CN103585119A - Stabilization preparation containing epoprostenol and medical salt of epoprostenol and preparation method of stabilization preparation - Google Patents
Stabilization preparation containing epoprostenol and medical salt of epoprostenol and preparation method of stabilization preparation Download PDFInfo
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Abstract
The invention discloses a stabilization preparation containing epoprostenol and medical salt of epoprostenol and a preparation method of the stabilization preparation. Through preparation of an epoprostenol-cyclodextrin inclusion compound, the problems about the stability and the vascular stimulation of a conventional epoprostenol preparation are solved, the compliance of a patient is improved greatly, and the dosing stimulation is reduced. At the same time, the invention discloses the preparation method of the stabilization preparation containing epoprostenol and medical salt of epoprostenol; according to the preparation method, the preparation process is simple, the stability is high, the stimulation is low, and the safety is good; and the production cost is reduced, the stabilization preparation can be industrially prepared, and requirements for epoprostenol and medical salt of epoprostenol in clinical application are met.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof and preparation method thereof.
Background technology
Epoprostenol, has another name called prostacyclin (PGX), prostacyclin I2 (PGI2), is the arachidonic acid metabolite that vascular endothelial cell produces, and energy anticoagulant, has strong diastole effect to arteria coronaria, whole body blood vessel and lung blood vessel.Clinically for unstable angina pectoris, myocardial infarction, Refractory Congestive Heart Failure, periperal vascular spasm and pulmonary hypertension, its antiplatelet aggregative activity can be used for preventing thrombosis, while being used for the treatment of some cardiovascular disease and hemodialysis as anticoagulant; Peripheral vascular disease, as raynaud disease, obviously reduces attack times and duration of seizure after medication; Also for platelet consumption syndrome and reduce loss that platelet circulates in vitro etc.
The dosage form that epoprostenol has gone on the market is at present injectable powder Flolan (GlaxoSmithKline), and every lyophilizing bottle comprises 0.5mg or 1.5mg epoprostenol, 3.76mg glycine, 2.93mg sodium chloride and 50mg mannitol.Also sodium hydroxide can be added to regulate pH.Also be furnished with in addition sterile diluent, contain 94mg glycine, 73.5mg sodium chloride, sodium hydroxide (regulating pH), appropriate water for injection is to the vial of 50ml, and the medicinal liquid of preparation has 10.2 ~ 10.8 pH again.Unstable chemcial property due to epoprostenol, half-life is shorter, therefore when clinical use, need use infusion pump to pass through the administration of central venous catheter continuous infusion, although slight illness that can reduction of patient, but central vein infusion administering mode need to carry out intubate operation to patient, also very inconvenience when bringing extra misery to patient.
In view of the unstable chemcial property of epoprostenol, especially potential hydrolytic instability makes it be difficult to research and develop into stabilization formulations.For this reason, research worker has been carried out various research to developing the epoprostenol preparation of stabilisation both at home and abroad.
China granted patent CN101410119B discloses epoprostenol at 23 ℃, and the degraded 50% in lower 10 hours of pH 9.3 conditions, therefore, is developed to the stability problem that first stable preparation need solve epoprostenol.The pharmaceutical composition of the alkalizing agent of a kind of pH > 11 is provided in this application, under the high pH condition forming at alkalizing agent, the stability of epoprostenol solution significantly improves, and it can preserve and within 24 ~ 48 hours, still keep 90% content not degrade under 15 ~ 30 ℃ of conditions.While considering clinical vein administration, for the comparatively suitable pH scope of patient, be 4 ~ 9, the too high or too low zest that all easily causes of pH, although described in this patent by regulating pH value to solve to a certain extent the stability problem of epoprostenol, there is the potential safety hazard of intravenously administrable and the side effect such as sense of discomfort that patient vessel stimulates generation in method.Therefore, be necessary to develop and a kind ofly can strengthen epoprostenol stability, can significantly reduce the stabilized preparations of the irritating epoprostenol of administration and pharmaceutical salts thereof again simultaneously.
