CN107884529B - Method for measuring drug encapsulation efficiency of fat emulsion preparation and application thereof - Google Patents
Method for measuring drug encapsulation efficiency of fat emulsion preparation and application thereof Download PDFInfo
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- CN107884529B CN107884529B CN201610861952.1A CN201610861952A CN107884529B CN 107884529 B CN107884529 B CN 107884529B CN 201610861952 A CN201610861952 A CN 201610861952A CN 107884529 B CN107884529 B CN 107884529B
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention provides a method for measuring the drug encapsulation efficiency of fat emulsion, which comprises the following steps: (1) filling the weak base anion exchange resin in a column tube, and dehydrating; (2) adding a fat emulsion preparation containing an anionic drug into a column tube, and then eluting; (3) and collecting the fat emulsion obtained by elution, and calculating the drug encapsulation rate of the fat emulsion preparation according to the content of the encapsulated drug in the fat emulsion drops obtained by elution and the dosage of the drug in the fat emulsion preparation before elution. The method solves the problems of poor separation degree of lipid emulsion droplets and free drugs and large measurement result in the prior art. The method has high accuracy and good repeatability, and can be used for alprostadil and other structures containing anions (namely COO)‑) The prescription process research and the quality control of the medicinal fat emulsion preparation.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a method for determining drug encapsulation rate of a fat emulsion preparation and application of the method in separation of encapsulated fat emulsion drugs and unencapsulated fat emulsion drugs.
Background
The prior methods for measuring the encapsulation efficiency of the fat emulsion preparation mainly comprise the following steps:
the first method is to measure the encapsulation efficiency of the fat emulsion preparation by adopting an ultrafiltration centrifugation method, and to use an ultrafiltration membrane to intercept emulsion drops so as to centrifuge out a water phase. In the experiment, the encapsulation efficiency of the alprostadil fat emulsion injection (the chemical structure of which is shown as the following) is tested by adopting an ultrafiltration tube (3K, 5K and 10K) of Sadolis and Borer. However, in practice, different filter membranes have different degrees of adsorption effects on alprostadil, that is, the method for measuring the encapsulation efficiency of the alprostadil fat emulsion injection results in larger measurement results.
The chemical structural formula of alprostadil is shown as follows:
the second method is to determine the encapsulation efficiency of the fat emulsion preparation by dialysis. This method can handle larger volumes of sample, but requires larger volumes of dialysate and longer times, and requires constant replacement of the dialysate. Furthermore, the method is not applicable to poorly water-soluble drugs. The inventor adopts the method to measure the encapsulation efficiency of the alprostadil fat emulsion injection, but because the medicine specification (5 mug/ml) is small and slightly soluble in water, a large amount of water is needed to dialyze out the free medicine, and then the concentration of the free medicine is measured. Due to the large dilution of the free drug, there is a limit in determining the encapsulation efficiency by this indirect method, and the concentration of alprostadil in the dialysate cannot reach the detection limit of liquid phase determination.
The third method is to use a dextran micro gel column to measure the entrapment rate of the drug-loaded liposome. Removing water in the dextran micro gel column, loading the drug-loaded fat emulsion on the dextran micro gel column, and centrifugally eluting the liposome; and then respectively measuring the total content concentration of the drug in the drug-loaded fat emulsion and the content concentration of the encapsulated drug eluted by the dextran micro gel column, and dividing the content concentration of the encapsulated drug eluted by the dextran micro gel column by the total content concentration of the drug in the fat emulsion to obtain the encapsulation rate of the drug-loaded liposome. The inventor also tried to determine the encapsulation efficiency of the alprostadil fat emulsion injection by adopting the method, but when the methodology of the method is verified, the inventor finds that when the free alprostadil is used for loading, the free alprostadil is eluted, namely, the separation degree of lipid emulsion drops and free medicine is poor, and the encapsulation efficiency determination result is inaccurate.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for determining the drug encapsulation efficiency of a fat emulsion preparation, which comprises the following steps:
(1) filling the weak base anion exchange resin in a column tube, and dehydrating;
(2) adding a fat emulsion preparation containing an anionic drug into a column tube, and then eluting;
(3) and collecting the fat emulsion drops obtained by elution, and calculating the drug encapsulation rate in the fat emulsion preparation according to the encapsulated drug content in the fat emulsion drops obtained by elution and the drug dosage of the fat emulsion preparation before elution.
