CN109828046B - Detection method of alprostadil injection - Google Patents
Detection method of alprostadil injection Download PDFInfo
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- CN109828046B CN109828046B CN201910135678.3A CN201910135678A CN109828046B CN 109828046 B CN109828046 B CN 109828046B CN 201910135678 A CN201910135678 A CN 201910135678A CN 109828046 B CN109828046 B CN 109828046B
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Abstract
The invention discloses a detection method of alprostadil injection, which comprises the following steps: taking 20 mu L of alprostadil reference substance solution for HPLC sample injection analysis; diluting the alprostadil injection with water, ultrafiltering and centrifuging, and taking 20 mu L for HPLC sample analysis; and calculating the encapsulation rate of the alprostadil injection according to an external standard method. The detection method provided by the invention has the advantages of high precision, good reproducibility and good stability, and can accurately determine the encapsulation rate of the alprostadil injection.
Description
Technical Field
The invention belongs to the technical field of medicine; relates to a detection method of an alprostadil medicinal preparation, in particular to a detection method of an alprostadil injection.
Background
The alprostadil is an endogenous physiologically active substance, belongs to a natural prostaglandin substance, and is also called prostaglandin E1. Alprostadil was approved by the U.S. FDA in 1981 and beggarton, sajieri pine and venn three scientists were awarded the nobel physiology or medical prize in 1982 for pharmacological mechanistic studies of alprostadil.
The chemical name of alprostadil is: 11a, 15(S) -dihydroxy-9-carbonyl-13-transprostaglandin having a molecular weight of 354.5. Alprostadil is white needle crystal or crystalline powder, is easily soluble in ethanol, is slightly soluble in water, and is dissolved in phosphate buffer (pH 7.4-8.0). Alprostadil for injection and alprostadil raw material are already collected in the second part of the chinese pharmacopoeias 2005 edition, 2010 edition and 2015 edition.
Alprostadil has the physiological effects of expanding vascular smooth muscle, inhibiting platelet aggregation, protecting vascular endothelial cells, inhibiting gastric acid secretion, stimulating intestinal and uterine smooth muscle, inhibiting exocrine pancreatic gland secretion, inhibiting lipid plaque, and stimulating insulin secretion. The traditional Chinese medicine composition is widely used for treating cerebrovascular diseases, cardiovascular diseases, respiratory diseases, diabetic complications, liver diseases, kidney diseases, acute pancreatitis, chronic gastritis, pulmonary hypertension, male erectile dysfunction, infertility and other diseases clinically.
Alprostadil is unstable chemically, is metabolized primarily in the lungs, is essentially ineffective when administered orally, and is 60-90% inactive once per pulmonary cycle. Because the half-life of the alprostadil is short, the alprostadil has to be administered by continuous intravenous injection for a long time (more than 5 h) and a large dose (100-. However, this can lead to blood vessel irritation, such as redness, swelling, pain, and even inflammation at the injection site.
In order to improve the above disadvantages, chinese patent application CN1287834A discloses a lyophilized powder injection preparation of cyclodextrin inclusion alprostadil. The preparation adopts a five-carbon ring structure and an alkyl side chain structure of beta-cyclodextrin derivatives and alpha-cyclodextrin inclusion alprostadil, and low-molecular dextran or mannitol as an excipient, and freeze-drying is carried out to obtain the freeze-dried powder injection preparation. The preparation can improve the chemical stability and physiological activity of alprostadil, and avoid adverse reactions such as local inflammation and pain in the injection process. However, in the inclusion compound, the beta-cyclodextrin and the alprostadil are mutually attracted by weak covalent bond interaction, the binding force of the beta-cyclodextrin and the alprostadil is weak, and dissociation occurs quickly after injection. The dissociated alprostadil is rapidly metabolized in the lung like a free medicament, the half-life period in vivo is only a few minutes, and the long curative effect is difficult to maintain. In addition, beta-cyclodextrin may also produce hemolytic reactions of erythrocytes.
