CN103044509B - Gamma-cytidine-5'-disodium triphosphate crystal compound, and preparation method and drug composition of crystal compound - Google Patents
Gamma-cytidine-5'-disodium triphosphate crystal compound, and preparation method and drug composition of crystal compound Download PDFInfo
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- 239000003814 drug Substances 0.000 title abstract description 5
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- 235000011178 triphosphate Nutrition 0.000 title abstract 2
- 239000001226 triphosphate Substances 0.000 title abstract 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 title abstract 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 43
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Abstract
The invention relates to a gamma-cytidine-5'-disodium triphosphate crystal, and a preparation method, a drug composition, and a drug preparation of the crystal. The solubility and the stability of the crystal are better than those of a substance in the prior art, and the crystal is more beneficial for pharmacy and long-term storage. The preparation is particularly suitable for being prepared into an injection and a powder injection.
Description
Technical field
The invention belongs to drug crystallization technical field, particularly a kind of γ-cytidine(C-5 ' crystallization of-triphosphoric acid disodium, its preparation method and pharmaceutical composition thereof and pharmaceutical preparation.
Background technology
γ-cytidine(C-5 '-triphosphoric acid disodium structural formula is as follows,
，
It belongs to nucleotide derivative, participates in the anabolism of nucleic acid and phosphatide in body, promotes protein synthesis.Can also regulate and promote synthesis and the structure of neurocyte, neurogliocyte and cells of vascular wall membranous structure, the neural cell injury caused by excitatory amino acid, free radical can be resisted, thus to above-mentioned cell, there is support survival, enhanced activity, delayed death, improve cell antibody Monoclonal, regeneration and repair ability, promote nervous process regrowth, and improve the neural function of domination blood vessel, play the effect of anti-angiogenic sclerosis.Participate in the synthesis of body membranous structure and can resolve into carbonic acid gas and water with the cytidine built in cell, and release energy.The clinical assisting therapy for cerebral concussion and the disease such as sequela, apoplexy sequela, autonomic nervous dysfunction, neurosis and cardiac insufficiency, Progressive symmetric erythrokeratodermia myocardial atrophy, hepatitis.
In clinical, it often uses as small-volume injection, transfusion and powder injection, but it is unstable in aqueous, is easily hydrolyzed, and therefore in production and storage process, all easily occurs that content reduces, and stability declines, thus affects drug effect.Carry out enhanced stability by adding the organic solvents such as propylene glycol in prior art, but this is disadvantageous for drug safety.This area needs the technical scheme of the stability improving it badly, thus easy to use, improves drug effect.Up to now, applicant also finds no γ-cytidine(C-5 ' crystalline compounds of-triphosphoric acid disodium is produced out.ZL201210257576.7 discloses crystallization that is a kind of and the compounds of this invention structurally similar compounds, but its structure is different from compound of the present invention, and institute's using method is also different, and the stability of gained crystallization improves.
The present inventor, in long-term research and production practice, have unexpectedly discovered that γ-cytidine(C-5 ' the new crystallization of-triphosphoric acid disodium, its solvability improves, and stability is stronger, efficiently solves the technical barrier existed in prior art.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, propose a kind of γ-cytidine(C-5 '-triphosphoric acid disodium crystalline compounds and preparation method thereof, and its pharmaceutical composition and pharmaceutical preparation are provided.
First, the invention provides a kind of γ-cytidine(C-5 ' crystalline compounds of-triphosphoric acid disodium, its X-ray powder diffraction in diffraction angle in diffraction angle 2 θ=3.28 ° ± 0.2 °, 6.58 ° ± 0.2 °, 12.70 ° ± 0.2 °, 13.34 ° ± 0.2 °, 19.97 ° ± 0.2 °, there is characteristic peak at 24.26 ° ± 0.2 ° and 25.43 ° ± 0.2 ° place.Its X-ray powder diffraction as shown in Figure 1.Infrared spectra is about 1730,1253 and 1097cm
-1there is charateristic avsorption band at place.Its infrared spectra as shown in Figure 2.
Secondly, the invention provides the described γ-cytidine(C-5 of preparation ' method of-triphosphoric acid disodium crystallization, comprising:
A, by γ-cytidine(C-5, the weight ratio of '-triphosphoric acid disodium be dissolved in amide solvent and form solution, temperature is 30-60 DEG C, amide solvent and γ-cytidine(C-5 '-triphosphoric acid disodium is 4-8: 1;
B, in above-mentioned solution, add suspensoid, obtain suspension, suspensoid weight be the 3-6 of amide solvent weight doubly;
C
,gained suspension is separated, dries, obtain γ-cytidine(C-5 '-triphosphoric acid disodium crystallization.
