CN108703950B - Emulsion injection of Lapiaptan - Google Patents

Emulsion injection of Lapiaptan Download PDF

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CN108703950B
CN108703950B CN201810979319.1A CN201810979319A CN108703950B CN 108703950 B CN108703950 B CN 108703950B CN 201810979319 A CN201810979319 A CN 201810979319A CN 108703950 B CN108703950 B CN 108703950B
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injection
emulsion
emulsion injection
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hydroxystearate
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CN108703950A (en
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曹亮
刘月华
秦嫚
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Fubicheng Shanghai Pharmaceutical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

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Abstract

The invention name is as follows: the invention relates to a Lapidan emulsion injection, which comprises Lapidan, medium-chain triglyceride, soybean oil, polyethylene glycol 15-hydroxystearate, poloxamer and water for injection, and does not comprise sodium oleate. The emulsion injection disclosed by the invention is good in compatibility with a packaging material of a polypropylene interface for a plastic infusion container, can effectively reduce the adsorption of the Laura, and can inhibit the migration of auxiliaries such as antioxidants in the packaging material to liquid medicine.

Description

Emulsion injection of Lapiaptan
Technical Field
The invention relates to an injection, in particular to an emulsion injection of rollepin.
Background
Chemotherapy-induced nausea and vomiting (CINV) are the most common adverse effects of chemotherapy in tumor patients, and severely affect the treatment of the disease. The risks of CINV generation are usually directly related to chemotherapeutic drugs, and the currently relevant guidelines all suggest that the emetic strength of chemotherapeutic drugs can be divided into 4 classes, high (cisplatin, mechlorethamine and cyclophosphamide, moderate (oxaliplatin, cytarabine, carboplatin, ifosfamide and anthracyclines), low (taxanes, etoposide, methotrexate and monoclonal antibodies) and very low (vinblastine, busulfan, fludarabine) emetic risk, it has been demonstrated that the combined use of a neurokinin-1 (NK 1) receptor blocker with a 5-hydroxytryptamine receptor blocker, a glucocorticoid drug such as dexamethasone, results in a significant reduction of the risk of CINV.
Latanin is approved by the United states Food and Drug Administration (FDA) to be marketed in 2015 9 months, is the latest long-acting and high-selectivity NK-1 receptor antagonist Latanin, has a half-life period as long as 180 h, and has more obvious advantages compared with other NK-1 receptor antagonists including aprepitant, such as selective combination with human NK-1 receptors, high affinity and the like; meanwhile, Lapidan is different from other NK-1 receptor antagonists (such as aprepitant and Netupidem), does not inhibit and induce CYP3A4, does not have potential risk when used together with medicines (such as midazolam, ondansetron and dexamethasone) which are mainly or partially metabolized by CYP3A4, and can effectively avoid interaction among the medicines.
The Lapitant is highly combined with human plasma protein, and the combination rate is as high as 99.8%. The apparent volume of distribution (Vd/F) of healthy subjects was 460L, indicating that Lapidan can be widely distributed in various tissues of the human body. In addition, rolipidem is metabolized primarily by CYP3a4, producing the active metabolite M19, a product of hydroxylation of CH2 at the C4 position of the pyrrolidine of rolipidem. Material balance studies have shown that M19 is the major metabolite in the circulation. M19 can delay the median tmax to 120 h (24-168 h), and t 1/2 has a mean value of 158 h. The ratio of the concentration of M19 to rubutan in plasma was about 50%. Lapatin is eliminated mainly by the hepatobiliary route. Single oral administration of 14C-Lapiaptan 180 mg, mean recovery of radioactive dose from urine and feces averaged 14.2% and 73%, respectively, over 6 weeks. Samples collected over 2 weeks were pooled and 8.3% of the dose recovered in urine was predominantly metabolite, while 37.8% of the dose recovered in feces was predominantly unchanged rollipitan. The roller-pentium prodrug or M19 was not found in pooled urine samples.
In an international multicenter clinical study, roller-triptan was used in combination with ondansetron and dexamethasone (treatment group) to prevent cisplatin-induced nausea and vomiting. The treatment group improved significantly at the end of treatment period 1 compared to ondansetron and dexamethasone alone (control). In another study, patients receiving treatment with anthraquinones in combination with cyclophosphamide were treated with rollepin in combination with granisetron and dexamethasone (treatment group) to prevent nausea and vomiting caused by anthraquinones in combination with cyclophosphamide. Complete remission rates at the end of treatment period 1, delayed phase treatment and control groups, compared to granisetron and dexamethasone (control) alone. In addition, studies show that the patient has the highest compliance and the lower incidence rate of adverse reactions in the antiemetic scheme combining rapitant, granisetron and dexamethasone, and the patient has relatively poor compliance in the antiemetic scheme combining aprepitant, granisetron and dexamethasone. Based on the advantages, the Lapidan provides a new and powerful treatment means for nausea and vomiting induced by chemotherapeutic drugs.