Chinese patent application CN101049313A discloses an alprostadil microsphere carrier injection. The injection takes refined lecithin as emulsified oil and takes fat particles of refined soybean oil as an alprostadil carrier. The injection finally forms O/W type emulsion of 0.12-0.38 μm. The injection reduces the stimulation of the alprostadil to blood vessels and greatly provides the curative effect. However, this injection is a thermodynamically unstable liquid emulsion, must be stored at 0-5 ℃, and has a shelf life of only one year.
Chinese patent CN105640888B discloses an alprostadil liposome injection and a preparation method thereof, which is mainly prepared from alprostadil, dioleoyl phosphatidyl glycerol, cholesterol, polyethylene glycol 2000 and trehalose. The liposome has an entrapment rate of about 90%, greatly improves the stability and bioavailability of the preparation, releases the drug stably and has more obvious curative effect. However, the liposome has a high cumulative release rate when released in vitro, and is unsatisfactory.
On the other hand, the alprostadil injection is mostly a special pharmaceutical preparation, and the detection method recorded in the Chinese pharmacopoeia is difficult to detect the alprostadil conveniently, quickly and with high sensitivity.
Therefore, in view of the above defects of the prior art, it is necessary to further find an alprostadil injection; meanwhile, a convenient, quick and high-sensitivity detection method is provided for the method.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a convenient, quick and high-sensitivity detection method of alprostadil injection.
In order to achieve the above object, in one aspect, the present invention provides a method for detecting alprostadil injection, which comprises:
(1) taking 20 mu L of alprostadil reference substance solution for HPLC sample injection analysis;
(2) diluting the alprostadil injection with water, ultrafiltering and centrifuging, and taking 20 mu L for HPLC sample analysis;
(3) and calculating the encapsulation rate of the alprostadil injection according to an external standard method.
The detection method provided by the invention is characterized in that the HPLC detection conditions of the steps (1) and (2) are as follows: c18A chromatographic column with specification of 4.6mm multiplied by 250mm multiplied by 5 μm; the detection wavelength is 281 nm; the flow rate is 0.8 mL/min; the mobile phase is a mixed solution of 0.1M potassium dihydrogen phosphate solution and acetonitrile according to the volume ratio of 60: 40; the reaction solution after the column is 1M potassium hydroxide solution; the post-column reaction tube is a polytetrafluoroethylene tube with the specification of 0.5mm multiplied by 10 mm; the column temperature was 40 ℃.
The detection method of the present invention, wherein the step (1) is: taking 1mg of alprostadil reference substance, adding absolute ethyl alcohol to dissolve the alprostadil reference substance, and fixing the volume to 100mL to prepare a reference substance of 10 mu g/mL; then diluted to a series of solutions of 0.5. mu.g/mL, 1. mu.g/mL, 2. mu.g/mL, 4. mu.g/mL, 6. mu.g/mL, 8. mu.g/mL using the mobile phase for HPLC sample injection analysis.
The detection method according to the present invention, wherein the peak areas A are pairedAnd (3) drawing a standard curve according to the concentration c to obtain the standard curve of the alprostadil reference substance as follows: a =19828c-356.1, r2= 0.9991; the linear relation of the concentration of the alprostadil reference substance is good in the range of 0.5-8 mug/mL.
The detection method of the invention, wherein the step (2) is: 1mL of alprostadil injection is added with water for injection to 10mL, an ultrafiltration centrifugal tube with the molecular weight cutoff of 5000 is used, and the mixture is centrifuged at 5000r/min to obtain filtrate for HPLC sample injection analysis.
The detection method provided by the invention is characterized in that the alprostadil injection is prepared according to the following method: (1') preparing an alprostadil clathrate; (2') preparing an alprostadil inclusion compound liposome suspension; (3') preparing an alprostadil clathrate liposome; (4') preparing the alprostadil injection.
The detection method of the present invention, wherein the step (1') is: dissolving alprostadil in PBS (phosphate buffer solution) with pH =7.4, adding hydroxypropyl-beta-cyclodextrin, and stirring and uniformly mixing; filtering with 0.45 μm microporous membrane, and freeze drying to obtain Alprostadil clathrate.