Through research, we find to adopt cyclodextrin inclusion technique to solve this problem.Cyclodextrin inclusion technique has had application widely at field of medicaments at present.Actual proof, cyclodextrin and derivant thereof are the enclose materials of a class high-quality, mainly contain the application of following several aspects: the water solublity that increases medicine; Improve the stability of medicine; Promote drug absorption, improve the bioavailability of medicine; Alleviate medicine to the stimulation of body and side effect; Carrier material as slow release and targeting preparation.The cyclodextrin of at present developmental research and derivant thereof reached hundreds of more than, but the water solublity that must simultaneously meet due to these compounds, the suitable little especially low many requirements such as nephrotoxicity of molecule inclusion characteristic, biological activity, the cyclodextrin derivative that therefore, can use as pharmaceutic adjuvant is also few.The beta-schardinger dextrin-of studying at present morely, HP-β-CD, sulphur fourth group-beta-cyclodextrin etc.The present invention is by carrying out enclose by epoprostenol and pharmaceutical salts and cyclodextrin or derivatives thereof, significantly strengthened on the one hand the stability of epoprostenol, greatly reduced on the other hand administration zest, thereby improved patient's medication compliance, overcome in traditional epoprostenol preparation and prior art the various defects and the deficiency that exist in epoprostenol and pharmaceutical salts research thereof.
Summary of the invention
The object of the invention is to strengthen by cyclodextrin inclusion technique the stability of epoprostenol and pharmaceutical salts preparation thereof, significantly reduce the administration zest of epoprostenol preparation simultaneously, thereby improve patient's medication compliance.The invention provides a kind of preparation technology is simple, stability is high, zest is low, safety is good epoprostenol and the stabilized preparations of pharmaceutical salts thereof, to meet the demand to epoprostenol and pharmaceutical salts preparation thereof in clinical practice.
In conjunction with existing achievement in research, the present invention seeks to be achieved through the following technical solutions:
A stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof, contains the epoprostenol and the cyclodextrin of pharmaceutical salts, 0.5% (weight)～10.0% (weight) and the lyophilizing proppant of derivant, 85.0% (weight)～98.0% (weight) and other the pharmaceutically acceptable excipient that comprise 0.5% (weight)～5.0% (weight) in this stabilized preparations.
Wherein, epoprostenol and pharmaceutical salts thereof comprise epoprostenol sodium salt.
Wherein, described cyclodextrin and derivant thereof are selected from one or more in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, Hydroxyproply-α-cyclodextrin, HP-β-CD, hydroxypropyl-gamma-cyclodextrin, carboxymethyl-beta-cyclodextrin, DM-β-CD and tertbutyl ether-beta-schardinger dextrin-.
Wherein, described lyophilizing proppant contains essential composition mannitol.
Wherein, in described lyophilizing proppant also containing in sorbitol, trehalose, lactose and sucrose to some extent one or more; The mass ratio of wherein stating mannitol and other saccharides is 1: 4～10: 1.
Prepare a stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof, this preparation method comprises the steps:
(1) take a certain amount of cyclodextrin of prescription and derivant thereof, in the water for injection letting cool in right amount (5～20 ℃ of temperature), dissolve, continue to stir 5 ~ 20min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (5～20 ℃), toward wherein slowly adding epoprostenol and pharmaceutical salts thereof, fully stir it is dissolved, and continue to stir 10 ~ 30min, obtain epoprostenol and pharmaceutical salts-cyclodextrin inclusion compound solution thereof;
(3) to make in step (2) toward adding lyophilizing proppant abundant stirring and dissolving in epoprostenol and pharmaceutical salts-cyclodextrin inclusion compound solution thereof, then gained solution is passed through to 0.2～0.6 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
(4) product is carried out to lyophilization, lyophilization condition is: pre-freeze temperature is-40 ℃～-20 ℃, and vacuum≤500mbar, evacuation temperature are-30 ℃～-20 ℃, and main baking temperature is 0～30 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
Wherein, described stabilized preparations is freeze-dried powder.
Wherein, described stabilized preparations is being 6.0 ~ 8.0 with the pH that water for injection redissolves after solution.
Wherein, described stabilized preparations is by the direct administration of intravenous injection.
Epoprostenol and pharmaceutical salts stabilized preparations thereof that the present invention prepares gained are white lyophilized injectable powder, in every freeze-dried powder, the content of epoprostenol and pharmaceutical salts thereof is 0.5～1.5mg, the pH value of this product gained medicinal liquid after use 10ml water for injection redissolves solution is 6.0～8.0, and all other indexs all meet injection requirement.