Calculating the formula:
preferably, in the above step (1), the weakly basic anion exchange resin is DEAE sepharose FF.
Preferably, in the step (1) above, the dehydration is centrifugal dehydration or vacuum suction dehydration.
Preferably, in the step (2) above, the anion-containing drug is a carboxyl-containing drug; more preferably, the fat emulsion preparation of the anion-containing medicament is an alprostadil injection.
Preferably, in the above step (2), the volume of the fat emulsion preparation of the anion-containing drug loaded into the column tube is 1% to 100%, preferably 15% to 25% of the column volume. Too large a volume of the fat emulsion formulation containing the anion-containing drug loaded into the cartridge will result in overloading the weakly basic anion exchange resin and the unencapsulated drug will also be eluted, affecting the separation and assay results.
Preferably, in the step (2) above, the elution is centrifugal elution or pressure elution. More preferably, the centrifugal elution condition is that the centrifugation is firstly carried out for 1-10 minutes at the speed of 500-3000rpm, and then the secondary elution is carried out by water; more preferably, the centrifugal elution condition is that firstly the centrifugation is carried out for 2 to 8 minutes at the speed of 800-2000rpm, and then the secondary elution is carried out by water; further preferably, the secondary elution is a centrifugal elution or a pressure elution; still further preferably, the second elution is carried out 1 to 20 times with the amount of water used for each time being 1 to 200% of the column volume, preferably 10 to 50%. The number of secondary elution is not too many, otherwise, besides the fat emulsion encapsulated with the drug in the column tube is eluted, the unencapsulated drug is also eluted, and the accuracy of encapsulation rate determination is affected.
The method of the invention adopts the weak base anion exchange resin column to measure the drug encapsulation efficiency of the fat emulsion preparation, and the method is suitable for the method containing anions (such as carboxyl COO) in the chemical structure-Etc.) such as alprostadil. Taking the alprostadil injection as an example, the DEAE (diethylaminoethyl) weak-base anion exchange resin adopted by the method can completely adsorb free alprostadil in the alprostadil fat emulsion, and the coated alprostadil can be quickly eluted by water, so that the complete separation of the free alprostadil and the lipid emulsion droplets coating the alprostadil is realized, and the accurate determination of the drug encapsulation rate is further carried out.
The method solves the problems of poor separation degree of lipid emulsion droplets and free drugs and large measurement result in the prior art. The method has high accuracy and good repeatability, and can be used for prescription process research and quality control of fat emulsion preparation containing medicines containing anions in the structures of alprostadil and the like.
The present invention also provides a method for separating an encapsulated drug from an unencapsulated drug in a fat emulsion formulation containing an anionic drug, the method comprising the steps of:
(a) filling the weak base anion exchange resin in a column tube, and dehydrating;
(b) adding the fat emulsion preparation containing the medicine with anions into the column tube, then eluting, and collecting the fat emulsion drops obtained by elution.
Preferably, in step (a) above, the weakly basic anion exchange resin is DEAE weakly basic anion exchange resin; more preferably, the weakly basic anion exchange resin is DEAE sepharose FF.
Preferably, in the step (a) above, the dehydration is centrifugal dehydration or vacuum suction dehydration.
Preferably, in the above step (b), the anion-containing drug is a carboxyl-containing drug; more preferably, the fat emulsion preparation of the anion-containing medicament is an alprostadil injection.
Preferably, in the above step (b), the volume of the fat emulsion preparation of the anion-containing drug loaded into the column tube is 1% to 100%, preferably 15% to 25% of the column volume.
Preferably, in the step (b) above, the elution is centrifugal elution or pressure elution. More preferably, the centrifugal elution condition is that the centrifugation is firstly carried out for 1-10 minutes at the speed of 500-3000rpm, and then the secondary elution is carried out by water; more preferably, the centrifugal elution condition is that firstly the centrifugation is carried out for 2 to 8 minutes at the speed of 800-2000rpm, and then the secondary elution is carried out by water; further preferably, the secondary elution is a centrifugal elution or a pressure elution; still further preferably, the second elution is carried out 1 to 20 times with the amount of water used for each time being 1 to 200% of the column volume, preferably 10 to 50%. The number of secondary elution is not too many, otherwise, besides the fat emulsion encapsulated with the drug in the column tube is eluted, the unencapsulated drug is also eluted, and the separation effect is affected.
