CN117250269A - In-vitro release method of aprepitant injection - Google Patents
In-vitro release method of aprepitant injection Download PDFInfo
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- CN117250269A CN117250269A CN202310993059.4A CN202310993059A CN117250269A CN 117250269 A CN117250269 A CN 117250269A CN 202310993059 A CN202310993059 A CN 202310993059A CN 117250269 A CN117250269 A CN 117250269A
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- aprepitant
- vitro release
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- phosphate
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- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 title claims abstract description 61
- 229960001372 aprepitant Drugs 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 title claims abstract description 51
- 238000002347 injection Methods 0.000 title claims abstract description 41
- 239000007924 injection Substances 0.000 title claims abstract description 41
- 238000000338 in vitro Methods 0.000 title claims abstract description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 71
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003729 cation exchange resin Substances 0.000 claims abstract description 13
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 10
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 9
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 9
- 239000008363 phosphate buffer Substances 0.000 claims description 9
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 7
- 238000007872 degassing Methods 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 230000010355 oscillation Effects 0.000 claims 1
- 238000001179 sorption measurement Methods 0.000 abstract description 37
- 239000003814 drug Substances 0.000 abstract description 31
- 239000000463 material Substances 0.000 abstract description 8
- 239000008267 milk Substances 0.000 abstract description 4
- 210000004080 milk Anatomy 0.000 abstract description 4
- 235000013336 milk Nutrition 0.000 abstract description 4
- 239000002245 particle Substances 0.000 abstract description 4
- 239000011347 resin Substances 0.000 description 39
- 229920005989 resin Polymers 0.000 description 39
- 239000002609 medium Substances 0.000 description 36
- 229940079593 drug Drugs 0.000 description 19
- 235000019441 ethanol Nutrition 0.000 description 18
- 239000007788 liquid Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 8
- 238000004364 calculation method Methods 0.000 description 7
- 238000000227 grinding Methods 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 239000002960 lipid emulsion Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- -1 forsythoside A compound Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DTOUWTJYUCZJQD-QJDQKFITSA-N Forsythiaside Natural products C[C@@H]1O[C@H](OC[C@H]2O[C@@H](OCCc3ccc(O)c(O)c3)[C@H](O)[C@@H](O)[C@@H]2OC(=O)C=Cc4ccc(O)c(O)c4)[C@H](O)[C@H](O)[C@H]1O DTOUWTJYUCZJQD-QJDQKFITSA-N 0.000 description 1
- 101000809257 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 4 Proteins 0.000 description 1
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 description 1
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 description 1
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 description 1
- 102100038463 Ubiquitin carboxyl-terminal hydrolase 4 Human genes 0.000 description 1
- 208000034699 Vitreous floaters Diseases 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- KPBZROQVTHLCDU-UHFFFAOYSA-N clevidipine Chemical compound CCCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl KPBZROQVTHLCDU-UHFFFAOYSA-N 0.000 description 1
- 229960003621 clevidipine butyrate Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012897 dilution medium Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000468 intravenous fat emulsion Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940043175 silybin Drugs 0.000 description 1
- 235000014899 silybin Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an in-vitro release method of aprepitant injection. The in-vitro release method provided by the invention adopts the cation exchange resin 50WX4 as an adsorption material and a phosphate buffer solution with the ethanol content v/v of 15-25% as a release medium, can be used for detecting the in-vitro release condition of the aprepitant injection, and is simple to operate, free medicine and milk particles can be thoroughly separated, so that the aprepitant injection is completely released.
Description
Technical Field
The invention belongs to the field of drug detection, and particularly relates to an in-vitro release method of aprepitant injection.
Background
The aprepitant injection is taken as an intravenous fat emulsion injection (i.e. emulsion), the quality control is an important ring in the production and development of the aprepitant injection, and the release is one of key detection items in the quality control. Through investigation, the dissolution detection of the aprepitant capsule mainly adopts USPI (spin basket method), USPII (paddle method) and USPIII (reciprocating cylinder method), but the separation of free medicine released by the aprepitant injection in a release medium and the milk particles cannot be realized by the method in consideration of the composition and the structure complexity of milk particles in the aprepitant injection, so the method is not applicable to the aprepitant injection.