With the clinical application of Lapidan, partial adverse reactions are found, and the rapid allergic reaction, anaphylactic shock and other severe allergic reactions even requiring hospitalization of Lapidan during or after infusion have been reported in the post-marketing research. Most of the reactions occur within the first few minutes, with symptoms including wheezing or dyspnea, swelling of the face or throat, hives or flushing, itching, abdominal cramps, abdominal pain or vomiting, back or chest pain, hypotension or shock.
Therefore, the safety of the emulsion injection of the rollitan is gradually emphasized, and the inventor finds in the previous experimental study that the existing emulsion injection of the rollitan is relatively stable, but when a plastic packaging material is adopted, the quality is uneven due to different processes of the plastic packaging material, and the existing emulsion injection of the rollitan is poor in compatibility with the plastic packaging material. Because of the influence of plastic packaging materials, the injection emulsion after being packaged still can be permeated by water vapor and oxygen, water and volatile medicines are permeated out, fat-soluble medicines are transferred to plastics, and the plastics adsorb the medicines; the effect of solvent and plastic, the influence of additives and processing decomposition products in the plastic on the medicine, and the problems of migration of metal elements, particle change, sealing property and the like.
However, there are few reports on the preparation of a rubitan injection emulsion, and US2017216205 discloses a fat emulsion injection of NK-1 receptor antagonist, and specifically discloses the formulation and process of a rubitan injection emulsion, specifically comprising 0.728% of rubitan, 14.55% of lecithin, 9.7% of soybean oil, 1.2% of ethanol, 5.43% of sucrose, 0.485% of sodium oleate, and 67.9% of water for injection. However, the patent only discloses that the freshly prepared injection emulsion has excellent particle size, particle size distribution and compatibility stability with 0.9% physiological saline. WO2018094394 discloses a formulation of rolipids, in particular a non-covalent complex formulation comprising rolipids and human serum albumin. However, these reports do not address the potential effects that packaging materials may have, nor do they address any of the measures proposed. However, the potential safety problem of the emulsion for injection of rollipitan is to be solved.
Disclosure of Invention
In order to solve the technical problems, the invention provides the Lautitan emulsion injection which has excellent compatibility with plastic packaging materials and can improve the safety of clinical medication.
In order to realize the technical effects, the invention provides a Lautitan emulsion injection.
The Lapiaptan emulsion injection comprises Lapiaptan, medium chain triglyceride, soybean oil, polyethylene glycol 15-hydroxystearate, poloxamer and water for injection, and does not comprise sodium oleate.
The emulsion of the invention is an oil-in-water emulsion.
More preferably, the emulsion injection of the present invention does not comprise ethanol and propylene glycol.
Further, the emulsion injection of the invention further comprises sodium chloride and phosphoric acid.
The emulsion injection has small and uniform particle size distribution, stable distribution of emulsion droplets and difficult aggregation, and the preferable average particle size is 150-220nm, and the preferable average particle size is 180-210 nm; PDI is 0.15-0.20, preferably 0.16-0.18.
The medium chain triglycerides of the present invention are selected from one or more of caprylic triglyceride, capric triglyceride.
In order to prevent thermal oxidation degradation reaction, antioxidants are usually added to maintain the excellent properties of the polymer material, and most of the antioxidants are phenolic antioxidants and phosphorous antioxidants, and are mostly ester-based antioxidants, and in some cases, the antioxidants are hydrolyzed into corresponding acids and alcohols. Because the transfusion packaging material is in direct contact with the liquid medicine, the auxiliary agent and the degradation product of the auxiliary agent in the packaging material are likely to migrate into the liquid medicine to cause safety risks. To solve the above problems.
The invention further provides the composition of the emulsion injection, and the emulsion injection comprises 0.1-3% of rollitan, 1-2% of medium-chain triglyceride, 0.2-1% of soybean oil, 4-10% of polyethylene glycol 15-hydroxystearate, 0.1-0.4% of poloxamer and 80-96% of water for injection, based on the total mass of the emulsion injection.
The emulsion injection of the invention also comprises 0.1 to 0.3 percent of phosphoric acid and 0.4 to 0.9 percent of sodium chloride.
The invention further provides a preparation method of the emulsion injection, which comprises the following steps:
heating, mixing and stirring the Laitaptan, the polyethylene glycol 15-hydroxystearate, the refined soybean oil and the medium chain triglyceride to prepare an oil phase; then stirring and mixing phosphoric acid, sodium chloride and poloxamer 188 with water for injection at room temperature to prepare a water phase; adding the water phase into the oil phase, homogenizing at high speed to obtain coarse emulsion, and homogenizing at high pressure with high pressure microfluidizer to obtain Laura emulsion injection
The invention has the technical effects that:
1. the emulsion injection disclosed by the invention is good in compatibility with a packaging material of a polypropylene interface for a plastic infusion container, and can effectively reduce the adsorption of the rollitan;
2. the fat emulsion injection can effectively reduce the migration of antioxidants in a plastic infusion container and improve the medication safety of medicines.