Preferably, the method of separating encapsulated drug from unencapsulated drug in the fat emulsion preparation of an anion-containing drug of the present invention further comprises eluting unencapsulated drug in the cartridge after step (b).
The invention also provides application of the weak-base anion exchange resin in determination of the encapsulation efficiency of the fat emulsion pharmaceutical preparation. Preferably, the weakly basic anion exchange resin is DEAE weakly basic anion exchange resin; more preferably, the weakly basic anion exchange resin is DEAE sepharose FF.
The invention also provides the use of a weakly basic anion exchange resin for separating encapsulated from unencapsulated drug in a fat emulsion formulation containing an anionic drug. Preferably, the weakly basic anion exchange resin is DEAE weakly basic anion exchange resin; more preferably, the weakly basic anion exchange resin is DEAE sepharose FF.
Detailed Description
The present invention will be described in more detail with reference to specific examples. It should be understood that although only examples are listed for alprostadil injection, the method of the present invention is also applicable to fat emulsion formulations of other anionic containing drugs in view of the properties of the weakly basic anion exchange resin itself.
Example 1
(1) Filling DEAE weakly-basic anion exchange resin into a 5ml syringe sleeve, and performing centrifugal dehydration to form a 5ml dry column;
(2) 1ml of alprostadil injection is loaded into a syringe sleeve and is centrifuged at the centrifugal speed of 1200rpm for 3 minutes;
(3) carrying out centrifugal elution with 1ml of water each time for 7 times; and collecting the eluted emulsion drops into a 10ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection. Three replicates were tested with the following results:
example 2
(1) Filling DEAE weak-base anion exchange resin into a 10ml syringe sleeve, and performing centrifugal dehydration to form a 10ml dry column;
(2) 5ml of alprostadil injection is added into a syringe sleeve and centrifuged at the centrifugal speed of 2000rpm for 8 minutes;
(3) carrying out centrifugal elution with 2ml of water each time for 5 times; collecting the eluted emulsion drops into a 20ml measuring flask, fixing the volume, measuring to obtain the content of the encapsulated drug, diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 3
(1) Filling DEAE weakly-basic anion exchange resin in a 50ml column tube, and performing centrifugal dehydration to form a 50ml dry column;
(2) 1ml of alprostadil injection is added into a column tube and is centrifuged for 2 minutes at the centrifugal speed of 3000 rpm;
(3) performing centrifugal elution with 1ml of water each time, and performing elution for 20 times; and collecting the eluted emulsion drops into a 25ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 4
(1) Filling DEAE weak-base anion exchange resin into a 100ml column tube, and performing centrifugal dehydration to form a 100ml dry column;
(2) 1ml of alprostadil injection is added into a column tube and is centrifuged for 2 minutes at the centrifugal speed of 500 rpm;
(3) carrying out centrifugal elution with 1ml of water each time for 7 times; and collecting the eluted emulsion drops into a 10ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 5
(1) Filling DEAE weakly-basic anion exchange resin into a 5ml column tube, and performing centrifugal dehydration to form a 5ml dry column;
(2) 0.5ml of alprostadil injection is loaded and centrifuged at the centrifugation speed of 1500rpm for 1 minute;
(3) carrying out centrifugal elution with 4ml of water each time for 2 times; transferring the collected and eluted emulsion drops into a 10ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 6
(1) Filling DEAE weak-base anion exchange resin into a 10ml column tube, and performing centrifugal dehydration to form a 10ml dry column;
(2) adding 0.5ml of alprostadil injection into a column tube, and centrifuging for 5 minutes at the centrifugal speed of 1000 rpm;
(3) performing centrifugal elution with 0.5ml of water each time for 6 times; transferring the collected and eluted emulsion drops into a 5ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 7
(1) Filling DEAE weak-base anion exchange resin into a 10ml column tube, and performing centrifugal dehydration to form a 10ml dry column;