The prior art also discloses various in vitro release detection methods for fat emulsion, such as flow cell method, forward dialysis method, reverse dialysis method, ultrafiltration centrifugation method, etcDocument 1: an examination report about aprepitant injection published by the FDA;document 2: zhang Penghua, et al, preparation, property and in vitro drug release studies of silybin fat emulsion, chinese pharmacist, 2014.01, 17, phase 4, pages 568-571;document 3: zhou Wenqi, et al, HPLC-ultrafiltration centrifugation to determine encapsulation efficiency of forsythoside A compound liposome, chinese modern applied medicine, 2013.09, volume 30, phase 9, pages 1001-1004). The method has the problems of hysteresis caused by drug crossing a dialysis membrane, incomplete ultrafiltration and centrifugal separation, complex investigation by an online detection method and the like.
While CN110736813a provides a novel method for assaying in vitro release of emulsions using resin adsorption, known emulsions tested include, but are not limited to: propofol fat emulsion, flurbiprofen ester emulsion, clevidipine butyrate emulsion and the like, wherein the resin adopted by the release method is macroporous resin and the release medium is phosphate buffer solution, but the inventor of the application finds that the aprepitant injection is not completely released when the aprepitant injection is measured by adopting the method in the patent through experimental research.
The invention aims to develop a simple and effective external release method of aprepitant injection liquid, which is used for simulating the in-vivo release condition of the aprepitant injection liquid and can evaluate the quality consistency of self-grinding preparations and reference preparations.
Disclosure of Invention
Through a great deal of research, the inventor of the application finds that the cation exchange resin 50WX4 is used as an adsorption material and a phosphate buffer solution with the ethanol content v/v of 15-25% is used as a release medium, so that the method can be used for detecting the in-vitro release condition of the aprepitant injection, is simple to operate, and free medicine and milk particles can be thoroughly separated, so that the aprepitant injection is completely released.
The invention provides an in-vitro release method of aprepitant injection, which is characterized by comprising the following steps of: adding cation exchange resin 50WX4 into a release medium, vibrating in a water bath for preheating, then adding aprepitant injection, continuously vibrating, taking the release medium at different time points, and measuring the content of aprepitant; wherein the release medium is phosphate buffer solution with ethanol content v/v of 15-25%.
Further, in the in vitro release method, after the release medium is taken, the release medium is diluted by absolute ethyl alcohol and filtered by a microporous filter membrane.
Further, the in vitro release method, wherein the amount of the cation exchange resin used is between 16% and 24% w/v.
Further, the in vitro release method wherein the phosphate is selected from the group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, ammonium dihydrogen phosphate, sodium monohydrogen phosphate, preferably potassium dihydrogen phosphate.
Further, the in vitro release method, wherein the release medium is ethanol with a content v/v of 20%.
Further, the in vitro release method, wherein the temperature and speed of the water bath shaking is 37 ℃, 150rpm. Further, the in vitro release method wherein the pH of the phosphate buffer is between 6 and 8, preferably pH 7.4.
Further, the in vitro release method, wherein the preparation method of the phosphate buffer solution comprises the following steps: dissolving potassium dihydrogen phosphate in water, adding sodium hydroxide solution, adding water, and adjusting pH to 7.4 with 0.2mol/L sodium hydroxide solution.
Further, the in vitro release method, wherein the preparation method of the phosphate buffer containing ethanol comprises the following steps: dissolving potassium dihydrogen phosphate in water, adding sodium hydroxide solution, adding water, adjusting pH with sodium hydroxide solution, adding anhydrous ethanol, mixing, and ultrasonic degassing.
The invention has the beneficial effects that:
the release method provided by the invention meets the requirement of simulating the release condition in aprepitant injection liquid, and can be used for evaluating the product quality of imitation enterprises and comparing and inspecting the consistency of the quality of imitation pharmaceutical preparations and original reference preparations.
