CN105541946A - Adenosine cyclophosphate crystalline compound - Google Patents
Adenosine cyclophosphate crystalline compound Download PDFInfo
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- CN105541946A CN105541946A CN201610137144.0A CN201610137144A CN105541946A CN 105541946 A CN105541946 A CN 105541946A CN 201610137144 A CN201610137144 A CN 201610137144A CN 105541946 A CN105541946 A CN 105541946A
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- camp
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines and particularly relates to an adenosine cyclophosphate crystalline compound shown in a formula (I). An X-ray powder diffraction spectrogram, obtained through Ci-K alpha ray measurement, of the compound is shown in Figure 1. The provided adenosine cyclophosphate crystalline compound has improved solubility and stability and has better medical value.
Description
Technical field
The invention belongs to medical art, be specifically related to crystal-form compound of a kind of cAMP and preparation method thereof.
Background technology
CAMP is protein kinase activator, is the derivative of Nucleotide.It is a kind of important substance with physiologically active extensively existed in human body, generates, can regulate the multifunctional movable of cell by under the catalysis of Triphosaden cyclase.Hormone regulation physiological function and substance metabolism effect is played in cell, the function of cytolemma can be changed, the calcium ion impelling net agonistic muscle to starch in matter enters myofiber, thus enhancing myocardial contraction, and the oxidasic activity of respiratory chain can be promoted, improve myocardial anoxia, alleviate coronary heart disease symptom and improve electrocardiogram(ECG.In addition, the synthesis adjustment etc. of sugar, metabolism of fat, nucleic acid, protein is played an important role.For stenocardia, myocarditis and cardiogenic shock.Palpitaition, the symptom such as out of breath, uncomfortable in chest of improving rheumatic heart disease are had certain effect.Can curative effect be improved to acute leukemia in conjunction with chemotherapy, also can be used for the inducer remission of acute leukemia.In addition, also certain curative effect is had to senile chronic bronchitis, various hepatitis and psoriatic.
CAMP chemical name is: 6-amino-9-β-D-RIBOSE base-9H-purine-4`, 5`-cyclic phosphoric acid hydrogen ester.Molecular formula: C
10h
12n
5o
6p, molecular weight: 329.21, cAMP is white or off-white powder, odorless, slightly soluble in water, and almost insoluble in ethanol or ether, its structural formula is:
At present, cAMP has powder injection and aqueous injection clinically.CAMP is a kind of medicine being slightly soluble in water, and therefore cAMP powder pin and liquid drugs injection are in traditional preparation technology, need improve water for injection temperature and increase solubilizing agent to improve the solubleness of product.CAMP is at high temperature easily decomposed, and uses solubilizing agent to add the blood vessel irritation of product simultaneously.In the situation that clinical heavy dose uses, serious threat is to the life and health of patient.Therefore, solve cAMP solubleness, raising Product Safety and stability are current primary technical barriers.
CN201210501569.7 provides a kind of new cAMP crystalline compounds, this compound has better solvability, general at about 83 ~ 85mg/mL, solubleness improves limitation, and the preparation technology of preparation still needs to stand larger challenge when dissolving cAMP.
CN201310300276.7 provides a kind of new cAMP crystallization method, adopt that the method can obtain even particle size, in quicksand like, glossiness is good, yield is high, the crystal formation of easy suction filtration, but this patent is not mentioned crystal formation prepared by the method and whether is made moderate progress to cAMP solubleness.
CN201310619163.3 provides a kind of new cAMP crystalline compounds, and the meglumine cyclic adenosine injection adopting this crystalline compounds to prepare has obvious stability advantage, does not disclose the solubleness of this cAMP crystal.
CN201510134004.3 provides a kind of method extracting cyclic monophosphate from fermented liquid, adopts the method can obtain cAMP crystallization, but the physical property of unexposed acquisition crystal.
In view of the quantity of cAMP is comparatively large, need further raising due to the defect of its solvability aspect in Clinical practice security, therefore research and develop better crystalline compounds and there is certain market requirement.
Summary of the invention
Polymorph in pharmaceuticals phenomenon is ubiquitous problem in present drug research.The polymorphism of medicine can affect its physico-chemical property, and then may have influence on the clinical efficacy of medicine.Material due to by the impact of various factors, makes in molecule or molecular linkage mode changes when crystallization, cause molecule or atom different in lattice vacancy arrangement, form different crystalline structure.The present inventor is after having carried out large quantifier elimination to cAMP, obtain a kind of cAMP crystal compound being different from the crystalline structure of prior art by change recrystallisation solvent, crystallization condition, and surprisingly found that in the water of this new cAMP crystal-form compound, solubleness is obviously better than the cAMP of prior art.