(2) adding 0.2ml of alprostadil injection into a column tube, and centrifuging at the centrifugal speed of 2000rpm for 1 minute;
(3) performing centrifugal elution with 0.2ml of water each time, and performing elution for 20 times; and collecting the eluted emulsion drops into a 5ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 8
(1) Filling DEAE weak-base anion exchange resin into a 3ml column tube, and performing centrifugal dehydration to form a 3ml dry column;
(2) 1ml of alprostadil injection is added into a column tube and is centrifuged for 2 minutes at the centrifugal speed of 800 rpm;
(3) carrying out centrifugal elution with 1ml of water each time for 8 times; and collecting the eluted emulsion drops into a 10ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 9
(1) Filling DEAE weakly-basic anion exchange resin into a 5ml column tube, and performing centrifugal dehydration to form a 5ml dry column;
(2) 2.5ml of alprostadil injection is added into a column tube and centrifuged for 3 minutes at the centrifugal speed of 1000 rpm;
(3) carrying out centrifugal elution with 1ml of water each time for 7 times; and collecting the eluted fat emulsion drops into a 10ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
example 10
(1) Filling DEAE weak-base anion exchange resin into a 4ml column tube, and performing centrifugal dehydration to form a 4ml dry column;
(2) 1ml of alprostadil injection is added into a column tube and is centrifuged at the centrifugal speed of 500rpm for 10 minutes;
(3) performing centrifugal elution with 8ml of water each time, and performing elution for 1 time; and collecting the eluted emulsion drops into a 25ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection.
Three replicates were tested with the following results:
comparative example 1 (Sephadex column method)
(1) Filling the G50 sephadex into a 5ml syringe sleeve, and performing centrifugal dehydration to form a 5.5ml dry column;
(2) loading 0.5ml of alprostadil injection into a syringe sleeve, and centrifuging at the centrifugal speed of 1200rpm for 2 minutes;
(3) performing centrifugal elution with 1ml of water each time for 2 times; and collecting the eluted emulsion drops into a 5ml measuring flask, fixing the volume, and measuring to obtain the content of the encapsulated medicine. Diluting the alprostadil injection to the theoretical concentration after column chromatography, measuring by the same method, and then calculating the encapsulation rate of the alprostadil injection. Three replicates were tested with the following results:
it can be seen that the encapsulation efficiency obtained with the G50 sephadex filling is lower. Methodological investigations were carried out with this G50 sephadex. The conclusion is that: the free drug is loaded independently, the elution times are slightly more, the free drug is eluted, and the result of the encapsulation efficiency measurement is higher. Thus, in order to control the effective binding of the free drug to the column, the number of water washes was reduced, but resulted in a decrease in the recovery of emulsion droplets, and thus the encapsulation efficiency was measured to be low. Thus DEAE anion exchange resin is more preferred than G50 sephadex.
Comparative example 2 (Ultrafiltration centrifugation)
(1) Adding 0.5ml of alprostadil injection into a 100k ultrafiltration centrifugal tube, balancing a rotor, and centrifuging for 20 minutes at 18000G;
(2) directly measuring the water solution filtered from the lower layer of the ultrafiltration centrifugal tube.
Three tests were performed with the following results:
it can be seen that the encapsulation efficiency obtained by the ultrafiltration centrifugation method is very high. The methodological investigation of the ultrafiltration centrifugation method shows that: the free drug aqueous solution (trace ethanol for assisting dissolution) is centrifuged by ultrafiltration tubes with different pore diameters, the free drugs have adsorption, and the adsorption rate is about 40% at least. Part of free drugs can not be eluted, and the encapsulation efficiency measurement result is higher, so that the accuracy of the result is influenced. Thus, DEAE anion exchange resins are more preferred than ultrafiltration centrifugation.
