CN104173281A - Urapidil hydrochloride injection and preparation method thereof - Google Patents
Urapidil hydrochloride injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to urapidil hydrochloride injection and a preparation method thereof, and belongs to the technical field of a drug preparation. The injection comprises the following raw materials of urapidil hydrochloride, an amino acid complex salt and 2-hydroxypropyl-beta-cyclodextrin at the mass ratio of 1 to (1-1.5) to (4-7). The urapidil hydrochloride injection has the characteristics of being easy to store and transport, sterilization-resistant, good in stability, not easy to go bad, and relatively convenient in clinical application.
Description
Technical field
The present invention relates to a kind of preparation and preparation method thereof, relate in particular to a kind of Urapidil hydrochloride injection and preparation method thereof, belong to technical field of medicine.
Background technology
Hypertension is a kind of commonly encountered diseases, frequently-occurring disease.Along with the raising of people's living standard, hyperpietic is growing, and particularly hypertensive crisis, patient with severe symptoms's number are in continuous growth.And for this class disease, not only injectable drug is less safely but also effectively clinically.Hypertension affects people's work and life, and hypertension is again coronary heart disease, the most important risk factor of cerebrovascular.In infraction, 50% is hyperpietic, and in brain sudden death patient, 76% is to have hypertension history.Therefore hypertensive danger is sudden death or disables.
Urapidil hydrochloride is the uracil derivative that benzene piperazine replaces, and is the vasodilator for the treatment of at present hypertensive crisis, severe hypertension, control average of operation periods hypertension and treatment congestive heart failure effective and safe, belongs to national essential drugs.Have the dual hypotensive effect of periphery and maincenter, periphery blood vessel dilating is mainly blocked postsynaptic α
1receptor, distends the blood vessels and significantly reduces Peripheral resistance.Also there is weak presynaptic α simultaneously
2retardation, the vasoconstrictive effect of blocking-up catecholamine; Central action is mainly by activating 5-hydroxy tryptamine-1A (5-HT1a) receptor, reduces the sympathetic feedback regulation of Medulla oblongata cardiovascular center and blood pressure lowering.At blood pressure lowering simultaneously, this product generally can not cause reflex tachycardia.
The clinical practice of Urapidil hydrochloride injection, because its good effect, side reaction are little, the welcome that is subject to patient and doctor easy to use, to promoting the update of China's miazines medicine, accelerates the paces of China's new drug research, significant.
This pharmaceutical preparation at present mainly contains injection, lyophilized injectable powder, tablet, capsule etc.Wherein tablet, capsule are oral formulations, because avoiding first pass effect drug effect to reduce.In order to improve curative effect, Urapidil hydrochloride can be made to injection, thereby avoid first pass effect.A kind of Urapidil hydrochloride injectable powder and preparation method thereof is disclosed in patent CN200310117368.8.Urapidil hydrochloride injectable powder described in this invention is made up of the injection adjuvant of acceptable salt and permission on urapidil or physiology, described acceptable salt is Urapidil hydrochloride, methanesulfonic acid urapidil, lactic acid urapidil etc., and described adjuvant is aminoacid, glucose, lactic acid, mannitol, dextran etc.Patent CN200810001182.9 discloses a kind of Urapidil hydrochloride injection lyophilized powder and preparation method thereof, and the described Urapidil hydrochloride freeze-dried powder of this invention is made up of Urapidil hydrochloride and pharmaceutical excipient mannitol or dextran.Although, lyophilized injectable powder compare injection possess stable, be easy to the advantages such as storage, transport, its clinical use inconvenience, needs to form solution after rehydration and uses, and has increased to intersect the risk of microbiological contamination.In addition, lyophilized injectable powder processing cost is high, and whole solution is without sterilization process, has the risk of batch products microbiological contamination, and workshop gnotobasis is had relatively high expectations.
In patent CN200410049988.7, disclose a kind of preparation method of Urapidil hydrochloride high-capacity injection and the application in preparation treatment hypertension drug thereof, said preparation contains Urapidil hydrochloride, isoosmotic adjusting agent, pH adjusting agent and water for injection.Wherein isoosmotic adjusting agent is selected from sodium chloride, glucose, dextran, mannitol, sorbitol, and wherein pH adjusting agent is selected from hydrochloric acid and sodium hydroxide.But patent do not solve yet at all Urapidil hydrochloride in injection solution poor stability, easily decompose the problems such as rotten, these have largely limited the extensive use of this medicine at injection type.
