CN117752596A - Aprepitant mixed micelle injection and preparation method and application thereof - Google Patents
Aprepitant mixed micelle injection and preparation method and application thereof Download PDFInfo
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- CN117752596A CN117752596A CN202311783195.7A CN202311783195A CN117752596A CN 117752596 A CN117752596 A CN 117752596A CN 202311783195 A CN202311783195 A CN 202311783195A CN 117752596 A CN117752596 A CN 117752596A
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- aprepitant
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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 156
- 229960001372 aprepitant Drugs 0.000 title claims abstract description 156
- 239000000693 micelle Substances 0.000 title claims abstract description 106
- 238000002347 injection Methods 0.000 title claims abstract description 68
- 239000007924 injection Substances 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 31
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000010008 shearing Methods 0.000 claims abstract description 27
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims abstract description 25
- 235000019416 cholic acid Nutrition 0.000 claims abstract description 25
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000004380 Cholic acid Substances 0.000 claims abstract description 24
- 229960002471 cholic acid Drugs 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 19
- 239000006185 dispersion Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 81
- 239000000243 solution Substances 0.000 claims description 69
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 108010007979 Glycocholic Acid Proteins 0.000 claims description 19
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 238000002156 mixing Methods 0.000 claims description 18
- 239000008215 water for injection Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 14
- 230000001954 sterilising effect Effects 0.000 claims description 13
- 230000001804 emulsifying effect Effects 0.000 claims description 12
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 10
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 claims description 10
- 229940099347 glycocholic acid Drugs 0.000 claims description 10
- 238000006386 neutralization reaction Methods 0.000 claims description 10
- 229940083466 soybean lecithin Drugs 0.000 claims description 10
- 230000001105 regulatory effect Effects 0.000 claims description 9
- 238000004945 emulsification Methods 0.000 claims description 8
- 229940067631 phospholipid Drugs 0.000 claims description 8
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 6
- DKPMWHFRUGMUKF-UHFFFAOYSA-N (3alpha,5alpha,6alpha,7alpha)-3,6,7-Trihydroxycholan-24-oic acid Natural products OC1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DKPMWHFRUGMUKF-UHFFFAOYSA-N 0.000 claims description 4
- JOYGXTIHTHBSOA-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-thiophen-2-ylprop-2-en-1-one Chemical compound C1=CC(Cl)=CC=C1C(=O)C=CC1=CC=CS1 JOYGXTIHTHBSOA-UHFFFAOYSA-N 0.000 claims description 4
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 4
- 229960003964 deoxycholic acid Drugs 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 229940083608 sodium hydroxide Drugs 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract description 12
- 238000011068 loading method Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 239000000787 lecithin Substances 0.000 abstract description 3
- 235000010445 lecithin Nutrition 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 abstract description 2
- 238000005352 clarification Methods 0.000 abstract description 2
- 229940121657 clinical drug Drugs 0.000 abstract description 2
- 229940067606 lecithin Drugs 0.000 abstract description 2
- 239000002052 molecular layer Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229940099352 cholate Drugs 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 10
- 238000011049 filling Methods 0.000 description 8
- 238000002834 transmittance Methods 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 239000000839 emulsion Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 239000002895 emetic Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 229940100691 oral capsule Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002812 cholic acid derivative Substances 0.000 description 1
- 150000001842 cholic acids Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- 230000007433 nerve pathway Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical group 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides aprepitant mixed micelle injection, and a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The cholate/lecithin mixed micelle system constructed by adopting specific cholic acid and phospholipid has good stability, can be well compatible with aprepitant so as to well encapsulate the aprepitant, can obviously improve the solubility of the aprepitant, and has higher safety under the condition of ensuring the stability of the aprepitant, thereby greatly improving the bioavailability of the aprepitant. The invention adopts a shearing dispersion method to prepare the mixed micelle, and the damage and shearing of a molecular layer are realized on raw and auxiliary materials, so that the mixed micelle with high drug loading capacity, clarification and good stability on aprepitant is formed, and the mixed micelle has better physical and chemical stability, so that the quality of the drug is easier to control, the process is simpler, the clinical drug is safer, the cost is lower, and the accessibility of the drug is improved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to aprepitant mixed micelle injection, and a preparation method and application thereof.