In described step c, suspension can be cooled before being separated by suspension, cooling temperature is 0-20 DEG C, can continue to stir 0.5-2 hour after cooling.
Described amide solvent is selected from the one in DMF, N,N-dimethylacetamide or ethanamide.
Described suspensoid is selected from the one in ethyl acetate, acetone or acetonitrile.
For obtaining high-quality γ-cytidine(C-5 '-triphosphoric acid disodium crystallization, product is decompression drying at 40 ~ 60 DEG C preferably.
Again, the invention provides a kind of pharmaceutical composition, comprise γ-cytidine(C-5 as above '-triphosphoric acid disodium crystallization and pharmaceutically acceptable carrier or vehicle.
In pharmaceutical composition, described γ-cytidine(C-5 '-triphosphoric acid disodium crystallization accounts for the 0.01-99.99wt% of composition.
When useful in preparing drug formulations, it will be appreciated by those skilled in the art that and according to the needs of concrete formulation, suitable carrier or vehicle can be added.When preparing tablet, can add disintegrating agent, weighting agent, lubricant, tackiness agent and glidant etc., they can be selected from starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose, hypromellose, polyvidone, dextrin, fiber and derivative thereof, croscarmellose sodium, low-substituted hydroxypropyl cellulose, Magnesium Stearate, talcum powder, silica gel etc.Also capsule, pill etc. can be prepared into.
In a preferred embodiment, described pharmaceutical composition can be prepared into injection liquid or powder injection.When preparing injection liquid, water for injection, propylene glycol, glycerine etc. can be added, and use sodium hydroxide, potassium hydroxide, hydrochloric acid etc. adjust ph; When preparing powder injection, vehicle can be added, such as glucose, lactose, N.F,USP MANNITOL, sucrose etc.The stablizer such as arginine, glycine can also be added in injection liquid or powder injection.
γ-cytidine(C-5 of the present invention ' advantage of-triphosphoric acid disodium crystallization preparation method is that operational condition is simple and easy to control, is applicable to suitability for industrialized production; Product degree of crystallinity is high simultaneously, and grain size number is comparatively large, and solvability and stability all improve a lot.
Accompanying drawing explanation
Fig. 1 is γ-cytidine(C-5 ' X-ray diffracting spectrum of-triphosphoric acid disodium crystallization;
Fig. 2 is γ-cytidine(C-5 ' infrared absorption spectrum of-triphosphoric acid disodium crystallization.
Embodiment
Explained further by following embodiment and set forth the present invention, but the scope that the present invention protects is not limited thereto.
embodiment 1
By 4.5g γ-cytidine(C-5 '-triphosphoric acid disodium joins in 23 g DMF solvents, and be warming up to 30 DEG C and make it to dissolve, obtain clear solution.Under agitation drip 80 g acetonitriles, go out crystalline substance.Be cooled to 5 DEG C with 0.2 DEG C/min, then continue to stir 1h.By gained suspension vacuum filtration, filter cake is vacuum drying at 40 DEG C, obtains γ-cytidine(C-5 '-triphosphoric acid disodium crystallization 4.12 g.
The XRD figure spectrum of this product as shown in Figure 1.Infrared absorption pattern as shown in Figure 2.
embodiment 2
By 3.0 g γ-cytidine(Cs-5 '-triphosphoric acid disodium input 18g ethanamide solvent, be warming up to 40 DEG C, stir and make it entirely molten.Add 100g ethyl acetate under continuously stirring, be then cooled to 0 DEG C with 0.2 DEG C/min, then continue to stir 1h.Filtered by suspension, 50 DEG C of Vacuum dry filter cake, obtain γ-cytidine(C-5 '-triphosphoric acid disodium crystallization 2.35g.
embodiment 3
By 5.0g γ-cytidine(C-5 '-triphosphoric acid disodium drops into 30 g N,N-dimethylacetamide solvents, is warming up to 50 DEG C, and stir and make it entirely molten.120g ethyl acetate is added under continuously stirring.Be cooled to 10 DEG C with 0.3 DEG C/min, then gained suspension continued to stir 0.5h.Filter gained suspension, vacuum-drying at 60 DEG C, obtains γ-cytidine(C-5 '-triphosphoric acid disodium crystallization 4.51g.
embodiment 4
By 3.5g γ-cytidine(C-5 '-triphosphoric acid disodium joins 15g DMF, and be warming up to 60 DEG C and make it to dissolve completely.Under agitation stream adds 80 g acetonitriles, then gained suspension is cooled to 5 DEG C, continues to stir 2h, vacuum filtration gained suspension, and vacuum drying at 60 DEG C, obtains γ-cytidine(C-5 '-triphosphoric acid disodium crystallization 3.08g.
embodiment 5
By 5.00 grams of γ-cytidine(Cs-5 '-triphosphoric acid disodium joins 28 gN, and in dinethylformamide, be warming up to 50 DEG C and make it to dissolve completely.Under agitation stream adds 145 g acetone, continues to stir 2h, and filter, at 50 DEG C, vacuum drying gained filter cake, obtains γ-cytidine(C-5 '-triphosphoric acid disodium crystallization 4.59g.