Closely be essential clinically and want that development cost is controlled, product is stable, safe and reliable urapidil injection products that can terminal sterilization.
Summary of the invention
Technical problem to be solved by this invention is the defect that overcomes prior art, and a kind of Urapidil hydrochloride injection is provided, and this injection has easy storage, transport, good stability, not perishable, the feature of more convenient clinical practice.In addition the present invention further provides, the preparation method of this Urapidil hydrochloride injection.
Technical problem of the present invention is realized by following technical scheme.
A kind of Urapidil hydrochloride injection, this injection contains Urapidil hydrochloride, aminoacid complex salt, 2-HP-BETA-CD, and the mass ratio of described Urapidil hydrochloride, aminoacid complex salt and 2-HP-BETA-CD is 1:1～1.5:4～7.
Above-mentioned Urapidil hydrochloride injection, the mass ratio of described Urapidil hydrochloride, aminoacid complex salt and 2-HP-BETA-CD is 1:1.1:6.6.
Above-mentioned Urapidil hydrochloride injection, described aminoacid complex salt is selected from L-arginine-ASPARTIC ACID, L-arginine-L-Glutimic acid, 1B-Pidolidone, wherein preferred L-arginine-ASPARTIC ACID.
Above-mentioned Urapidil hydrochloride injection, its pH value is 5.0～7.5.
A method of preparing above-mentioned Urapidil hydrochloride injection, comprises the steps:
First, 2-HP-BETA-CD is carried out in aqueous slkali to ring expansion in molecule;
Secondly,, by Urapidil hydrochloride and aminoacid complex salt, join stirring and dissolving in water for injection and form complex solution;
Finally, complex solution is joined and in 2-HP-BETA-CD aqueous slkali, obtain Urapidil hydrochloride-aminoacid complex salt-2-HP-BETA-CD complex solution.
The method of the above-mentioned Urapidil hydrochloride injection of above-mentioned preparation, comprises the steps:
(1) by recipe quantity 2-HP-BETA-CD, join in 1000ml water for injection, stirring and dissolving, with between sodium hydroxide solution adjust pH to 9.0～11.0 of 0.1N, is heated to 40～60 DEG C and stir 1～2h by solution, obtains solution 1;
(2) by the Urapidil hydrochloride of recipe quantity and amino complex salt, join in 9000ml water for injection, under room temperature, stir 1～2h and dissolve, obtain solution 2;
(3) solution 2 is added in solution 1, continue to stir 30min, with between hydrochloric acid solution adjust pH to 5.0～7.5 of 0.1N, obtain solution 3;
(4) solution 3 is added under room temperature to 0.1% (g/v) active carbon, under room temperature, stir 0.5～1h decolouring, after finishing, decolouring removes active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, filtrate is through 115 DEG C, the sterilizing of 30min hot pressing steam, hunt leak laggard portable lighter inspection, packaging, obtain Urapidil hydrochloride injection of the present invention.
Urapidil hydrochloride injection of the present invention and preparation method thereof has following technique effect:
Than adopting, the Urapidil hydrochloride injection of conventional soln method preparation is more stable, the higher sterilising temp of tolerance; The present invention, through repetition test, selects adjuvant 2-HP-BETA-CD, adopts complexation technology, and Urapidil hydrochloride and aminoacid complex salt are made to complex; Through repetition test, determine the optimum condition that forms stable urapidil-aminoacid complex salt-2-HP-BETA-CD complex, use product to there is industrialization value.