In the present invention, hydroxypropyl- β -cyclodextrin has a molecular weight of 1541.
According to the detection method, in the step (1'), the weight ratio of the alprostadil to the hydroxypropyl-beta-cyclodextrin is 1 (3.2-5.2).
Preferably, in the step (1'), the weight ratio of the alprostadil to the hydroxypropyl-beta-cyclodextrin is 1 (3.4-5.0); more preferably, in the step (1'), the weight ratio of alprostadil to hydroxypropyl-beta-cyclodextrin is 1 (3.6-4.8); and, most preferably, in said step (1'), the weight ratio of alprostadil to hydroxypropyl-beta-cyclodextrin is 1 (3.8-4.6).
In a specific embodiment, in step (1'), the weight ratio of alprostadil to hydroxypropyl-beta-cyclodextrin is 1: 4.2.
The detection method according to the present invention, wherein, in the step (1'), the stirring time is 0.5 to 6 hours.
Preferably, in the step (1'), the stirring time is 0.5 to 5 hours; more preferably, in step (1'), the stirring time is 1-4 h; and, most preferably, in said step (1'), the stirring time is 1-3 h.
In a specific embodiment, in said step (1'), the stirring time is 2 h.
The detection method of the present invention, wherein the step (2') is: dissolving the alprostadil inclusion compound, hydrogenated soybean phospholipid, cholesterol and cholesterol sulfate sodium salt in chloroform, removing the solvent by rotary evaporation at 40 ℃ to form a lipid film, and continuously carrying out rotary evaporation for 5-30 min; adding 5-15wt% sucrose water solution, hydrating at room temperature, and homogenizing under high pressure to obtain suspension of alprostadil clathrate liposome.
According to the detection method, in the step (2'), the weight ratio of the hydrogenated soybean phospholipid, the hydrogen cholesterol and the sodium salt of cholesterol sulfate ester to the alprostadil is (70-170): (5-15): (2.5-7.5): 1.
Preferably, in the step (2'), the weight ratio of the hydrogenated soybean phospholipids, the hydrogen cholesterol and the sodium salt of cholesterol sulfate to the alprostadil is (80-160): 6-14): 3-7): 1; more preferably, in the step (2'), the weight ratio of the hydrogenated soybean phospholipids, the hydrogen cholesterol and the sodium salt of cholesterol sulfate to the alprostadil is (90-150): (7-13): (3.5-6.5): 1; and, most preferably, in said step (2'), the weight ratio of hydrogenated soybean phospholipids, hydrocortisone and sodium salt of cholesterol sulfate to alprostadil is (100-) -140 (8-12) (4-6): 1.
In a specific embodiment, in the step (2'), the weight ratio of the hydrogenated soybean phospholipids, the hydrocouol and the sodium salt of cholesterol sulfate to the alprostadil is 120:10:5: 1.
According to the detection method, in the step (2'), the volume-weight ratio of the sucrose aqueous solution to the alprostadil is (20-60):1 mL/mg.
Preferably, in the step (2'), the volume-to-weight ratio of the sucrose aqueous solution to the alprostadil is (25-55):1 mL/mg; more preferably, in the step (2'), the volume-to-weight ratio of the sucrose aqueous solution to the alprostadil is (30-50):1 mL/mg; and, most preferably, in step (2'), the volume-to-weight ratio of the sucrose aqueous solution to alprostadil is (35-45):1 mL/mg.
In a specific embodiment, in the step (2'), the volume-to-weight ratio of the sucrose aqueous solution to the alprostadil is 40:1 mL/mg.
The detection method according to the present invention, wherein, in the step (2'), the pressure is 1500-.
Preferably, in step (2'), the pressure is 2000-; more preferably, in said step (2'), said pressure is 2500-; and, most preferably, in step (2'), the pressure is 3000-.
In a specific embodiment, in step (2'), the pressure is 5000 psi.
The detection method of the present invention, wherein the step (3') is: filtering the alprostadil inclusion compound liposome suspension by a microporous filter membrane, filling 1 mL/branch of alprostadil inclusion compound liposome suspension into penicillin bottles, and freeze-drying to obtain the alprostadil inclusion compound liposome.