Background
Chemotherapy-induced nausea and vomiting (CINV) are the most common adverse reactions in chemotherapy in tumor patients, and aprepitant, which is a emetic agent that is mature in clinical application, can maintain central activity for a long period of time, inhibit acute and delayed vomiting associated with emetic chemotherapy, and increase the activity of standard antiemetic treatment against chemotherapy-induced vomiting, unlike other emetic nerve pathways. However, aprepitant has low solubility and poor absorption, the solubility in water is only 0.55 mug/mL, the gastrointestinal tract absorption is small, the oral bioavailability is low, and the aprepitant is a main factor for restricting the drug effect of the aprepitant to be exerted. At present, aprepitant is mainly an oral capsule preparation, but the preparation of injection emulsion is also appeared in recent years due to the low bioavailability of the oral capsule so as to improve the bioavailability.
In the case of oral formulations, there are mainly several ways to improve the bioavailability of aprepitant: 1. aprepitant is made into a solid dispersion, for example, chinese patents CN102525879 and CN102525880 make aprepitant and a water-soluble polymer such as copovidone into a solid dispersion; 2. preparing aprepitant into nano solid suspension or capsule, pulverizing or micronizing the active ingredient into nano preparation such as Chinese patent CN104586814, CN103251556 or CN107260705, or encapsulating aprepitant into nano crystal lipid microcapsule such as Chinese patent CN105456228; 3. the aprepitant and monosaccharide are formed into nano eutectic compound and then spray dried, such as Chinese patent CN104367551.
However, the bioavailability of the aprepitant oral preparation is still not ideal, so that the aprepitant intravenous injection emulsion is developed in recent years, the bioavailability is further improved, for example, WO2016/044784, CN102379845, WO2013177501, CN109432002, CN109010272 and CN101439018A all disclose the preparation process of the aprepitant microemulsion for injection, and most of the aprepitant microemulsion for injection is prepared by adopting soybean oil, ethyl oleate and the like for injection as oil phases, phospholipid as an emulsifier and sodium oleate as a co-emulsion. Due to poor solubility and poor permeability of aprepitant, regulations require that the average droplet size of the pellets in the injectable emulsion should not exceed 500nm or 0.5 μm, and that the weighted percentage of fat pellets volume (PFAT 5) greater than 5 μm should not exceed 0.05%, while the emulsion is thermodynamically unstable, with the increase in droplet size and aggregation leading to demulsification over time. In addition, possible chemical degradation in parenteral fat emulsions involves oxidation of unsaturated fatty acid residues present in triglycerides and lecithins, and phospholipid hydrolysis leading to the formation of free fatty acids and lysophospholipids, thus presenting a problem of chemical instability. Therefore, the preparation of the aprepitant intravenous injection emulsion is difficult, the cost is high, the use and the storage are extremely inconvenient, and the safety of the medicine is not easy to control.
Chinese patent CN110934829a discloses an aprepitant nano-micelle preparation comprising aprepitant, a phospholipid, sucrose, ethanol and water for injection, wherein the phospholipid comprises phosphatidylcholine and phosphatidylglycerol. The injection of the invention has better physical and chemical stability, safer clinical administration and improved accessibility of medicine. However, the dosage of the auxiliary materials of the preparation is large, the ethanol which is an organic solvent is used, a high-pressure homogenizer is needed, and the homogenization is carried out under the pressure of more than 1200bar, so that the cost of the product is high, and the application has a certain limitation.