Because Urapidil hydrochloride is 6-{3-[4-(2-anisyl)-1-piperazinyl] propyl group } amino-1, 3-dimethyl-2, 4 (1H, 3H)-hybar X structure, it is easily molten in water or 0.1mol/L hydrochloric acid solution, salience(-cy) in aqueous solution, can not be by conventional method and the direct complexation of 2-HP-BETA-CD, be difficult to direct complexation and form Urapidil hydrochloride-beta-schardinger dextrin-complex, must dose a kind of special composition as medium, due to the special construction of Urapidil hydrochloride, by special composition is first carried out with it carrying out molecule embedding with 2-HP-BETA-CD again after complexation, the final complex that forms, the present invention has found vehicular special composition through repetition test---aminoacid complex salt, and take special technical process, first, be 9.0～11.0 by controlling pH value of water solution, 2-HP-BETA-CD is carried out in aqueous slkali to ring expansion in molecule, again by Urapidil hydrochloride and aminoacid complex salt, join stirring and dissolving in water for injection and form complex solution, finally complex solution is added in 2-HP-BETA-CD aqueous slkali, through stirring, and with sour adjust pH to 5.0～7.5, thereby obtain Urapidil hydrochloride-aminoacid complex salt-2-HP-BETA-CD complex solution.Employing the method is easy and simple to handle, condition is easily controlled, be easy to suitability for industrialized production.
Brief description of the drawings
Fig. 1 infrared spectrogram
Detailed description of the invention
Below by detailed description of the invention, the present invention is described in further detail, but these detailed description of the invention do not form any restriction to the present invention.
Embodiment 1
Prescription 1:
(1) recipe quantity 2-HP-BETA-CD is joined in 1000ml water, stirring and dissolving, with 0.1N sodium hydroxide solution adjust pH to 9.0, is heated to 40 DEG C by solution and stirs 1h, obtains solution 1;
(2) recipe quantity Urapidil hydrochloride, L-arginine-ASPARTIC ACID are joined in 50L reactor, add 9000ml water for injection stirring and dissolving, under room temperature, stir 2h, obtain solution 1;
(3) solution 2 is added in solution 1, be incubated 40 DEG C and stir 30min, with 0.1N hydrochloric acid solution adjust pH to 7.5, obtain solution 3.
(4) solution 3 is added under room temperature to 0.1% (g/v) active carbon, stir after 1h, remove active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, after filtrate embedding through 115 DEG C, hot pressing steam sterilizing in 30 minutes, hunt leak laggard portable lighter inspection, packaging, obtain stable Urapidil hydrochloride injection finished product.
Embodiment 2
Prescription 2:
(1) by recipe quantity 2-HP-BETA-CD, add 1000ml water stirring and dissolving, with recipe quantity 0.1N sodium hydroxide solution adjust pH to 11.0, solution is heated to 40 DEG C and stirs 1h, obtain solution 1;
(2) recipe quantity Urapidil hydrochloride, 1B-Pidolidone are added in 50L reactor, add 9000ml water for injection stirring and dissolving, under room temperature, stir 2h, obtain solution 1;
(3) solution 2 is added in solution 1, be incubated 40 DEG C and stir 30min, with 0.1N hydrochloric acid solution adjust pH to 5.0, obtain solution 3.
(4) solution 3 is added under room temperature to 0.1% (g/v) active carbon, stir after 1h, remove active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, after filtrate embedding through 115 DEG C, hot pressing steam sterilizing in 30 minutes, hunt leak laggard portable lighter inspection, packaging, obtain stable Urapidil hydrochloride injection finished product.
Embodiment 3
Prescription 3:
(1) by recipe quantity 2-HP-BETA-CD, add 1000ml water stirring and dissolving, with recipe quantity 0.1N sodium hydroxide solution adjust pH to 10.5, solution is heated to 40 DEG C and stirs 1h, obtain solution 1;
(2) recipe quantity Urapidil hydrochloride, 1B-Pidolidone are added in 50L reactor, add 9000ml water for injection stirring and dissolving, under room temperature, stir 2h, obtain solution 1;
(3) solution 2 is added in solution 1, be incubated 40 DEG C and stir 30min, with 0.1N hydrochloric acid solution adjust pH to 6.5, obtain solution 3.
(4) solution 3 is added under room temperature to 0.1% (g/v) active carbon, stir after 1h, remove active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, after filtrate embedding through 115 DEG C, hot pressing steam sterilizing in 30 minutes, hunt leak laggard portable lighter inspection, packaging, obtain stable Urapidil hydrochloride injection finished product.