The object of the present invention is to provide a kind of cAMP crystal-form compound, this crystal-form compound is a kind of new crystal structure of cAMP, and this crystalline structure has the solubleness of improvement.
Meanwhile, the preparation method of described cAMP crystal-form compound is provided provide.
For realizing object of the present invention, the present invention adopts following technical scheme:
CAMP crystal-form compound shown in a kind of formula (I), wherein,
The X-ray powder diffractogram that described cAMP crystal-form compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
Further, the X-ray powder diffractogram data of this cAMP crystal formation are as follows:
In some embodiments, cAMP crystal-form compound of the present invention can be formed pharmaceutical composition together with other pharmaceutically acceptable auxiliary materials, the formulation of described pharmaceutical composition is liquid drugs injection or freeze-dried powder.
In some embodiments, cAMP crystal-form compound of the present invention can be applied in preparation treatment stenocardia, myocarditis and cardiogenic shock medicine.
In some embodiments, the pharmaceutical composition of cAMP crystal-form compound of the present invention can application in application in preparation treatment stenocardia, myocarditis and cardiogenic shock medicine.
In some embodiments, cAMP crystal-form compound of the present invention can be applied in preparation treatment stenocardia, myocarditis and cardiogenic shock medicine.
In some embodiments, the pharmaceutical composition of cAMP crystal-form compound of the present invention can be applied in preparation treatment stenocardia, myocarditis and cardiogenic shock medicine.
In some embodiments, cAMP crystal-form compound of the present invention can be used for improving the application in the palpitaition of rheumatic heart disease, the symptom medicine such as out of breath, uncomfortable in chest in preparation treatment.
In some embodiments, the pharmaceutical composition of cAMP crystal-form compound of the present invention can be used for improving the application in the palpitaition of rheumatic heart disease, the symptom medicine such as out of breath, uncomfortable in chest in preparation treatment.
The present invention also provides the preparation method of described cAMP crystal-form compound further, and the method comprises the steps:
Getting cAMP adds in 5.5 times amount DMF, be heated to be back to entirely molten, under return stirring condition, slow dropping methyl alcohol and 93% volumes of aqueous ethanol are than the mixing solutions for 1:12, until solution occurs muddy, in the bath of agitation condition underlying cryosel, soldier is cold, slowly rise to room temperature, hold over night, filters, drying and get final product.
The related substance of cAMP crystal-form compound of the present invention and composition thereof and detection method of content adopt relevant cAMP and adenosine cyclophosphate for injection in " Chinese Pharmacopoeia " (2015) 587th ~ 588 to be correlated with related substance and detection method of content.
Accompanying drawing explanation
Fig. 1: the X-ray powder diffraction pattern of the cAMP crystal-form compound that the embodiment of the present invention 1 is obtained.
Specific embodiments
Following is in conjunction with specific embodiments and experimental example, sets forth the present invention further.But these embodiments are only limitted to the present invention instead of for limiting the scope of the invention is described.The experimental technique of unreceipted specific experiment condition in the following example, usually conveniently condition.
Embodiment 1: cAMP crystal-form compound
Getting cAMP adds in 5.5 times amount DMF, be heated to be back to entirely molten, under return stirring condition, slow dropping methyl alcohol and 93% volumes of aqueous ethanol are than the mixing solutions for 1:12, until solution occurs muddy, in the bath of agitation condition underlying cryosel, soldier is cold, slowly rise to room temperature, hold over night, filters, drying and get final product.Detecting purity with HPLC is 99.8%.
The cAMP crystal-form compound obtained is used the X-ray powder diffraction that the measurement of Cu-K alpha-ray obtains, as shown in Figure 1.
Embodiment 2: the composition of cAMP and injection liquid
CAMP composite formula:
CAMP crystal-form compound (embodiment 1) 20.0g
N.F,USP MANNITOL 80.0
PH adjusting agent is appropriate
Adenosine cyclophosphate freeze-dry powder pin preparation technology
Water for injection adds to 2000ml;
Be prepared into 1000.