Utilize technical scheme of the present invention, particularly utilize preferred stabilized preparations assembled scheme in the present invention, the stabilized preparations that can prepare different epoprostenols and pharmaceutical salts content thereof, described stabilized preparations can keep good stability within the scope of the suitable pH of injection administration, compare the misery that epoprostenol conventional formulation had both avoided intubate to perform the operation and bring to patient, can also greatly reduce by strong basicity pH(pH > 10 simultaneously) the administration zest brought to patient, pain while alleviating patient infusion, has strengthened patient's compliance.Cyclodextrin inclusion compound process of preparing of the present invention is simple, is applicable to a large amount of preparations and suitability for industrialized production epoprostenol stabilized preparations.About epoprostenol and pharmaceutical salts-cyclodextrin inclusion compound stabilized preparations thereof, have no any document and open report.
The specific embodiment
The specific embodiment of form, is described in further detail content of the present invention by the following examples.But this should be interpreted as to scope of the present invention only limits to following examples.All technical schemes realizing based on content of the present invention all belong to scope of the present invention.Obviously, according to content of the present invention, according to ordinary skill knowledge and the customary means of this area, do not departing under the prerequisite of basic fundamental thought of the present invention, can also make modification, replacement or the change of other various ways.
Embodiment 1
Prescription:
Epoprostenol 0.5g
Alpha-cyclodextrin 1.5g
Mannitol 50g
* water for injection adds to 1000mL
Make 1000ml
* water for injection will be removed in freezing dry process
Preparation technology:
(1) take alpha-cyclodextrin 1.5g, in the water for injection cooling in about 850ml (5 ℃ of temperature), dissolve, continue to stir 10min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (5 ℃), toward wherein slowly adding 0.5g epoprostenol, fully stir it is dissolved, and continue to stir 10min, the water for injection that adds again surplus to cool, obtains epoprostenol-cyclodextrin inclusion compound solution;
(3) in epoprostenol-cyclodextrin inclusion compound solution, add 50g mannitol abundant stirring and dissolving, then gained solution is passed through to 0.6 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
(4) product is carried out to lyophilization, lyophilization condition is: pre-freeze temperature is-40 ℃, and vacuum≤500mbar, evacuation temperature are-30 ℃, and main baking temperature is 10 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
Embodiment 2
Prescription:
Epoprostenol 1.5g
Beta-schardinger dextrin-3.0g
Mannitol 40g
* water for injection adds to 1000mL
Make 1000ml
* water for injection will be removed in freezing dry process
Preparation technology:
(1) take beta-schardinger dextrin-1.5g, in the water for injection cooling in about 750ml (10 ℃ of temperature), dissolve, continue to stir 20min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (10 ℃), toward wherein slowly adding 1.5g epoprostenol, fully stir it is dissolved, and continue to stir 20min, the water for injection that adds again surplus to cool, obtains epoprostenol-cyclodextrin inclusion compound solution;
(3) in epoprostenol-cyclodextrin inclusion compound solution, add 40g mannitol abundant stirring and dissolving, then gained solution is passed through to 0.45 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
(4) product is carried out to lyophilization, lyophilization condition is: pre-freeze temperature is-30 ℃, and vacuum≤500mbar, evacuation temperature are-25 ℃, and main baking temperature is 20 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
Embodiment 3
Prescription:
Cycloprostin 1.0g
Hydroxyproply-α-cyclodextrin 2.0g
Mannitol 9g
Sucrose 36g
* water for injection adds to 1000mL
Make 1000ml
* water for injection will be removed in freezing dry process
Preparation technology:
(1) take Hydroxyproply-α-cyclodextrin 1.5g, in the water for injection cooling in about 800ml (20 ℃ of temperature), dissolve, continue to stir 15min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (20 ℃), toward wherein slowly adding 1.0g epoprostenol, fully stir it is dissolved, and continue to stir 30min, the water for injection that adds again surplus to cool, obtains epoprostenol-cyclodextrin inclusion compound solution;
(3) in epoprostenol-cyclodextrin inclusion compound solution, add 9g mannitol and 36g sucrose abundant stirring and dissolving, then gained solution is passed through to 0.22 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
(4) product is carried out to lyophilization, lyophilization condition is: pre-freeze temperature is-25 ℃, and vacuum≤500mbar, evacuation temperature are-20 ℃, and main baking temperature is 30 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
Embodiment 4
Prescription:
Cycloprostin 1.0g
Alpha-cyclodextrin 2.0g
Mannitol 114g
Trehalose 56g
* water for injection adds to 1000mL
Make 1000ml
* water for injection will be removed in freezing dry process
Preparation technology:
(1) take alpha-cyclodextrin 2.0g, in the water for injection cooling in about 850ml (5 ℃ of temperature), dissolve, continue to stir 10min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (5 ℃), toward wherein slowly adding 1.0g Cycloprostin, fully stir it is dissolved, and continue to stir 10min, the water for injection that adds again surplus to cool, obtains Cycloprostin-cyclodextrin inclusion compound solution;
(3) in Cycloprostin-cyclodextrin inclusion compound solution, add 114g mannitol and 56g trehalose abundant stirring and dissolving, then gained solution is passed through to 0.6 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
Product is carried out to lyophilization, and lyophilization condition is: pre-freeze temperature is-40 ℃, and vacuum≤500mbar, evacuation temperature are-30 ℃, and main baking temperature is 10 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
Embodiment 5
Prescription:
Cycloprostin 10.0g
HP-β-CD 20.0g
Mannitol 170g
Lactose 17g
* water for injection adds to 1000mL
Make 1000ml
* water for injection will be removed in freezing dry process
Preparation technology:
(1) take HP-β-CD 20.0g, in the water for injection cooling in about 850ml (5 ℃ of temperature), dissolve, continue to stir 10min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (5 ℃), toward wherein slowly adding 10.0g Cycloprostin, fully stir it is dissolved, and continue to stir 10min, the water for injection that adds again surplus to cool, obtains Cycloprostin-cyclodextrin inclusion compound solution;
(3) in Cycloprostin-cyclodextrin inclusion compound solution, add 170g mannitol and 17g lactose abundant stirring and dissolving, then gained solution is passed through to 0.6 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
(4) product is carried out to lyophilization, lyophilization condition is: pre-freeze temperature is-40 ℃, and vacuum≤500mbar, evacuation temperature are-30 ℃, and main baking temperature is 10 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
Embodiment 6
Prescription:
Cycloprostin 4.0g
Gamma-cyclodextrin 8.0g
Mannitol 73.3g
Sorbitol 14.6g
* water for injection adds to 1000mL
Make 1000ml
* water for injection will be removed in freezing dry process
Preparation technology:
(1) take gamma-cyclodextrin 8.0g, in the water for injection cooling in about 850ml (5 ℃ of temperature), dissolve, continue to stir 10min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (5 ℃), toward wherein slowly adding 4.0g epoprostenol, fully stir it is dissolved, and continue to stir 10min, the water for injection that adds again surplus to cool, obtains epoprostenol-cyclodextrin inclusion compound solution;
(3) in epoprostenol-cyclodextrin inclusion compound solution, add 73.3g mannitol and 14.6g sorbitol abundant stirring and dissolving, then gained solution is passed through to 0.6 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
(4) product is carried out to lyophilization, lyophilization condition is: pre-freeze temperature is-38 ℃, and vacuum≤500mbar, evacuation temperature are-30 ℃, and main baking temperature is 10 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
The stability contrast of comparing embodiment self-control epoprostenol stabilized preparations and commercially available ordinary preparation (Flolan)
To adopting the present patent application embodiment 1 prepared epoprostenol stabilized preparations and commercially available common epoprostenol preparation (Flolan) to carry out stability contrast, investigate, detailed process is as follows:
Test method: above-mentioned self-control epoprostenol stabilized preparations sample is redissolved and separated with 10ml water for injection, commercially available common epoprostenol preparation (Flolan) is redissolved to solution with its subsidiary special-purpose lysate simultaneously, then sample is placed under 25 ℃, 60 ± 5%RH condition, carry out stability test investigation, in setting-out 0,2,4,6,8,16,24,48 and 72h sampling, detect.
Detect index: pH, content, related substance
Result of the test: in Table 1 and table 2
Table 1 stability test result (self-control epoprostenol stabilized preparations)
| Time (h) | pH | Content (%) | Related substance (%) |
| 0 | 7.53 | 100.0 | 0.1 |
| 2 | 7.51 | 99.8 | 0.3 |
| 4 | 7.52 | 99.6 | 0.5 |
| 6 | 7.49 | 99.4 | 0.7 |
| 8 | 7.51 | 99.1 | 1.0 |
| 16 | 7.50 | 99.0 | 1.1 |
| 24 | 7.49 | 98.5 | 1.6 |
| 48 | 7.48 | 98.6 | 1.5 |
| 72 | 7.49 | 98.4 | 1.7 |
Table 2 stability test result (commercially available epoprostenol ordinary preparation-Flolan)
| Time (h) | pH | Content (%) | Related substance (%) |
| 0 | 10.50 | 100.0 | 0.1 |
| 2 | 10.42 | 96.5 | 3.5 |
| 4 | 10.23 | 92.3 | 7.8 |
| 6 | 10.09 | 88.9 | 11.1 |
| 8 | 9.85 | 82.4 | 17.7 |
| 16 | 9.52 | 77.8 | 22.3 |
| 24 | 9.41 | 68.5 | 31.6 |
| 48 | 9.20 | 52.4 | 47.7 |
| 72 | 9.01 | 46.3 | 53.8 |
From stability comparing result, commercially available epoprostenol ordinary preparation content when placing 6h, lower than 90%, has not met drug standard, can not be for clinical patients; Meanwhile, adopt self-control epoprostenol stabilized preparations prepared by cyclodextrin inclusion compound but at 72h, to keep stable chemical nature, content is only declined by less than 2%, as can be seen here, self-control cyclodextrin inclusion compound epoprostenol stabilized preparations can strengthen the stability of epoprostenol extremely significantly, meets clinical application demand.