The detection method of the present invention, wherein the step (4') is: and adding 5% glucose injection into the alprostadil clathrate liposome for hydration reconstruction, and standing at room temperature for 10-30min to obtain the alprostadil injection.
Compared with the prior art, the invention has the following beneficial technical effects:
compared with the prior art, the invention has the following beneficial technical effects:
i) the detection method is suitable for detecting the specific alprostadil injection;
ii) the detection method has high precision, good reproducibility and good stability, and can accurately determine the encapsulation rate of the alprostadil injection.
Detailed Description
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications can be made by those skilled in the art after reading the contents of the present invention, and those equivalents also fall within the scope of the invention defined by the appended claims.
The following examples will aid understanding of the present invention, but are not intended to limit the scope of the present invention.
In the present invention, the average particle diameter and the distribution thereof are measured as follows: a small amount of alprostadil injection liquid of the embodiment and the comparative example of the invention is added into water, is vibrated to be uniformly dispersed and is tested by a laser particle sizer.
The HPLC detection conditions are as follows: c18A chromatographic column with specification of 4.6mm multiplied by 250mm multiplied by 5 μm; the detection wavelength is 281 nm; the flow rate is 0.8 mL/min; the mobile phase is a mixed solution of 0.1M potassium dihydrogen phosphate solution and acetonitrile according to the volume ratio of 60: 40; the reaction solution after the column is 1M potassium hydroxide solution; the post-column reaction tube is a polytetrafluoroethylene tube with the specification of 0.5mm multiplied by 10 mm; the column temperature is 40 ℃; the amount of the sample was 20. mu.L.
Taking 1mg of alprostadil reference substance, adding absolute ethyl alcohol to dissolve the alprostadil reference substance, and fixing the volume to 100mL to prepare a reference substance solution of 10 mu g/mL. Then, the solution was diluted to 0.5. mu.g/mL, 1. mu.g/mL, 2. mu.g/mL, 4. mu.g/mL, 6. mu.g/mL, or 8. mu.g/mL using the mobile phase, and the sample was injected and measured under the HPLC detection conditions. Drawing a standard curve by using the peak area A to the concentration c to obtain the standard curve of the alprostadil reference substance as follows: a =19828c-356.1, r2= 0.9991. The result shows that the linear relation of the concentration of the alprostadil reference substance is good within the range of 0.5-8 mug/mL.
Through methodology research, the precision and stability of the HPLC detection method are high, the average recovery rate is over 99.0%, and RSD =0.43% (n = 3).
1mL of the alprostadil injection of the embodiment and the comparative example of the invention is taken and added with absolute ethyl alcohol respectively to be dissolved, the volume is determined to be 10mL, and the marked amount of the alprostadil is measured respectively.
1mL of alprostadil injection in the embodiment and the comparative example of the invention is added with water for injection to 10mL, an ultrafiltration centrifugal tube with the molecular weight cutoff of 5000 is used, the mixture is centrifuged at 5000r/min to obtain filtrate, and the encapsulation efficiency is determined according to the HPLC detection method.
1mL of the alprostadil injection of the embodiment and the comparative example of the invention is added with 5 percent glucose injection to 5mL respectively, and the mixture is shaken at room temperature in the dark. Sampling at 0.5h, 1h, 2h, 4h, 8h, 12h, 16h and 24h respectively, and centrifuging at 5000r/min by using an ultrafiltration centrifugal tube with molecular weight cutoff of 5000 to obtain filtrate; 20 μ L of the drug was measured and the cumulative release rate was calculated.