γ-cytidine(C-5 prepared by above-described embodiment 2 ~ 5 '-triphosphoric acid disodium crystallization all conforms to embodiment 1 at diffraction angle 2 θ °, infrared spectra in X-ray powder diffraction.
embodiment 6 stability study
Get γ-cytidine(C-5 '-triphosphoric acid disodium crystallization is placed in plate, the stability test carried out under splitting following condition (1. 40 DEG C, the lx illumination of storage condition 2:4500 lx ± 500) in right amount.Measurement result is as shown in table 1 ~ 2.
Table 1 high-temperature stability is observed
Table 2 high-temperature stability is observed
Visible, under high temperature and high light conditions, crystallization of the present invention is more stable, under high light and hot conditions, still maintain very high content, produces impurity few, proves its excellent in stability, be suitable for preparation and the standing storage of pharmaceutical preparation.Particularly γ-cytidine(C-5 '-triphosphoric acid disodium at high temperature stability extreme difference, and crystallization of the present invention improves significantly in this respect.
embodiment 7 solubility study
Test sample: crystallization prepared by the embodiment of the present invention 1; Commercially available γ-cytidine(C-5 '-triphosphoric acid disodium
Test method: with reference to Pharmacopoeia of the People's Republic of China version in 2010 note on the use page 2.Trial-product is claimed to put in the water of 25 ± 2 DEG C of certain capacities, the powerful jolting 30 seconds every 5 minutes; Observe the dissolving situation in 30 minutes, as during without visual visible particles of solute or drop, be considered as dissolving completely.
Table 1 solubleness comparative test result
| Sample | Outward appearance | Solubleness (mg/ml) |
| Commercially available γ-cytidine(C-5 '-triphosphoric acid disodium | Achromaticity and clarification | 50.10 |
| γ-cytidine(C-5 of the present invention '-triphosphoric acid disodium crystallization | Achromaticity and clarification | 61.30 |
Crystals solubility of the present invention improves compared with amorphous body, and this is for preparing injection liquid or powder injection is very favourable.
embodiment 8 formulation example
1. γ-cytidine(C-5 ' transfusion of-triphosphoric acid disodium crystallization sodium-chlor
| γ-cytidine(C-5 '-triphosphoric acid disodium crystallization | 0.5 kg |
| Arginine | 3.5 kg |
| Sodium bicarbonate | 2.5 kg |
| Sodium-chlor | 8 kg |
| Water for injection | To 500L |
| Make 1000 bottles |
Sodium bicarbonate is water-soluble, and then add arginine, stir and make them dissolve, regulator solution pH is to about 8.2, then add sodium-chlor, add the gac of 0.1 (w/v), stir, de-charcoal, add to the full amount of water for injection, with the filter of millipore filtration essence, filling, encapsulating.
2. crystal lyophilized powder pin
| γ-cytidine(C-5 '-triphosphoric acid disodium crystallization | 100 g |
| N.F,USP MANNITOL | 200 g |
| Arginine | 90 g |
| Make 5000 |
In container, add the water for injection being about cumulative volume 70%, add Cytidine Disodium Triphosphate, N.F,USP MANNITOL (or lactose) and arginine (or glycine) under agitation successively, be adjusted to about pH 6 with 0.1mol/L hydrochloric acid soln, add to the full amount of water for injection, add 0.1% gac, stir 1h, Sterile Filtration, filling, put into vacuum freezing drying oven, pre-freeze 5h, opens the formal freeze-drying of vacuum pump, freeze-drying time 24 hours, tamponade, roll lid, packaging, to obtain final product.
Thus, the invention describes γ-cytidine(C-5 ' crystallization of-triphosphoric acid disodium and preparation method thereof, and pharmaceutical composition and pharmaceutical preparation, be to be understood that, pharmaceutical arts can refer to present disclosure, and when not departing from content of the present invention, spirit and scope, the link such as appropriate change raw material, processing parameter is to realize technology of the present invention.Special needs to be pointed out is that these similar replacements and change apparent to those skilled in the art do not depart from spirit of the present invention, scope and content.