the vascular stimulation test of test example 1 epoprostenol stabilized preparations
This experimental observation the blood vessel irritation reaction of epoprostenol stabilized preparations to rabbit, test is established 2 groups altogether, is respectively single-dose group and multiple dosing group, every group of each 3 animals, every animals administer of single-dose group 1 time, multiple dosing group administration every day 1 time, successive administration 7 days.Two groups all adopt consubstantiality own control, and epoprostenol stabilized preparations redissolves separates medicinal liquid (0.5mg/ml, 1ml/kg) auris dextra drug administration by injection, and 1ml//time, control sides (left ear) waits capacity normal saline.
Result shows: administration and viewing duration and observe while drawing materials, administration part has no the abnormal phenomenas such as obvious hyperemia, redness, ulcer and scleroma.Histopathologic examination's administration local vascular has no the abnormal change relevant to medicine.Under this experimental condition, epoprostenol stabilized preparations concentration is 0.5mg/ml, capacity 1ml/kg Shi，Dui vascular tissue nonirritant damaging action.
the external hemolytic test of test example 2 epoprostenol stabilized preparations to rabbit erythrocyte
Get 12 numberings of clean tube, 1 ~ No. 5 pipe, for need testing solution pipe, is managed negative control tube for No. 6, manages positive control tube No. 7.Shown according to the form below, add successively 2% rabbit erythrocyte suspension and 5% glucose injection, after mixing, be positioned over 37 ℃ ± 0.5 ℃ calorstat and place half an hour; Then add respectively epoprostenol stabilized preparations or distilled water after not commensurability redissolution solution, shake up, put incubation in 37 ℃ ± 0.5 ℃ calorstat.During beginning, every 15 minutes, observe once, after 1 hour, every 1 hour, observe once, observe 3 hours, assay method is as shown in table 3.The clear and bright redness of solution, the pipe end is complete hemolysis when residual without erythrocyte; The clear and bright redness of solution or brown, it is part haemolysis that the pipe end has a small amount of erythrocyte residual; Erythrocyte all sinks, and supernatant liquid achromatism and clarity is without haemolysis; Though haemolysis, does not have brownish red or rufous flocculent deposit in solution, does not disperse after jolting, showing has red blood cell condensation, and experimental result is as shown in table 4.
Medicinal liquid (0.5mg/ml) method of testing after table 3 epoprostenol stabilized preparations redissolves and separates
| Test tube numbering | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% red blood cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| 5% glucose injection (ml) | 2.0 | 2.1 | 2.2 | 2.3 | 2.4 | 2.5 | - |
| Test sample (ml) | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 | - | - |
| Water for injection (ml) | - | - | - | - | - | - | 2.5 |
Table 4 concentration is the hemolytic test result of medicinal liquid to 2% rabbit erythrocyte suspension after the epoprostenol stabilized preparations redissolution of 0.5mg/ml is separated
Note: 1～No. 5 pipe, for test sample A liquid pipe, is managed negative contrast for No. 6, manages positive contrast No. 7
From the above results, under this experimental condition, concentration be after 0.5mg/ml epoprostenol stabilized preparations redissolve to be separated medicinal liquid in vitro to rabbit erythrocyte without haemolysis, do not cause red blood cell condensation, can be for injecting.
Claims (9)
1. a stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof, it is characterized in that, in this stabilized preparations, contain lyophilizing proppant and other pharmaceutically acceptable excipient of the epoprostenol of 0.5% (weight)～5.0% (weight) and the cyclodextrin of pharmaceutical salts, 0.5% (weight)～10.0% (weight) and derivant, 85.0% (weight)～98.0% (weight) thereof.