Disclosure of Invention
The invention aims to provide aprepitant mixed micelle injection, a preparation method and application thereof, and the aprepitant mixed micelle injection can improve solubility and oral bioavailability of aprepitant.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an aprepitant mixed micelle injection, which is prepared from the following raw materials of aprepitant, phospholipid, cholic acid, sodium hydroxide and water for injection;
the phospholipid comprises soybean lecithin and/or egg yolk lecithin;
the cholic acid comprises one or two of glycocholic acid, deoxycholic acid and hyocholic acid;
the mass ratio of the phospholipid to the aprepitant is 4-15:1;
the mass ratio of the cholic acid to aprepitant is 3-12:1;
the mass ratio of the sodium hydroxide to the aprepitant is 0.1-1:1;
the aprepitant content in the aprepitant mixed micelle injection is more than or equal to 98wt%;
the preparation method of the aprepitant mixed micelle injection comprises the following steps:
mixing sodium hydroxide, water for injection and cholic acid under the protection of nitrogen, and carrying out neutralization reaction to obtain sodium cholate solution;
mixing the sodium cholate solution with phospholipid, and emulsifying to obtain mixed micelle solution;
mixing the mixed micelle solution with aprepitant, and performing shearing dispersion to obtain the aprepitant mixed micelle solution;
and regulating the pH value of the aprepitant mixed micelle solution to 7.5-9.5, and sterilizing to obtain the aprepitant mixed micelle injection.
Preferably, the mass ratio of the cholic acid to aprepitant is 5-10:1.
Preferably, the mass ratio of the phospholipid to aprepitant is 5-12:1.
Preferably, the mass ratio of the sodium hydroxide to the aprepitant is 0.2-0.8:1.
The invention provides a preparation method of aprepitant mixed micelle injection, which comprises the following steps:
mixing sodium hydroxide, water for injection and cholic acid under the protection of nitrogen, and carrying out neutralization reaction to obtain sodium cholate solution;
mixing the sodium cholate solution with phospholipid, and emulsifying to obtain mixed micelle solution;
mixing the mixed micelle solution with aprepitant, and performing shearing dispersion to obtain the aprepitant mixed micelle solution;
and regulating the pH value of the aprepitant mixed micelle solution to 7.5-9.5, and sterilizing to obtain the aprepitant mixed micelle injection.
Preferably, the neutralization reaction is carried out at a temperature of 50-60 ℃ for 10min.
Preferably, the temperature of the emulsification is 60-70 ℃ and the time is 60min, the emulsification is performed under the high-speed shearing condition, and the rotating speed of the high-speed shearing is 10000rpm.
Preferably, the rotation speed of the shearing dispersion is 10000rpm, the temperature is 60-70 ℃ and the time is 120min.
Preferably, the reagent used for adjusting the pH value of the aprepitant mixed micelle solution is hydrochloric acid solution.
The invention provides an aprepitant mixed micelle injection or an application of the aprepitant mixed micelle injection prepared by the preparation method in the technical scheme in preparation of aprepitant medicaments.
In the aprepitant mixed micelle injection provided by the invention, a bile salt/lecithin mixed micelle system constructed by specific cholic acid and phospholipid is adopted, and the specific cholic acid and the phospholipid are compounded with aprepitant, so that the aprepitant mixed micelle injection has good stability, can be well compatible with aprepitant to encapsulate the aprepitant, can obviously improve the solubility of the aprepitant, has higher safety under the condition of ensuring the stability of the aprepitant, and further greatly improves the bioavailability of the aprepitant.
The aprepitant mixed micelle injection is clear liquid, the light transmittance is not lower than 80%, and the adverse reaction of the medicine in clinical use can be effectively reduced without using organic solvents such as ethanol and the like.
According to the invention, the mixed micelle is prepared by adopting a shearing dispersion method, and the damage and shearing of a molecular layer are realized on raw and auxiliary materials, so that the mixed micelle with high drug loading capacity, clarification and good stability on aprepitant is formed, so that the injection has better physical and chemical stability, the quality of the drug is easier to control, the clinical drug is safer, the cost is lower, and the accessibility of the drug is improved.
The aprepitant mixed micelle injection can be subjected to terminal sterilization, the sterility assurance level is improved, and the sterilization filter process is safer than a sterilization filter process adopted by commercial aprepitant injection products.