Detailed Description
Example 1:
the Lapidan emulsion injection comprises the following components:
lapiaptan 0.18 g;
medium chain triglycerides 1.2 g;
0.4g of refined soybean oil;
5g of polyethylene glycol 15-hydroxystearate;
0.25g of phosphoric acid;
0.6g of sodium chloride;
poloxamer 1880.3 g
94g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Laitaptan, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium chain triglyceride at 50 ℃ and 250rpm for 25 minutes to obtain an oil phase; then stirring and mixing phosphoric acid, sodium chloride and poloxamer 188 with water for injection at room temperature at 350rpm for 20 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 25000rpm for 1 minute to obtain coarse emulsion, and homogenizing for 6 times at high pressure by using a high-pressure microfluidizer to obtain Larvatan emulsion injection.
Example 2:
the Lapidan emulsion injection comprises the following components:
0.2g of Lapiantan;
medium chain triglycerides 1.5 g;
0.5g of refined soybean oil;
6g of polyethylene glycol 15-hydroxystearate;
0.2g of phosphoric acid;
0.5g of sodium chloride;
poloxamer 1880.5 g
90g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Laitaptan, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium chain triglyceride at 60 ℃ and 200rpm for 20 minutes to obtain an oil phase; then stirring and mixing phosphoric acid, sodium chloride and poloxamer 188 with water for injection at room temperature at 400rpm for 20 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 20000rpm for 2 min to obtain coarse emulsion, and homogenizing for 6 times under high pressure by using a high pressure microfluidizer to obtain Larvatan emulsion injection.
Example 3:
the Lapidan emulsion injection comprises the following components:
0.2g of Lapiantan;
medium chain triglycerides 1.5 g;
0.5g of refined soybean oil;
6g of polyethylene glycol 15-hydroxystearate;
0.2g of phosphoric acid;
poloxamer 1880.6 g
91g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Laitaptan, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium chain triglyceride at 55 ℃ and 200rpm for 20 minutes to prepare an oil phase; then stirring and mixing phosphoric acid and poloxamer 188 with water for injection at room temperature at 400rpm for 15 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 22000rpm for 1 minute to obtain coarse emulsion, and homogenizing for 6 times at high pressure by using a high-pressure microfluidizer to obtain Lazopentan emulsion injection.
Example 4:
the Lapidan emulsion injection comprises the following components:
0.2g of Lapiantan;
medium chain triglycerides 2.5 g;
0.6g of refined soybean oil;
4g of polyethylene glycol 15-hydroxystearate;
0.25g of phosphoric acid;
0.5g of sodium chloride;
poloxamer 1880.5 g
92g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Laitaptan, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium chain triglyceride at 60 ℃ and 200rpm for 20 minutes to obtain an oil phase; then stirring and mixing phosphoric acid, sodium chloride and poloxamer 188 with water for injection at room temperature at 400rpm for 20 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 20000rpm for 2 min to obtain coarse emulsion, and homogenizing for 6 times under high pressure by using a high pressure microfluidizer to obtain Larvatan emulsion injection.
Example 5:
the Lapidan emulsion injection comprises the following components:
0.2g of Lapiantan;
medium chain triglycerides 2.5 g;
0.6g of refined soybean oil;
4g of polyethylene glycol 15-hydroxystearate;
0.25g of phosphoric acid;
2g of cane sugar;
poloxamer 1880.5 g
92g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Laitaptan, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium chain triglyceride at 60 ℃ and 200rpm for 20 minutes to obtain an oil phase; then stirring and mixing phosphoric acid, sucrose and poloxamer 188 with water for injection at room temperature at 400rpm for 20 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 20000rpm for 2 min to obtain coarse emulsion, and homogenizing for 6 times under high pressure by using a high pressure microfluidizer to obtain Larvatan emulsion injection.
Example 6:
the Lapidan emulsion injection comprises the following components:
lapiaptan 0.18 g;
medium chain triglycerides 1.2 g;
0.4g of refined soybean oil;
5g of polyethylene glycol 15-hydroxystearate;
0.3g of sodium dihydrogen phosphate;
0.6g of sodium chloride;
94g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Laitaptan, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium chain triglyceride at 50 ℃ and 250rpm for 25 minutes to obtain an oil phase; then stirring and mixing sodium dihydrogen phosphate and sodium chloride with water for injection at room temperature at 350rpm for 20 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 25000rpm for 1 minute to obtain coarse emulsion, and homogenizing for 6 times at high pressure by using a high-pressure microfluidizer to obtain Larvatan emulsion injection.
Example 7:
the Lapidan emulsion injection comprises the following components:
lapiaptan 0.18 g;
medium chain triglycerides 1.2 g;
0.4g of refined soybean oil;
5g of polyethylene glycol 15-hydroxystearate;
0.25g of phosphoric acid;
0.6g of sodium chloride;
sodium oleate 0.3g
94g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Laitaptan, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium chain triglyceride at 50 ℃ and 250rpm for 25 minutes to obtain an oil phase; then stirring and mixing phosphoric acid, sodium chloride and poloxamer 188 with water for injection at room temperature at 350rpm for 20 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 25000rpm for 1 minute to obtain coarse emulsion, and homogenizing for 6 times at high pressure by using a high-pressure microfluidizer to obtain Larvatan emulsion injection.
Comparative example 1:
the Lapidan fat emulsion injection comprises the following components:
1.08g of Lapiaptan;
21.6g of egg yolk lecithin;
1.8g of ethanol;
14.5g of refined soybean oil;
7g of sucrose;
0.8g of sodium oleate;
100g of water for injection.
The preparation method comprises the following steps:
heating, mixing and stirring Lapalutan, egg yolk lecithin (LIPOID E80) and ethanol at 55 deg.C and 250rpm for 20 min, adding refined soybean oil into the above solution, and stirring for 25 min to obtain oil phase; then stirring and mixing sucrose and sodium oleate with water for injection at room temperature at 350rpm for 20 minutes to prepare a water phase; and adding the water phase into the oil phase, homogenizing at 25000rpm for 1 minute to obtain coarse emulsion, and homogenizing for 6 times at high pressure by using a high-pressure microfluidizer to obtain the Lapiantan fat emulsion injection.
Experimental example 1:
emulsion quality evaluation experiment: examples 1-3, 6-7 and comparative example 1 were each measured
Particle size and distribution: the emulsion particle distribution was evaluated by measuring the average particle diameter and PDI of the particles by dynamic light scattering.
Zeta potential: the zeta potential of the emulsion droplet particles was measured using laser doppler microelectrophoresis.
TABLE 1 Laura emulsion injection
Sample (I) Average particle diameter/nm PDI Zeta potential/mV
Example 1 203.1±3.5 0.164 -51.3
Example 2 199.7±2.8 0.153 -49.8
Example 3 207.3±2.3 0.161 -50.1
Example 6 214.7±5.3 0.198 -41.4
Example 7 218.3±4.6 0.186 -42.1
Comparative example 1 205.7±3.7 0.184 -46.3
The above results indicate that the emulsion for injection prepared in the examples of the present invention is equivalent to the existing emulsion for injection made of rollitan in terms of average particle size, uniformity of particle size distribution, charge stability, etc., and thus, the emulsion for injection prepared in the present invention has excellent quality stability.
Experimental example 2:
drug adsorption rate experiments: the injection emulsions prepared in examples 1 to 3 and 6 to 7 and comparative example 1 were poured into the packaging material of the polypropylene port of the plastic infusion container, respectively, and placed upside down at 4 ℃ and 60 ℃ for 10 days, respectively, and the adsorption rate of the packaging material to the drug was calculated by comparing the content results of the samples measured at 4 ℃ and 60 ℃. If the result of the adsorption rate of the packing material to the medicine is below 2 percent, the result generally falls within the measurement error range, which indicates that the packing material has no adsorption effect on the medicine basically.
TABLE 2 experimental results of drug adsorption rates
Sample (I) 4 days 6 days 8 days 10 days
Example 1 0.9% 1.5% 2.0% 2.2%
Example 2 1.1% 1.4% 1.9% 2.3%
Example 3 0.8% 1.6% 1.8% 2.0%
Example 6 1.2% 2.1% 2.8% 3.6%
Example 7 1.3% 2.2% 3.0% 4.1%
Comparative example 1 0.9% 1.8% 2.6% 4.1%
The experimental results show that the packaging material of the polypropylene interface for the plastic infusion container has small adsorption effect on the Laitan in the injection emulsion, the injection emulsion containing poloxamer can effectively reduce drug adsorption, and the existing emulsion is difficult to effectively inhibit the adsorption of the packaging material on the drugs.
Experimental example 3:
migration experiment of antioxidant to liquid medicine in plastic infusion packaging material:
in order to prevent thermal oxidation degradation reaction, antioxidants are usually added to the polymer material for transfusion packaging at present to maintain the excellent performance of the polymer material, and most of the antioxidants are phenolic antioxidants and phosphorous antioxidants, and are mostly ester structures, and in some cases, the antioxidants can be hydrolyzed into corresponding acids and alcohols. Because the infusion packaging material is in direct contact with the liquid medicine, the auxiliary agents and the degradation products of the auxiliary agents in the packaging material are likely to migrate into the liquid medicine to cause safety risks, and therefore, how to inhibit the migration and degradation of the auxiliary agents also provides challenges for the screening of the injection emulsion prescription. The invention takes the degradation product 3, 5-di-tert-butyl-4-hydroxy phenylpropionic acid as an index to investigate the migration condition of the antioxidant in the liquid medicine in the packaging material. The samples of examples 1 to 3, 6 to 7 and comparative example 1 were each filled into a packaging material of a polypropylene port for a plastic infusion container, and left at room temperature for 3 months, and the content in the drug solution was measured by high performance liquid chromatography.
TABLE 3 migration experiment of antioxidant degradation products to medical solution in plastic infusion packaging material
Sample (I) 1 month 2 month 3 month
Example 1 Not detected Not detected Not detected
Example 2 Not detected Not detected Not detected
Example 3 Not detected Not detected Not detected
Example 6 Not detected 0.012% 0.021%
Example 7 Not detected 0.011% 0.028%
Comparative example 1 Not detected 0.013% 0.032%
In the above experiments, the inventors found that the injection emulsion of the present invention can effectively reduce the migration of the antioxidant, and the inventors also carried out other prescription experiments, and none of them had good inhibition on the migration of the antioxidant, and the mechanism of how to inhibit the antioxidant by the injection emulsion of the present invention still needs to be further studied.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full scope of the invention.