Claims (27)
1. A method for determining the drug encapsulation efficiency of a fat emulsion formulation, the method comprising the steps of:
(1) filling the weak base anion exchange resin in a column tube, and dehydrating;
(2) adding a fat emulsion preparation containing an anionic drug into a column tube, and then eluting;
(3) collecting the fat emulsion obtained by elution, and calculating the drug encapsulation rate of the fat emulsion preparation according to the content of encapsulated drugs in the fat emulsion drops obtained by elution and the dosage of the drugs of the fat emulsion preparation before elution;
wherein, in the step (2), the elution is centrifugal elution, and the centrifugal elution condition is that the centrifugation is firstly carried out for 1-10 minutes at the speed of 500-3000rpm, and then the secondary elution is carried out by water; and in the step (2), the fat emulsion preparation of the anion-containing medicament is alprostadil injection.
2. The method of claim 1, wherein the weakly basic anion exchange resin is a DEAE weakly basic anion exchange resin.
3. The method of claim 1, wherein the weakly basic anion exchange resin is DEAE sepharose FF.
4. The method according to claim 1, wherein in step (1), the dehydration is centrifugal dehydration or vacuum suction dehydration.
5. The method according to claim 1, wherein, in the step (2), the volume of the fat emulsion preparation of the anion-containing drug loaded into the column tube is 1% to 100% of the column volume.
6. The method according to claim 1, wherein, in the step (2), the volume of the fat emulsion preparation of the anion-containing drug loaded into the column tube is 15% to 25% of the column volume.
7. The method as claimed in claim 1, wherein the conditions of the centrifugal elution are that the centrifugation is carried out at 800-.
8. The method of claim 1, wherein the secondary elution is a centrifugal elution or a pressure elution.
9. The method of claim 1, wherein the second elution is performed 1-20 times using 1-200% water per column volume.
10. The process of claim 9, wherein the amount of water used per pass is 10-50% of the column volume.
11. A method of separating encapsulated drugs from unencapsulated drugs in a fat emulsion formulation of an anionic drug comprising the steps of:
(a) filling the weak base anion exchange resin in a column tube, and dehydrating;
(b) adding the fat emulsion preparation containing the medicine of anions into a column tube, then eluting, and collecting the fat emulsion drops obtained by elution;
wherein, in the step (b), the elution is centrifugal elution, and the centrifugal elution condition is that the centrifugation is firstly carried out for 1-10 minutes at the speed of 500-3000rpm, and then the secondary elution is carried out by water; and in the step (b), the fat emulsion preparation of the anion-containing medicament is alprostadil injection.
12. The process of claim 11, wherein in step (a), the weakly basic anion exchange resin is DEAE weakly basic anion exchange resin.
13. The method of claim 11, wherein the weakly basic anion exchange resin is DEAE sepharose FF.
14. The method of claim 11, wherein in step (a), the dewatering is centrifugal dewatering or vacuum suction dewatering.
15. The method according to claim 11, wherein in step (b), the volume of the fat emulsion preparation of the anion-containing drug loaded into the column tube is 1% to 100% of the column volume.
16. The method according to claim 11, wherein in step (b), the volume of the fat emulsion preparation of the anion-containing drug loaded into the column tube is 15% to 25% of the column volume.
17. The method as claimed in claim 11, wherein the centrifugation and elution conditions are that centrifugation is performed at 800-.
18. The method of claim 11, wherein the secondary elution is a centrifugal elution or a pressure elution.
19. The method of claim 11, wherein the second elution is performed 1-20 times using 1-200% water per column volume.
20. The process of claim 19 wherein the amount of water used per pass is from 10 to 50% of the column volume.
21. The method of claim 11, further comprising eluting unencapsulated drug within the cartridge after step (b).
22. The application of the weak base anion exchange resin in determining the drug encapsulation efficiency of the fat emulsion preparation of the drug containing anions is alprostadil injection.
23. Use according to claim 22, wherein the weakly basic anion exchange resin is a DEAE weakly basic anion exchange resin.
24. The use according to claim 22, wherein the weakly basic anion exchange resin is DEAE sepharose FF.
25. The application of the weak base anion exchange resin in separating encapsulated medicine from unencapsulated medicine in a fat emulsion preparation of medicine containing anions, wherein the fat emulsion preparation of the medicine containing the anions is alprostadil injection.
26. The use according to claim 25, wherein the weakly basic anion exchange resin is DEAE weakly basic anion exchange resin.
27. The use according to claim 25, wherein the weakly basic anion exchange resin is DEAE sepharose FF.
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