Embodiment 4
Prescription 4:
(1) by recipe quantity 2-HP-BETA-CD, add 1000ml water stirring and dissolving, with 0.1N sodium hydroxide solution adjust pH to 10.0, solution is heated to 40 DEG C and stirs 1h, obtain solution 1;
(2) recipe quantity Urapidil hydrochloride, 1B-Pidolidone are added in 50L reactor, add 9000ml water for injection stirring and dissolving, under room temperature, stir 2h, obtain solution 1;
(3) solution 2 is added in solution 1, be incubated 40 DEG C and stir 30min, with 0.1N hydrochloric acid solution adjust pH to 7.0, obtain solution 3.
(4) solution 3 is added under room temperature to 0.1% (g/v) active carbon, stir after 1h, remove active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, after filtrate embedding through 115 DEG C, hot pressing steam sterilizing in 30 minutes, hunt leak laggard portable lighter inspection, packaging, obtain stable Urapidil hydrochloride injection finished product.
Embodiment 5
Prescription 5:
(1) by recipe quantity 2-HP-BETA-CD, add 1000ml water stirring and dissolving, with 0.1N sodium hydroxide solution adjust pH to 9.5, solution is heated to 40 DEG C and stirs 1h, obtain solution 1;
(2) recipe quantity Urapidil hydrochloride, L-arginine-L-Glutimic acid are added in 50L reactor, add 9000ml water for injection stirring and dissolving, under room temperature, stir 2h, obtain solution 1;
(3) solution 2 is added in solution 1, be incubated 50 DEG C and stir 30min, with recipe quantity 0.1N hydrochloric acid solution adjust pH to 5.0, obtain solution 3.
(4) solution 3 is added under room temperature to 0.1% (g/v) active carbon, stir after 1h, remove active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, after filtrate embedding through 115 DEG C, hot pressing steam sterilizing in 30 minutes, hunt leak laggard portable lighter inspection, packaging, obtain stable Urapidil hydrochloride injection finished product.
Embodiment 6
Prescription 6:
(1) by recipe quantity 2-HP-BETA-CD, add 1000ml water stirring and dissolving, with 0.1N sodium hydroxide solution adjust pH to 9.5, solution is heated to 40 DEG C and stirs 1h, obtain solution 1;
(2) recipe quantity Urapidil hydrochloride, L-arginine-ASPARTIC ACID are added in 50L reactor, add 9000ml water for injection stirring and dissolving, under room temperature, stir 2h, obtain solution 1;
(3) solution 2 is added in solution 1, be incubated 55 DEG C and stir 30min, with 0.1N hydrochloric acid solution adjust pH to 6.0, obtain solution 3.
(4) solution 3 is added under recipe quantity active carbon room temperature and stirred after 1h depyrogenation under room temperature, remove active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, after filtrate embedding through 121 DEG C, hot pressing steam sterilizing in 15 minutes, hunt leak laggard portable lighter inspection, packaging, obtain stable Urapidil hydrochloride injection finished product.
The detection of embodiment 7 clathrates
Adopt ftir analysis to prove that the prepared Urapidil hydrochloride injection of embodiment 1 is Urapidil hydrochloride-L-arginine-ASPARTIC ACID-2-HP-BETA-CD complex, but not physical mixture.
Physical mixture is that Urapidil hydrochloride simply mixes according to 1:1 with 2-HP-BETA-CD.
Infrared spectrum analysis adopts KBr pressed disc method to measure.
In Fig. 1, four curves are respectively from the top down:
1, the infrared spectrogram of 2-HP-BETA-CD;
2, the infrared spectrogram of Urapidil hydrochloride;
3, the infrared spectrogram of 2-HP-BETA-CD-Urapidil hydrochloride mixture;
The infrared spectrogram of 4, Urapidil hydrochloride-L-arginine-ASPARTIC ACID-2-HP-BETA-CD complex.
Embodiment 8
Only use the Urapidil hydrochloride injection of conventional method preparation not adopt technical scheme preparation of the present invention, also be commercially available Urapidil hydrochloride injection as a comparison case, the Urapidil hydrochloride injection of preparing using embodiment of the present invention 1-6 is as test example, after all solution embeddings all through 121 DEG C, hot pressing steam sterilizing in 60 minutes, hunt leak laggard portable lighter inspection, packaging, detect color and the related substance of all preparations, more stable property, the results are shown in following table 1
Table 1 autoclaving steam sterilization under pressure stability test
Result shows, the sample stability of the embodiment of the present invention 1 is better, and all embodiment good stabilities, in comparative example, illustrate that the Urapidil hydrochloride injection that adopts technology of the present invention to prepare has good stability.