Detailed Description
The method for in vitro release of aprepitant injection provided by the invention is described in detail below by some examples, but the invention is not limited to the examples below. Any method and materials similar or equivalent to those described can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or manufacturer recommended conditions. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Liquid chromatography: chromatographic column: octadecylsilane chemically bonded silica column (RP 18, 4.6x150 mm,5 μm or equivalent potency column), mobile phase: 0.1% phosphoric acid aqueous solution: acetonitrile=55: 45, flow rate: 1.0ml/min, column temperature: 35 ℃, detection wavelength: 210nm, sample volume: 20 μl.
The method for calculating the release rate comprises (1) characterizing the release condition of the aprepitant injection in a release medium and also evaluating the adsorption condition of resin on the free aprepitant drug released by the aprepitant injection in the medium, and (2) when the detected sample is the free drug, the release rate is called as the adsorption rate and characterizes the adsorption condition of the resin on the free drug:
er: aprepitant adsorption rate; cn: at t=n, the aprepitant content of the sample; vo: releasing the volume of the medium; ve: sampling volume; ci: releasing aprepitant concentration in the medium during the ith sampling; n: sampling times at different time points; m0: total aprepitant mass loaded.
Release medium (phosphate buffer with 20% ethanol (v/v): 13.61g of potassium dihydrogen phosphate is taken, 1000ml of water is added for dissolution, 395ml of 0.2mol/L sodium hydroxide solution is added, water is added to 2000ml, the pH value is regulated to 7.4 by 0.2mol/L sodium hydroxide solution, 500ml of absolute ethyl alcohol is added for uniform mixing, and ultrasonic degassing is carried out.
Aprepitant: purchased from Jiangsu Huiyuan pharmaceutical Co., ltd
Comparative example: release method according to example 2 Using CN110736813A
Release medium: phosphate buffer (PBS, pH7.4, 137mmol/L sodium chloride, 2.7137mmol/L potassium chloride, na) 2 HPO 4 10mmol/L，KH 2 PO 4 2mmol/L)
Release temperature: 37 DEG C
Resin type: macroporous adsorption resin AB-8
Adding 8g macroporous adsorption resin into 200ml release medium, adding 1ml aprepitant injection, stirring at 37 ℃ to dissolve, taking 0.5ml release medium at a specific time, fixing volume to 1ml by methanol, measuring the concentration of aprepitant by HPLC, and calculating the release rate.
The release rate of aprepitant injection is 6.7% in 5min, 14% in 30min and 60min, the release rate basically reaches a platform in 30min recorded in CN110736813A instruction book, namely the resin adsorption reaches saturation, and only about 14% is released, so that the experimental method cannot meet the requirement of external release of aprepitant injection, and the characteristic of quick release of the preparation cannot be reflected.
Example 1: investigating the effect of different ethanol concentration of release medium (sample is free drug)
The influence of release mediums with different ethanol concentrations on resin adsorption is examined (in order to eliminate auxiliary material interference, free medicines are adopted for experimental study).
Aprepitant free drug: 160mg of aprepitant is weighed into a 20ml volumetric flask, dissolved in ethanol, fixed in volume and shaken well.
The in vitro release method comprises the following steps: the macroporous exchange resin AB-8 g is weighed into an conical flask respectively, 100ml of release medium is added, wherein the release medium contains ethanol (0%, 5%, 10%, 15%, 20%, 25% or 35%) with different concentrations, and the release medium is preheated by shaking in a water bath at 37 ℃ and 150rpm. To the flask was added 0.2ml of aprepitant free drug and the flask was shaken in a water bath at 37℃and 150rpm. At various times, 1ml of release medium was taken, the sample was diluted with 1ml of absolute ethanol and filtered through a microporous filter membrane. Measuring the aprepitant content of the sampled products at different time points by using a liquid chromatograph, and examining the influence of different ethanol concentrations on the adsorption of the free drug (adsorption rate: the adsorption condition of resin on the free drug of aprepitant is characterized, and the calculation method is consistent with that of the release rate).