Claims (7)
1. γ-cytidine(C-5 ' crystalline compounds of-triphosphoric acid disodium crystallization, its X-ray powder diffraction in diffraction angle 2 θ=3.28 ° ± 0.2 °, 6.58 ° ± 0.2 °, 12.70 ° ± 0.2 °, 13.34 ° ± 0.2 °, 19.97 ° ± 0.2 °, there is characteristic peak at 24.26 ° ± 0.2 ° and 25.43 ° ± 0.2 ° place.
2. the crystalline compounds of claim 1, its X-ray powder diffraction as shown in Figure 1.
3. the crystalline compounds of claim 1, its infrared spectra is at about 1730cm
-1, 1253cm
-1and 1097cm
-1there is charateristic avsorption band at place.
4. the crystalline compounds of claim 3, its infrared spectra as shown in Figure 2.
5. prepare the method for the arbitrary crystalline compounds of claim 1-4, comprising:
A, by γ-cytidine(C-5, the weight ratio of '-triphosphoric acid disodium be dissolved in amide solvent and form solution, temperature is 30-60 DEG C, amide solvent and γ-cytidine(C-5 '-triphosphoric acid disodium is 4-8: 1;
B, in above-mentioned solution, add suspensoid, obtain suspension, suspensoid weight be the 3-6 of amide solvent weight doubly;
C, by gained suspension be separated, dry, obtain γ-cytidine(C-5 '-triphosphoric acid disodium crystallization;
Wherein, in described step c, cooled by suspension before being separated by suspension, cooling temperature is 0-20 DEG C, continues to stir 0.5-2 hour after cooling;
Described amide solvent is selected from the one of DMF, N,N-dimethylacetamide or ethanamide.
Described suspensoid is selected from the one in ethyl acetate, acetone or acetonitrile.
Decompression drying carries out at 40 ~ 60 DEG C.
6. a pharmaceutical composition, comprises γ-cytidine(C-5 that claim 1-4 is arbitrary '-triphosphoric acid disodium crystallization and pharmaceutically acceptable carrier or vehicle.
7. the pharmaceutical composition of claim 6, wherein said γ-cytidine(C-5 '-triphosphoric acid disodium crystallization accounts for the 0.01-99.99wt% of composition.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003031464A2 (en) * | 2001-10-10 | 2003-04-17 | Neose Technologies, Inc. | Remodeling and glycoconjugation of peptides |
| CN101058823A (en) * | 2007-05-22 | 2007-10-24 | 北京双鹭药业股份有限公司 | Method of preparing cytidine disodium triphosphate and application |
| CN102268054A (en) * | 2011-04-12 | 2011-12-07 | 宁辉 | Beta-cytidine-5 '-triphosphoarginine derivative ester and its preparation method and use |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003031464A2 (en) * | 2001-10-10 | 2003-04-17 | Neose Technologies, Inc. | Remodeling and glycoconjugation of peptides |
| CN101058823A (en) * | 2007-05-22 | 2007-10-24 | 北京双鹭药业股份有限公司 | Method of preparing cytidine disodium triphosphate and application |
| CN102268054A (en) * | 2011-04-12 | 2011-12-07 | 宁辉 | Beta-cytidine-5 '-triphosphoarginine derivative ester and its preparation method and use |
Non-Patent Citations (1)
| Title |
|---|
| Ethan S. Simon,等.Convenient Syntheses of Cytidine 5’-Triphosphate, Guanosine 5’-Triphosphate, and Uridine 5’-Triphosphate and Their Use in the Preparation of UDP-glucose, UDP-glucuronic Acid, and GDP-mannose.《J. Org. Chem.》.1990,第55卷(第6期),第1834-1841页. * |
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Application publication date: 20130417 Assignee: HAINAN HUALON PHARMACEUTICAL Co.,Ltd. Assignor: Ning Hui Contract record no.: 2015370000053 Denomination of invention: Gamma-cytidine-5'-disodium triphosphate crystal compound, and preparation method and drug composition of crystal compound Granted publication date: 20150401 License type: Common License Record date: 20150416 Application publication date: 20130417 Assignee: SHANDONG PKU HIGH-TECH HUATAI PHARMACEUTICAL Co.,Ltd. Assignor: Ning Hui Contract record no.: 2015370000052 Denomination of invention: Gamma-cytidine-5'-disodium triphosphate crystal compound, and preparation method and drug composition of crystal compound Granted publication date: 20150401 License type: Common License Record date: 20150416 |
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