By embodiment in the present invention 1 and comparative example accelerated test 6 months and place and carry out stability test for 6 months under 25 DEG C, relative humidity 60% condition under 40 DEG C, the condition of relative humidity 75% respectively.Result of the test is in table 2.
Table 2 long-term stable experiment
Result shows, the sample stability of the embodiment of the present invention 1 is better, and good stability, in comparative example, illustrates that the Urapidil hydrochloride injection that adopts technology of the present invention to prepare still has good stability under long term storage condition.
Above specific embodiments of the invention are described; but it will be appreciated that, the present invention is not limited to above-mentioned specific embodiment, and those skilled in the art can be without departing from the inventive concept of the premise; make various changes and modifications, these all belong to protection scope of the present invention.
Claims (7)
1. a Urapidil hydrochloride injection, it is characterized in that, this injection contains Urapidil hydrochloride, aminoacid complex salt, 2-HP-BETA-CD, and the mass ratio of described Urapidil hydrochloride, aminoacid complex salt and 2-HP-BETA-CD is 1:1～1.5:4～7.
2. Urapidil hydrochloride injection according to claim 1, is characterized in that, the mass ratio of described Urapidil hydrochloride, aminoacid complex salt and 2-HP-BETA-CD is 1:1.1:6.6.
3. Urapidil hydrochloride injection according to claim 2, is characterized in that, described aminoacid complex salt is selected from L-arginine-ASPARTIC ACID, L-arginine-L-Glutimic acid, 1B-Pidolidone.
4. Urapidil hydrochloride injection according to claim 3, is characterized in that, described aminoacid complex salt is L-arginine-ASPARTIC ACID.
5. Urapidil hydrochloride injection according to claim 4, is characterized in that, this injection pH value is 5.0～7.5.
6. a method of preparing the Urapidil hydrochloride injection as described in claim 1 to 5 any one, is characterized in that, comprises the steps:
First, 2-HP-BETA-CD is carried out in aqueous slkali to ring expansion in molecule;
Secondly,, by Urapidil hydrochloride and aminoacid complex salt, join stirring and dissolving in water for injection and form complex solution;
Finally, complex solution is joined and in 2-HP-BETA-CD aqueous slkali, obtain Urapidil hydrochloride-aminoacid complex salt-2-HP-BETA-CD complex solution.
7. the method for preparing Urapidil hydrochloride injection according to claim 6, is characterized in that, comprises the steps:
(1) by recipe quantity 2-HP-BETA-CD, join in 1000ml water, stirring and dissolving, with between sodium hydroxide solution adjust pH to 9.0～11.0 of 0.1N, is heated to 40～60 DEG C and stir 1～2h by solution, obtains solution 1;
(2) by the Urapidil hydrochloride of recipe quantity and amino complex salt, add in 9000ml water for injection, under room temperature, stir 1～2h and dissolve, obtain solution 2;
(3) solution 2 is added in solution 1, continue to stir 30min, with between hydrochloric acid solution adjust pH to 5.0～7.5 of 0.1N, obtain solution 3;
(4) solution 3 is added under room temperature to 1% (g/v) active carbon, under room temperature, stir 0.5～1h decolouring, after finishing, decolouring removes active carbon with 0.8um membrane filtration, filtrate is with 0.22 μ m degerming filtering with microporous membrane, filtrate is through 115 DEG C, the sterilizing of 30min hot pressing steam, hunt leak laggard portable lighter inspection, packaging, obtain Urapidil hydrochloride injection of the present invention.
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| CN115770215A (en) * | 2022-12-13 | 2023-03-10 | 南京正科医药股份有限公司 | Urapidil hydrochloride injection and preparation method thereof |
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Address after: 052165 Shijiazhuang economic and Technological Development Zone, the Three Gorges Road, Hebei Patentee after: Hebei pharmaceutical Limited by Share Ltd Address before: 052165 Shijiazhuang economic and Technological Development Zone, the Three Gorges Road, Hebei Patentee before: HEBEI YIPIN PHARMACEUTICAL CO., LTD. |