its preparation method |
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Address after: Nanxiang Road 224100 Jiangsu province Dafeng Yancheng City District No. 266 Applicant after: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd. Address before: Cheng Wei Road Nanjing city Jiangsu province 210046 No. 9 Jiangsu Xianlin University Life Science and Technology Innovation Park Applicant before: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd. |
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