Example 1:
dissolving 5mg of alprostadil in 100mL of PBS buffer solution with pH =7.4, adding 21mg of hydroxypropyl-beta-cyclodextrin, stirring for 2h, and uniformly mixing; filtering with 0.45 μm microporous membrane, and freeze drying to obtain Alprostadil clathrate. Dissolving the alprostadil inclusion compound, 600mg of hydrogenated soybean phospholipid, 50mg of cholesterol and 25mg of cholesterol sulfate sodium salt in 10mL of chloroform, performing rotary evaporation at 40 ℃ to remove the solvent to form a lipid film, and continuously performing rotary evaporation for 10 min; adding 200mL of 7.5wt% sucrose aqueous solution, hydrating at room temperature, and homogenizing for 3 times at 5000psi under high pressure to obtain alprostadil clathrate liposome suspension; filtering with 0.45 μm microporous membrane, loading into penicillin bottles with 1 mL/piece, and freeze drying to obtain Alprostadil clathrate liposome. When the alprostadil clathrate compound liposome is used, 1 branch of alprostadil clathrate compound liposome is added with 1mL of 5 percent glucose injection for hydration and reconstruction, and the alprostadil injection in the embodiment 1 is obtained after standing for 15min at room temperature.
Example 2:
dissolving 5mg of alprostadil in 100mL of PBS buffer solution with pH =7.4, adding 19mg of hydroxypropyl-beta-cyclodextrin, stirring for 1h, and uniformly mixing; filtering with 0.45 μm microporous membrane, and freeze drying to obtain Alprostadil clathrate. Dissolving the alprostadil inclusion compound, 500mg of hydrogenated soybean phospholipid, 40mg of cholesterol and 20mg of cholesterol sulfate sodium salt in 10mL of chloroform, performing rotary evaporation at 40 ℃ to remove the solvent to form a lipid film, and continuously performing rotary evaporation for 5 min; adding 200mL of 5wt% sucrose aqueous solution, hydrating at room temperature, and homogenizing at 3000psi under high pressure for 3 times to obtain alprostadil clathrate liposome suspension; filtering with 0.45 μm microporous membrane, loading into penicillin bottles with 1 mL/piece, and freeze drying to obtain Alprostadil clathrate liposome. When the alprostadil clathrate compound liposome is used, 1 branch of alprostadil clathrate compound liposome is added with 1mL of 5 percent glucose injection for hydration reconstruction, and the alprostadil injection in the embodiment 2 is obtained after standing for 10min at room temperature.
Example 3:
dissolving 5mg of alprostadil in 100mL of PBS buffer solution with pH =7.4, adding 23mg of hydroxypropyl-beta-cyclodextrin, stirring for 3 hours, and uniformly mixing; filtering with 0.45 μm microporous membrane, and freeze drying to obtain Alprostadil clathrate. Dissolving the alprostadil inclusion compound, 700mg of hydrogenated soybean phospholipid, 60mg of cholesterol and 30mg of cholesterol sulfate sodium salt in 10mL of chloroform, performing rotary evaporation at 40 ℃ to remove the solvent to form a lipid film, and continuously performing rotary evaporation for 30 min; adding 200mL of 15wt% sucrose aqueous solution, hydrating at room temperature, and homogenizing for 3 times at 8000psi under high pressure to obtain alprostadil clathrate liposome suspension; filtering with 0.45 μm microporous membrane, loading into penicillin bottles with 1 mL/piece, and freeze drying to obtain Alprostadil clathrate liposome. When the alprostadil clathrate compound liposome is used, 1 branch of alprostadil clathrate compound liposome is added with 1mL of 5 percent glucose injection for hydration and reconstruction, and the alprostadil injection in the embodiment 3 is obtained after standing for 30min at room temperature.
Comparative example 1
The same as example 1, but without hydroxypropyl-. beta. -cyclodextrin.
Comparative example 2
The same procedure as in example 1, except that the sodium salt of cholesterol sulfate was not added.
Comparative example 3
The same as example 1, but only 5mg of cholesterol sulfate sodium salt are added.
The average particle diameters of examples 1 to 3 of the present invention and comparative examples 1 to 3, and the distribution, labeled amount and encapsulation efficiency thereof were tested according to the aforementioned methods, specifically referring to Table 1.