2. a kind of stabilized preparations stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof according to claim 1, is characterized in that, epoprostenol and pharmaceutical salts thereof comprise epoprostenol sodium salt.
3. a kind of stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof according to claim 1, it is characterized in that, described cyclodextrin and derivant thereof are selected from one or more in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, Hydroxyproply-α-cyclodextrin, HP-β-CD, hydroxypropyl-gamma-cyclodextrin, carboxymethyl-beta-cyclodextrin, DM-β-CD and tertbutyl ether-beta-schardinger dextrin-.
4. according to a kind of stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof described in any one in claim 1 to 2, it is characterized in that, described lyophilizing proppant contains essential composition mannitol.
5. a kind of stabilized preparations stabilized preparations that comprises epoprostenol and pharmaceutical salts thereof according to claim 3, is characterized in that also containing in described lyophilizing proppant in sorbitol, trehalose, lactose and sucrose one or more; Wherein the mass ratio of mannitol and other saccharides is 1: 4～10: 1.
6. a preparation method of preparing the stabilized preparations described in any one in claim 1 to 4, this preparation method comprises the steps:
(1) take recipe quantity cyclodextrin and derivant thereof, in the water for injection letting cool in right amount (5～20 ℃ of temperature), dissolve, continue to stir 5 ~ 20min, obtain cyclodextrin saturated solution;
(2) when maintaining the temperature of cyclodextrin saturated solution (5～20 ℃), toward wherein slowly adding epoprostenol and pharmaceutical salts thereof, fully stir it is dissolved, and continue to stir 10 ~ 30min, obtain epoprostenol and pharmaceutical salts-cyclodextrin inclusion compound solution thereof;
(3) to adding lyophilizing proppant abundant stirring and dissolving in the epoprostenol making in step (2) and pharmaceutical salts-cyclodextrin inclusion compound solution thereof, then gained solution is passed through to 0.2～0.6 μ m filtering with microporous membrane, pack cillin bottle into and also after half tamponade, send into freeze dryer;
(4) product is carried out to lyophilization, lyophilization condition is: pre-freeze temperature is-40 ℃～-20 ℃, and vacuum≤500mbar, evacuation temperature are-30 ℃～-20 ℃, and main baking temperature is 0～30 ℃, the dry vacuum≤500mbar of trunk;
(5) lyophilization complete after inflated with nitrogen tamponade and get final product.
7. according to stabilized preparations described in any one in claim 1 to 6 and preparation method thereof, it is characterized in that, described stabilized preparations is freeze-dried powder.
8. according to stabilized preparations described in any one in claim 1 to 7 and preparation method thereof, it is characterized in that, described stabilized preparations is 6.0 ~ 8.0 with the pH that water for injection redissolves after solution.
9. according to stabilized preparations described in any one in claim 1 to 8 and preparation method thereof, it is characterized in that, described stabilized preparations is by the direct administration of intravenous injection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109153660A (en) * | 2016-03-23 | 2019-01-04 | 奇诺因药物和化学工厂私人有限公司 | The method for being used to prepare the Cycloprostin with enhancing stability |
| CN109330982A (en) * | 2018-09-13 | 2019-02-15 | 常州市第四制药厂有限公司 | Epoprostenol freeze-dried powder and preparation method thereof |
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| CN102198095A (en) * | 2011-05-03 | 2011-09-28 | 北京中海康医药科技发展有限公司 | Epoprostenol fat emulsion and preparation method thereof |
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| CN101410119A (en) * | 2006-02-03 | 2009-04-15 | 西多斯有限责任公司 | Novel epoprostenol formulation and method of making thereof |
| CN101120916A (en) * | 2006-08-08 | 2008-02-13 | 北京儒展生化药物研究中心 | Prostaglandin E2 injection and manufacturing method thereof |
| CN102198095A (en) * | 2011-05-03 | 2011-09-28 | 北京中海康医药科技发展有限公司 | Epoprostenol fat emulsion and preparation method thereof |
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| CN109153660A (en) * | 2016-03-23 | 2019-01-04 | 奇诺因药物和化学工厂私人有限公司 | The method for being used to prepare the Cycloprostin with enhancing stability |
| CN109153660B (en) * | 2016-03-23 | 2022-10-11 | 奇诺因药物和化学工厂私人有限公司 | Method for preparing epoprostenol sodium with enhanced stability |
| CN109330982A (en) * | 2018-09-13 | 2019-02-15 | 常州市第四制药厂有限公司 | Epoprostenol freeze-dried powder and preparation method thereof |
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