TABLE 1 adsorption Rate of Release Medium for different ethanol concentrations
As can be seen from table 1: when the concentration of ethanol in the release medium is 0%, 5% and 10%, the liquid level has floaters, namely the free medicine is separated from the release medium and floats on the liquid level, and although the adsorption rate of 60min is as high as 93% -98%, the adsorption rate of the resin obtained by calculating the content of the free medicine in the release medium cannot truly represent the adsorption condition. When the concentration of ethanol in the release medium is 35%, the adsorption of the resin is reduced, which means that the adsorption of the resin on the medicine is influenced while the solubility of the release medium on the medicine is increased due to the overlarge concentration of ethanol.
Only when the concentration of ethanol in the release medium is 15-25%, the taken release medium sample is normal in state, and the adsorption condition of the resin on the medicine can be met.
Example 2: examine the influence of different types of resin (the sample is free drug)
(1) Resin type:
investigating the adsorption effect of different types of resins on aprepitant free drugs: (1) macroporous adsorbent resin D101, purchased from national pharmaceutical group chemical reagent limited; (2) macroporous adsorption resin AB-8, purchased from Tianjin optical complex fine chemical engineering institute; (3) cation exchange resin DOwex 50WX8, H+ -form,50-100mesh (hereinafter abbreviated as 50WX 8), available from Allatin; (4) cation exchange resin DOwex 50WX4, na+ -form,200-400mesh (hereinafter abbreviated as 50WX 4), purchased from Sigma; (5) macroporous adsorption resin H-4, which is purchased from and forms new materials; (6) macroporous adsorption resin NKA-II, which is purchased from and forms new materials; (7) cation exchange resin 50WX2, na+ -form,100-200mesh (hereinafter abbreviated as 50WX 2), purchased from Sigma; (8) macroporous adsorption resin S-8, which is purchased from and forms new materials.
(2) The preparation method comprises the following steps: the in vitro release method comprises the following steps: 8g of each of the different types of resins (D101, AB-8, 50WX4, H-40, NKA-II, 50WX2 and S-8) was weighed into a conical flask, 100ml of a release medium (20% ethanol in phosphate buffer) was added thereto, and the mixture was preheated by shaking in a water bath at 37℃and 150rpm. To the flask was added 0.2ml of aprepitant free drug and the flask was shaken in a water bath at 37℃and 150rpm. At various times, 1ml of release medium was taken, the sample was diluted with 1ml of absolute ethanol and filtered through a microporous filter membrane. The aprepitant content of the samples taken at different time points is measured by a liquid chromatograph, and the adsorption of different values to the free medicine is examined (the calculation method is consistent with the calculation method of the release rate).
TABLE 2 adsorption of different types of resins to aprepitant free drug
As can be seen from the data in Table 2, when only cation exchange resin 50WX4 (serial numbers 2-4) is used, the adsorption rate in 15min is as high as 72.5%, the requirement of rapid release is met, and the adsorption rate is not much different from that in 60min, which indicates that the reason that the release in 15min does not reach complete release may be caused by the fact that the resin consumption is too small, rather than the resin type.
Other types of resins are only released for about 35-48% in 15min until about 75% in 60min, which means that the adsorption speed of the resins is too slow, and even if the resin dosage is increased, the adsorption speed cannot be increased, and the quick-release effect cannot be met (the reference preparation review data published by FDA official networks show that the variety adopts a USP4 release method, and the release rate of aprepitant injection in 15min is more than 70% in combination with the detection result of I company according to the reference preparation release method).
Example 3: examine the influence of the addition amount of the resin (the sample is free drug)
Examine the influence of the addition amount of the resin on the resin adsorption
Respectively weighing 50WX 4g, 16g and 24g of cation exchange resin in a conical flask, adding 100ml of release medium (phosphate buffer containing 20% ethanol), and vibrating in a water bath at 37 ℃ and 150rpm for preheating. To the flask was added 0.2ml of aprepitant free drug and the flask was shaken in a water bath at 37℃and 150rpm. At various times, 1ml of release medium was taken, the sample was diluted with 1ml of absolute ethanol and filtered through a microporous filter membrane. The aprepitant content of the samples taken at different time points is measured by a liquid chromatograph, and the adsorption of different resin addition amounts to the free medicine is examined (the calculation method is consistent with the calculation method of the release rate).