Preparation method comprises the following steps:
1) supplementary material of recipe quantity is taken;
2) cAMP adds the sterile water for injection of dosing amount 800mL, stirring and dissolving, then adds the N.F,USP MANNITOL of recipe quantity, stirring and dissolving;
3) add 200mL sterile water for injection, stir and make to mix;
4) survey solution ph, 1 equivalent NaOH solution adjusts pH to be 5.0 ~ 7.0;
5) needle-use activated carbon of dosing amount 0.05% is added, heated and stirred 15 minutes, filtering decarbonization;
6) the millipore filtration essence filter of 0.22 micron;
7) clarity test;
8) inspection of semifinished product;
9) clarity test qualified after liquid medicine filling (is made 1000 bottles) in aseptic antibiotic glass bottle;
10) freeze-drying in Freeze Drying Equipment is put;
11) freeze-drying terminates, and jumps a queue, rolls lid;
12) finished product is examined entirely, packaging warehouse-in.
Comparative example 1:
Preparing cAMP crystal by patent CN201210501569.7 specification sheets embodiment 1 method, obtain white powder, is comparative example 1 sample.
Comparative example 2:
Preparing cAMP crystal by patent CN201310619163.3 specification sheets embodiment 1 method, obtain white powder, is comparative example 2 sample.
Comparative example 3:
Commercially available cAMP is comparative example 5 sample.
Comparative example 4:
Comparative example 1 adenosine crystal-form compound (embodiment 1) 20.0g
N.F,USP MANNITOL 80.0
PH adjusting agent is appropriate
Adenosine cyclophosphate freeze-dry powder pin preparation technology is with embodiment 2.
Test example 1: dissolubility test
With reference to Chinese Pharmacopoeia version in 2000 two note on the use parts, take testing sample appropriate, accurately weighed, be placed in the water of 25 DEG C ± 2 certain capacities, be placed in every five minutes on vibrator and vibrated for 30 seconds; Sample dissolution situation in investigating 30 minutes, during as cannot see particles of solute, is namely considered as dissolving completely.Experimental result is in table 1:
Solubility experiment in table 1 water
| Sample | Water (25 DEG C ± 2) |
| Embodiment 1 | 204.8mg/mL |
| Comparative example 1 | 84.4mg/mL |
| Comparative example 2 | 56.2mg/mL |
| Comparative example 3 | 75.1mg/mL |
Found out by above-mentioned experimental data, the solubleness of crystal-form compound of the present invention is greater than comparative example.
Test example 2: stability test
Stability test object investigates product time dependent rule under the impact of temperature, humidity, light, for pharmaceutical production, packaging, transport condition provide scientific basis.
1, illumination experiment
Operation: get cAMP crystal-form compound of the present invention and comparative example is laid in (about 2mm thickness) in culture dish in right amount, places 10 days under being placed in 4500Lx scholar 500Lx strong illumination condition, detects in sampling in the 5th day, 10 days.Detection method is described above.
Table 2 illumination experiment result
2, high temperature experiment
Get cAMP crystal-form compound of the present invention and comparative example is laid in (about 2mm thickness) in culture dish in right amount, the thermostat container being placed in 60 DEG C is placed 10 days, detects in sampling in the 5th, 10 day.The same illumination experiment of detection method.
Table 3 high temperature experimental result
3, high humidity experiment
Get cAMP crystal-form compound of the present invention and comparative example is laid in (about 2mm thickness) in culture dish, place 10 days under being placed in the condition of room temperature 25 DEG C of scholars 2 DEG C, relative humidity RH90% scholar 5%, detect in sampling in the 5th, 10 day.The same illumination experiment of detection method.
Table 4 high humidity experimental result
4, Acceleration study
Get cAMP crystal-form compound of the present invention and comparative example, under putting temperature 40 DEG C ± 2 DEG C, relative humidity RH75% ± 5% condition, place 6 months, in sampling at the 1st, 2,3,6 the end of month once, the same illumination experiment of detection method.
Table 5 Acceleration study result
From above-mentioned experimental data, cAMP crystal-form compound of the present invention is better at illumination, high temperature, high humidity and Acceleration study condition stability inferior, is conducive to the long storage periods of finished product.
Test example 3: solubility is tested
This experimental example has investigated the impact of the solubility of the embodiment of the present invention 2 adenosine cyclophosphate for injection and comparative example 4 adenosine cyclophosphate for injection.The results are shown in Table 6, table 7.
Table 6, performance (dissolution rate) result of redissolving
Table 7, performance (solid precipitation) result of redissolving
As can be seen from the above table, after placement for some time, adenosine cyclophosphate for injection of the present invention speed of redissolving is greater than comparative example adenosine cyclophosphate for injection redissolution speed.Therefore, the product solvability adopting preparation method of the present invention to prepare is more stable, not easily separates out solid matter, thus substantially increases the drug safety of patient.