Claims (3)

1. The application of a rollitan emulsion injection in preparing a medicament for reducing antioxidant migration in a plastic infusion container is characterized in that the rollitan emulsion injection consists of 0.1-3% of rollitan, 1-2% of medium-chain triglyceride, 0.2-1% of soybean oil, 4-10% of polyethylene glycol 15-hydroxystearate, 0.1-0.4% of poloxamer medium-chain 188, 0.1-0.3% of phosphoric acid, 0.4-0.9% of sodium chloride and 80-96% of water for injection, wherein the triglyceride is selected from one or more of caprylic triglyceride and capric triglyceride.
2. The use as claimed in claim 1, wherein the average particle size of the emulsion injection is 150-220 nm; PDI is 0.15-0.20.
3. The use as claimed in claim 1, wherein the emulsion injection has an average particle size of 180-210nm and PDI of 0.16-0.18.
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CN109394693A (en) * 2018-12-25 2019-03-01 广州白云山汉方现代药业有限公司 A kind of smooth emulsion of roller and its preparation method and application
CN109453115A (en) * 2018-12-25 2019-03-12 广州白云山汉方现代药业有限公司 A kind of smooth intravenous injection emulsion of roller and its preparation method and application
CN110368363B (en) * 2019-08-22 2021-10-15 北京诺康达医药科技股份有限公司 Aprepitant fat emulsion injection and preparation method thereof

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CN105503870A (en) * 2009-08-14 2016-04-20 欧科生医股份有限公司 Intravenous formulations of neurokinin-1 antagonists
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