The preparation method disclosed by the invention is simple in process, suitable for industrial production, capable of reducing cost and improving accessibility of medicines, and has guiding significance for industrial application.
Detailed Description
The invention provides an aprepitant mixed micelle injection, which is prepared from the following raw materials of aprepitant, phospholipid, cholic acid, sodium hydroxide and water for injection;
the phospholipid comprises soybean lecithin and/or egg yolk lecithin;
the cholic acid comprises one or two of glycocholic acid, deoxycholic acid and hyocholic acid;
the mass ratio of the phospholipid to the aprepitant is 4-15:1;
the mass ratio of the cholic acid to aprepitant is 3-12:1;
the mass ratio of the sodium hydroxide to the aprepitant is 0.1-1:1;
the aprepitant content in the aprepitant mixed micelle injection is more than or equal to 98wt%;
the preparation method of the aprepitant mixed micelle injection comprises the following steps:
mixing sodium hydroxide, water for injection and cholic acid under the protection of nitrogen, and carrying out neutralization reaction to obtain sodium cholate solution;
mixing the sodium cholate solution with phospholipid, and emulsifying to obtain mixed micelle solution;
mixing the mixed micelle solution with aprepitant, and performing shearing dispersion to obtain the aprepitant mixed micelle solution;
and regulating the pH value of the aprepitant mixed micelle solution to 7.5-9.5, and sterilizing to obtain the aprepitant mixed micelle injection.
In the present invention, the cholic acid includes one or two of glycocholic acid, deoxycholic acid and hyocholic acid, preferably glycocholic acid; when the cholic acid is two of the above, the ratio of the two cholic acids is not particularly limited, and any ratio can be used.
In the invention, the mass ratio of the cholic acid to the aprepitant is 3-12:1, preferably 5-10:1, and more preferably 6-8:1.
In the present invention, the phospholipid comprises soybean lecithin and/or egg yolk lecithin, preferably soybean lecithin; when the phospholipid is soybean lecithin and egg yolk lecithin, the ratio of the soybean lecithin to the egg yolk lecithin is not particularly limited, and any ratio can be used.
In the invention, the mass ratio of the phospholipid to the aprepitant is 4-15:1, preferably 5-12:1, and more preferably 8-10:1.
In the invention, the mass ratio of the sodium hydroxide to the aprepitant is 0.1-1:1, preferably 0.2-0.8:1, and more preferably 0.25-0.5:1.
In the invention, the amount of the water for injection is preferably such that the aprepitant content in the aprepitant mixed micelle injection is more than or equal to 98wt%, and the drug loading rate (the concentration of the aprepitant in the injection) of the aprepitant mixed micelle injection is 1-10 mg/mL, more preferably 2-6 mg/mL.
The aprepitant mixed micelle injection disclosed by the invention is amber clear liquid, which shows that aprepitant can be encapsulated by 100%.
The invention provides a preparation method of aprepitant mixed micelle injection, which comprises the following steps:
mixing sodium hydroxide, water for injection and cholic acid under the protection of nitrogen, and carrying out neutralization reaction to obtain sodium cholate solution;
mixing the sodium cholate solution with phospholipid, and emulsifying to obtain mixed micelle solution;
mixing the mixed micelle solution with aprepitant, and performing shearing dispersion to obtain the aprepitant mixed micelle solution;
and regulating the pH value of the aprepitant mixed micelle solution to 7.5-9.5, and sterilizing to obtain the aprepitant mixed micelle injection.
All preparation steps of the aprepitant mixed micelle injection disclosed by the invention are carried out under the protection of nitrogen.
The sodium hydroxide is preferably added into water for injection, heated to the temperature of neutralization reaction under stirring, dissolved, then added with cholic acid, and neutralized under stirring to obtain sodium cholate solution. The stirring is not particularly limited in the present invention, and the reaction is ensured to proceed smoothly according to a process well known in the art.