The results of the calculation of the different resin addition amounts are shown in the following table.
TABLE 3 adsorption Rate for different resin loadings
As can be seen from table 3: the adding amount of the resin is increased, the adsorption effect of the resin is obviously improved, and when the adding amount is 16-24%, the adsorption rate of 5min is up to 99%, so that the detection requirement of quick-release medicines can be met.
Thus, according to an examination of the release method in examples 1-3, the in vitro release of aprepitant injection was tested using a phosphate buffer solution of cation exchange resin 50WX4 at an add-on level of 16% -24% w/v and a dilution medium of 15-25% ethanol v/v.
Example 4: in vitro release test (aprepitant injection as sample)
Aprepitant injection (imitation): homemade by Shijizhuang Limited company, shijia, an odd pharmaceutical technology in Shi-yaku group
Aprepitant injection (reference): purchased from Heron Therapeutics
Respectively weighing 50WX 4g of cation exchange resin into different conical flasks, adding 100ml of release medium, and vibrating and preheating in a water bath at 37 ℃ and 150rpm. Respectively adding reference preparation aprepitant injection 0.2ml into the bottle, and continuing water bath shaking. At various times, 1ml of release medium was taken, the sample was diluted with 1ml of absolute ethanol and filtered through a microporous filter membrane. The aprepitant content of the samples taken at different time points was determined by liquid chromatography.
The results of the aprepitant injection liquid external release rate calculation are shown in the following table.
TABLE 4 external Release Rapiditant injection liquid
From table 4, it can be seen that: compared with the comparative example, the release rate of the self-grinding aprepitant injection in 15min is only 10.9%, and the release rate of the self-grinding aprepitant injection in 15min reaches 94%, so that the release method of the invention meets the requirement of simulating the in-vivo release condition. The in-vitro release method can be used for evaluating the quality of the aprepitant injection self-grinding product and comparing and inspecting the consistency of the quality of the self-grinding imitation preparation and the quality of the original grinding reference preparation.
Claims (8)
1. An in vitro release method of aprepitant injection is characterized by comprising the following steps: adding cation exchange resin 50WX4 into a release medium, vibrating in a water bath for preheating, then adding aprepitant injection, continuously vibrating, taking the release medium at different time points, and measuring the content of aprepitant; wherein the release medium is phosphate buffer solution with ethanol content v/v of 15-25%.
2. The method for in vitro release according to claim 1, wherein the release medium is diluted with absolute ethanol and filtered through a microporous filter membrane.
3. The in vitro release method according to claim 1, wherein the amount w/v of cation exchange resin is between 16% and 24%.
4. The in vitro release method according to claim 1, wherein the phosphate is selected from the group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium phosphate, ammonium dihydrogen phosphate, sodium dihydrogen phosphate, preferably potassium dihydrogen phosphate.
5. The in vitro release method according to claim 1, wherein the release medium is ethanol with a content v/v of 20%.
6. The in vitro release method according to claim 1, wherein the temperature and speed of the water bath oscillation is 37 ℃, 150rpm; further, the in vitro release method wherein the pH of the phosphate buffer is between 6 and 8, preferably pH 7.4.
7. The in vitro release method of claim 1, wherein the phosphate buffer is prepared by: dissolving potassium dihydrogen phosphate in water, adding sodium hydroxide solution, adding water, and adjusting pH to 7.4 with 0.2mol/L sodium hydroxide solution.
8. The in vitro release method according to claim 1, wherein the preparation method of the phosphate buffer containing ethanol comprises: dissolving potassium dihydrogen phosphate in water, adding sodium hydroxide solution, adding water, adjusting pH with sodium hydroxide solution, adding anhydrous ethanol, mixing, and ultrasonic degassing.
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