Should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. the cAMP crystal-form compound shown in formula I,
Formula I
It is characterized in that, the X-ray powder diffraction that described cAMP crystal-form compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. one kind comprises the pharmaceutical composition of cAMP crystal-form compound described in power 1.
3. pharmaceutical composition as claimed in claim 2, is characterized in that the formulation of described composition is liquid drugs injection or freeze-dried powder.
4. preparing the application in treatment stenocardia, myocarditis and cardiogenic shock medicine as weighed cAMP crystal-form compound as described in 1 for one kind.
5. one kind as weighed the application in preparation treatment stenocardia, myocarditis and cardiogenic shock medicine of pharmaceutical composition as described in 2.
6. one kind as weighed cAMP crystal-form compound as described in 1 in preparation treatment for improving the application in the palpitaition of rheumatic heart disease, the symptom medicine such as out of breath, uncomfortable in chest.
7. one kind as weighed pharmaceutical composition as described in 2 in preparation treatment for improving the application in the palpitaition of rheumatic heart disease, the symptom medicine such as out of breath, uncomfortable in chest.
8. preparing the application in treatment senile chronic bronchitis, various hepatitis and psoriasis as weighed cAMP crystal-form compound as described in 1 for one kind.
9. one kind as weighed the application in preparation treatment senile chronic bronchitis, various hepatitis and psoriasis of pharmaceutical composition as described in 2.
10., as weighed a preparation method for cAMP crystal-form compound as described in 1, it is characterized in that comprising following steps:
Getting cAMP adds in 5.5 times amount DMF, be heated to be back to entirely molten, under return stirring condition, slow dropping methyl alcohol and 93% volumes of aqueous ethanol are than the mixing solutions for 1:12, until solution occurs muddy, in the bath of agitation condition underlying cryosel, soldier is cold, slowly rise to room temperature, hold over night, filters, drying and get final product.
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| CN201610137144.0A CN105541946A (en) | 2016-03-11 | 2016-03-11 | Adenosine cyclophosphate crystalline compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565796A (en) * | 2016-11-04 | 2017-04-19 | 南京工业大学 | Cyclic adenosine phosphate sodium salt solvate crystal and preparation method thereof |
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| CN103319557A (en) * | 2013-07-17 | 2013-09-25 | 南京工业大学 | Crystallization method of cyclic adenosine monophosphate |
| CN104151385A (en) * | 2014-08-15 | 2014-11-19 | 刘琬一 | Method for extracting cyclic adenosine monophosphate and application of cyclic adenosine monophosphate |
| CN104788522A (en) * | 2015-03-26 | 2015-07-22 | 安徽省皖北药业股份有限公司 | Method for extracting cyclic adenosine monophosphate from fermentation liquid |
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2016
- 2016-03-11 CN CN201610137144.0A patent/CN105541946A/en active Pending
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| CN102268057A (en) * | 2010-06-04 | 2011-12-07 | 南京工业大学 | Crystallization method for 3',5'-cyclic adenosine monophosphate |
| CN102988402A (en) * | 2012-11-29 | 2013-03-27 | 罗诚 | Pharmaceutical composition containing adenosine cyclophosphate compound and preparation method of pharmaceutical composition |
| CN103006552A (en) * | 2012-12-18 | 2013-04-03 | 河南辅仁怀庆堂制药有限公司 | Formulation process of adenosine cyclophosphate for injection |
| CN103319557A (en) * | 2013-07-17 | 2013-09-25 | 南京工业大学 | Crystallization method of cyclic adenosine monophosphate |
| CN104151385A (en) * | 2014-08-15 | 2014-11-19 | 刘琬一 | Method for extracting cyclic adenosine monophosphate and application of cyclic adenosine monophosphate |
| CN104788522A (en) * | 2015-03-26 | 2015-07-22 | 安徽省皖北药业股份有限公司 | Method for extracting cyclic adenosine monophosphate from fermentation liquid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565796A (en) * | 2016-11-04 | 2017-04-19 | 南京工业大学 | Cyclic adenosine phosphate sodium salt solvate crystal and preparation method thereof |
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Address after: 450016 Henan, Zhengzhou province by the open area of the South Road, No. 16, the building of the United States and the United States, room 1410, Liuzhou Applicant after: Yan Hulin Address before: Zhenghualu jinshuiqu 450016 Henan city of Zhengzhou province No. 90 Applicant before: Yan Hulin |
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Application publication date: 20160504 |