In the present invention, the temperature of the neutralization reaction is preferably 50 to 60 ℃, more preferably 55 ℃; the time is preferably 10 minutes.
The invention is preferably heated to the emulsification temperature under the high-speed shearing condition, and phospholipid is added into sodium cholate solution for emulsification; the temperature of the emulsification is preferably 60-70 ℃, more preferably 65 ℃; the time is preferably 60min, the emulsification is performed under high-speed shearing conditions, and the rotating speed of the high-speed shearing is preferably 10000rpm; the emulsification is preferably carried out in a high shear dispersing emulsifier.
Preferably, the aprepitant is added into the mixed micelle solution under the high-speed shearing condition and heated to the shearing and dispersing temperature; the rotation speed of the shearing dispersion is preferably 10000rpm, the temperature is preferably 60-70 ℃, and more preferably 65 ℃; the time is preferably 120min.
In the invention, the reagent used for adjusting the pH value of the aprepitant mixed micelle solution is preferably hydrochloric acid solution, and the mass concentration of the hydrochloric acid solution is preferably 3wt%; the pH is preferably adjusted to 8.5.
After the pH value is regulated to 7.5-9.5, the invention preferably adopts a 0.22 mu m filter membrane (PES) for filtration, nitrogen filling and filling, the residual oxygen content of the headspace in the bottle is controlled to be less than or equal to 5 percent, and sterilization is carried out, thus obtaining the aprepitant mixed micelle injection.
The invention provides an aprepitant mixed micelle injection or an application of the aprepitant mixed micelle injection prepared by the preparation method in the technical scheme in preparation of aprepitant medicaments. The application method of the aprepitant mixed micelle injection is not particularly limited, and the aprepitant mixed micelle injection can be applied according to methods well known in the art.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The aprepitant mixed micelle injection provided by the embodiment is prepared from the following components:
aprepitant 10.0g, glycocholic acid 60.0g, soybean lecithin 80.0g, sodium hydroxide 5.0g and water for injection 845.0g;
the preparation process is carried out under the protection of nitrogen filling:
weighing 5.0g of sodium hydroxide, adding 845g of water for injection, heating to 55 ℃ under magnetic stirring, adding 60.0g of glycocholic acid after the sodium hydroxide is dissolved, continuously stirring until the glycocholic acid is completely dissolved, and neutralizing for 10min to form a sodium glycocholate solution;
starting a high-shear dispersing emulsifying machine, heating to 65 ℃ under the high-shear condition of 10000rpm, adding 80.0g of phospholipid into glycocholate solution, and emulsifying for 60min to form mixed micelle solution;
continuously maintaining the temperature at 65 ℃ under the high-speed shearing condition of 10000rpm, slowly adding 10.0g of aprepitant into the mixed micelle solution, and shearing and dispersing for 120min to form the aprepitant mixed micelle solution;
adjusting the pH value of the aprepitant mixed micelle solution to 8.5 by using a 3wt% hydrochloric acid solution, filtering the obtained mixed micelle by using a 0.22 mu m filter membrane (PES), filling nitrogen, controlling the residual oxygen content in the headspace of a bottle to be less than or equal to 5%, and sterilizing to obtain the aprepitant mixed micelle injection, wherein the drug loading rate is 10mg/mL, and the aprepitant content is 99.2%.