TABLE 1
| Numbering | Average particle diameter | Particle size distribution/nm | Marked amount/%) | Encapsulation efficiency/% |
| Example 1 | 154.3±9.2 | 40-320 | 102.1 | 91.8 |
| Example 2 | 161.8±10.6 | 30-350 | 101.9 | 87.5 |
| Example 3 | 159.1±9.7 | 20-370 | 103.4 | 90.3 |
| Comparative example 1 | 132.5±6.8 | 50-290 | 100.2 | 92.4 |
| Comparative example 2 | 241.2±16.2 | 20-640 | 99.8 | 67.5 |
| Comparative example 3 | 187.0±13.2 | 20-490 | 101.6 | 81.9 |
The cumulative release rates over time were tested according to the methods described above for inventive examples 1-3 and comparative examples 1-3, see in particular table 2.
TABLE 2
| Time/h | Example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| 0.5 | 2.7 | 2.4 | 2.6 | 17.2 | 5.1 | 3.4 |
| 1 | 3.1 | 2.8 | 3.0 | 20.3 | 7.5 | 4.9 |
| 2 | 3.4 | 3.3 | 3.5 | 24.8 | 10.3 | 5.7 |
| 4 | 3.9 | 3.8 | 4.1 | 30.4 | 14.6 | 7.3 |
| 8 | 5.1 | 5.2 | 5.2 | 33.7 | 18.7 | 9.8 |
| 12 | 6.3 | 6.5 | 6.7 | 36.3 | 21.2 | 11.3 |
| 16 | 7.6 | 7.9 | 8.0 | 39.6 | 24.8 | 13.1 |
| 24 | 9.1 | 9.5 | 9.9 | 44.1 | 28.6 | 15.7 |
The results show that the average particle size of the alprostadil injection of the embodiments 1-3 of the invention is smaller and the particle size distribution is narrower due to the addition of the hydroxypropyl-beta-cyclodextrin and the cholesterol sulfate sodium salt; and simultaneously, higher encapsulation efficiency can be realized. On the other hand, from the results of comparative examples 1 and 2, it is seen that hydroxypropyl- β -cyclodextrin and cholesterol sulfate sodium salt have a synergistic effect on the cumulative release rate at the time of in vitro release, resulting in a sustained release effect of the alprostadil injection of the present invention, which can significantly improve bioavailability.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (1)
1. A preparation method of alprostadil injection comprises the following steps:
(1') preparing an alprostadil clathrate; (2') preparing an alprostadil inclusion compound liposome suspension; (3') preparing an alprostadil clathrate liposome; (4') preparing an alprostadil injection;
the step (1') is as follows: dissolving alprostadil in PBS (phosphate buffer solution) with pH =7.4, adding hydroxypropyl-beta-cyclodextrin, and stirring and uniformly mixing; filtering with 0.45-micron microporous filter membrane, and freeze-drying to obtain alprostadil clathrate; the weight ratio of the alprostadil to the hydroxypropyl-beta-cyclodextrin is 1 (3.2-5.2);
the step (2') is as follows: dissolving the alprostadil inclusion compound, hydrogenated soybean phospholipid, cholesterol and cholesterol sulfate sodium salt in chloroform, removing the solvent by rotary evaporation at 40 ℃ to form a lipid film, and continuously carrying out rotary evaporation for 5-30 min; adding 5-15wt% of sucrose aqueous solution, hydrating at room temperature, and homogenizing under a certain pressure at high pressure to obtain alprostadil clathrate liposome suspension; the weight ratio of the hydrogenated soybean phospholipid, the cholesterol, the sodium salt of cholesterol sulfate and the alprostadil is (70-170): 5-15): 2.5-7.5): 1; the volume-weight ratio of the sucrose aqueous solution to the alprostadil is (20-60) to 1 mL/mg;
the step (3') is as follows: filtering the alprostadil inclusion compound liposome suspension by a microporous filter membrane, filling 1 mL/branch of alprostadil inclusion compound liposome suspension into penicillin bottles, and freeze-drying to obtain alprostadil inclusion compound liposome;
the step (4') is as follows: and adding 5% glucose injection into the alprostadil clathrate liposome for hydration reconstruction, and standing at room temperature for 10-30min to obtain the alprostadil injection.
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