Example 2
The aprepitant mixed micelle injection provided by the embodiment is prepared from the following components:
aprepitant 2.0g, glycocholic acid 6.0g, soybean lecithin 10.0g, sodium hydroxide 0.5g and water for injection 981.5g;
the preparation process is carried out under the protection of nitrogen filling:
weighing 0.5g of sodium hydroxide, adding the sodium hydroxide into 981.5g of water for injection, heating to 55 ℃ under magnetic stirring, adding 6.0g of glycocholate after the sodium hydroxide is dissolved, continuously stirring until the glycocholate is completely dissolved, and neutralizing for 10min to form glycocholate solution;
starting a high-shear dispersing emulsifying machine, heating to 65 ℃ under the high-shear condition of 10000rpm, adding 10.0g of phospholipid into glycocholate solution, and emulsifying for 60min to form mixed micelle solution;
continuously maintaining the temperature at 65 ℃ under a high-speed shearing condition of 10000rpm, adding 2.0g of aprepitant into the mixed micelle solution, and carrying out shearing dispersion for 120min to form the aprepitant mixed micelle solution;
and (3) regulating the pH value of the solution to 7.5 by using a 3wt% hydrochloric acid solution, filtering the obtained mixed micelle through a 0.22 mu m filter membrane (PES), filling nitrogen, controlling the residual oxygen content in the headspace of the bottle to be less than or equal to 5%, and sterilizing to obtain the aprepitant mixed micelle injection, wherein the drug loading rate is 2mg/mL.
Example 3
The aprepitant mixed micelle injection is prepared from the following components:
aprepitant 6.0g, glycocholic acid 40.0g, soybean lecithin 50.0g, sodium hydroxide 2.0g and water for injection 902.0g;
the preparation process is carried out under the protection of nitrogen filling:
weighing 2.0g of sodium hydroxide, adding the sodium hydroxide into 902.0g of water for injection, heating to 55 ℃ under magnetic stirring, adding 40.0g of glycocholate after the sodium hydroxide is dissolved, continuously stirring until the glycocholate is completely dissolved, and neutralizing for 10min to form glycocholate solution;
starting a high-shear dispersing emulsifying machine, heating to 65 ℃ under the high-shear condition of 10000rpm, adding 50.0g of phospholipid into glycocholate solution, and emulsifying for 60min to form mixed micelle solution;
continuously maintaining the temperature at 65 ℃ under a high-speed shearing condition of 10000rpm, adding 6.0g of aprepitant into the mixed micelle solution, and carrying out shearing dispersion for 120min to form the aprepitant mixed micelle solution;
and (3) regulating the pH value of the solution to 9.5 by using a 3wt% hydrochloric acid solution, filtering the obtained mixed micelle through a 0.22 mu m filter membrane (PES), filling nitrogen, controlling the residual oxygen content in the headspace of the bottle to be less than or equal to 5%, and sterilizing to obtain the aprepitant mixed micelle injection, wherein the drug loading rate is 6mg/mL.
Test case
1) According to the general rule 0401 of the 2020 edition of Chinese pharmacopoeia, the transmittance of the aprepitant mixed micelle injection prepared in examples 1-3 is measured by an Shimadzu UV2600 ultraviolet-visible spectrophotometer, and the result shows that the injection in example 1 is amber clear liquid, the transmittance is 83.4%, and the headspace residual oxygen amount is 1.5%; the injection described in example 2 is a light amber clear liquid with a light transmittance of 90.5% and a headspace oxygen residue of 2.1%; the injection described in example 3 was an amber clear liquid with a light transmittance of 88.2% and a headspace oxygen residue of 1.8%.
2) Stability test: the drug stability of the aprepitant mixed micelle injection (the sample prepared in the example 1) provided by the invention is examined by adopting an acceleration experiment method, the prepared aprepitant preparation is placed in a stability test box with the temperature of 30+/-2 ℃, and the samples are respectively sampled once in the 0 th month, the 1 st month, the 2 nd month, the 3 rd month and the 6 th month, and the properties, the light transmittance, the pH value and the content of the sample are checked on schedule, so that the results are shown in Table 1.
TABLE 1 example 1 accelerated stability test results of aprepitant Mixed micelle injection
| Time | Traits (3) | Transmittance of light | pH value of | Aprepitant content |
| 0 month | Amber clear liquid | 83.4％ | 8.5 | 99.2wt％ |
| 1 month | Amber clear liquid without crystallization and precipitation | 82.1％ | 8.3 | 100.2wt％ |
| 2 months of | Amber clear liquid without crystallization and precipitation | 82.3％ | 8.5 | 99.8wt％ |
| 3 months of | Amber clear liquid without crystallization and precipitation | 83.1％ | 8.6 | 99.9wt％ |
| 6 months of | Amber clear liquid without crystallization and precipitation | 81.7％ | 8.4 | 100.3wt％ |
The results in table 1 show that: at the temperature of 30+/-2 ℃, the aprepitant mixed micelle injection provided by the invention has the advantages that the appearance of no crystallization or precipitation phenomenon exists for 6 months, the characteristics are clear, the micelle system in the injection is well compatible with aprepitant, the light transmittance, the pH value and the content measurement result are relatively stable, and the requirements of medicine quality control are met.
The aprepitant mixed micelle injection provided by the invention accelerates for 6 months at the temperature of 30 ℃, has better stability, and shows that the aprepitant mixed micelle injection can be stored at the temperature of 2-8 ℃ and has the effective period of not less than 2 years.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The aprepitant mixed micelle injection is characterized in that the preparation raw materials comprise aprepitant, phospholipid, cholic acid, sodium hydroxide and water for injection;
the phospholipid comprises soybean lecithin and/or egg yolk lecithin;
the cholic acid comprises one or two of glycocholic acid, deoxycholic acid and hyocholic acid;
the mass ratio of the phospholipid to the aprepitant is 4-15:1;
the mass ratio of the cholic acid to aprepitant is 3-12:1;
the mass ratio of the sodium hydroxide to the aprepitant is 0.1-1:1;
the aprepitant content in the aprepitant mixed micelle injection is more than or equal to 98wt%;
the preparation method of the aprepitant mixed micelle injection comprises the following steps:
mixing sodium hydroxide, water for injection and cholic acid under the protection of nitrogen, and carrying out neutralization reaction to obtain sodium cholate solution;
mixing the sodium cholate solution with phospholipid, and emulsifying to obtain mixed micelle solution;
mixing the mixed micelle solution with aprepitant, and performing shearing dispersion to obtain the aprepitant mixed micelle solution;
and regulating the pH value of the aprepitant mixed micelle solution to 7.5-9.5, and sterilizing to obtain the aprepitant mixed micelle injection.
2. The aprepitant mixed micelle injection according to claim 1, wherein the mass ratio of cholic acid to aprepitant is 5-10:1.
3. The aprepitant mixed micelle injection according to claim 1, wherein the mass ratio of the phospholipid to the aprepitant is 5-12:1.
4. The aprepitant mixed micelle injection according to claim 1, wherein the mass ratio of sodium hydroxide to aprepitant is 0.2-0.8:1.
5. The preparation method of aprepitant mixed micelle injection according to any one of claims 1 to 4, which is characterized by comprising the following steps:
mixing sodium hydroxide, water for injection and cholic acid under the protection of nitrogen, and carrying out neutralization reaction to obtain sodium cholate solution;
mixing the sodium cholate solution with phospholipid, and emulsifying to obtain mixed micelle solution;
mixing the mixed micelle solution with aprepitant, and performing shearing dispersion to obtain the aprepitant mixed micelle solution;
and regulating the pH value of the aprepitant mixed micelle solution to 7.5-9.5, and sterilizing to obtain the aprepitant mixed micelle injection.
6. The method according to claim 5, wherein the neutralization reaction is carried out at a temperature of 50 to 60℃for a period of 10 minutes.
7. The method according to claim 5, wherein the emulsification is performed under high-speed shearing conditions at a rotational speed of 10000rpm at a temperature of 60 to 70 ℃ for 60 minutes.
8. The method according to claim 5, wherein the shearing dispersion is carried out at a rotation speed of 10000rpm, a temperature of 60 to 70℃and a time of 120 minutes.
9. The preparation method according to claim 5, wherein the reagent for adjusting the pH of the aprepitant mixed micelle solution is a hydrochloric acid solution.
10. The use of the aprepitant mixed micelle injection according to any one of claims 1 to 4 or the aprepitant mixed micelle injection prepared by the preparation method according to any one of claims 5 to 9 in the preparation of aprepitant medicaments.
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