CN111514100A - Aprepitant injection - Google Patents

Aprepitant injection Download PDF

Info

Publication number
CN111514100A
CN111514100A CN201910104324.2A CN201910104324A CN111514100A CN 111514100 A CN111514100 A CN 111514100A CN 201910104324 A CN201910104324 A CN 201910104324A CN 111514100 A CN111514100 A CN 111514100A
Authority
CN
China
Prior art keywords
aprepitant
injection
phosphatidylethanolamine
phospholipid
ethanol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201910104324.2A
Other languages
Chinese (zh)
Inventor
林静文
其他发明人请求不公开姓名
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Landan Pharmaceutical Technology Co ltd
Original Assignee
Beijing Landan Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Landan Pharmaceutical Technology Co ltd filed Critical Beijing Landan Pharmaceutical Technology Co ltd
Priority to CN201910104324.2A priority Critical patent/CN111514100A/en
Publication of CN111514100A publication Critical patent/CN111514100A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides an aprepitant injection which contains aprepitant, phospholipid, ethanol, oil for injection and water for injection. The phospholipid contains phosphatidylcholine and phosphatidylethanolamine, wherein the phosphatidylcholine accounts for not less than 68% of the total weight of the phospholipid, and the phosphatidylethanolamine accounts for not more than 9% of the total weight of the phospholipid, preferably 3% -9%, and more preferably 6% -9%. Further, the weight ratio of ethanol to phosphatidylethanolamine is 1:1 to 7:1, preferably 1:1 to 5: 1. The aprepitant injection provided by the invention has good compatibility stability after long-term storage.

Description

Aprepitant injection
Technical Field
The invention relates to the technical field of medicaments, in particular to an aprepitant injection.
Background
Nausea and vomiting are among the more common adverse effects of current malignant patients after chemotherapy, and can be classified into acute, delayed and full-term according to the occurrence time. Untimely control of the symptoms will lead to a reduction in the quality of life of the patient and reduced treatment compliance. The NK-1 inhibitor is widely applied to the treatment of nausea and vomiting in chemotherapy at present, and has a remarkable curative effect. Aprepitant is a representative drug in NK-1 inhibitors, blocks the action point of substance P by combining with NK-1 receptors, can occupy the NK-1 receptors in the brain through a blood brain barrier, has high selectivity and high affinity, has low affinity to NK-2 and NK-3 receptors, and has better nausea and vomiting reducing effect than other drugs.
Aprepitant oral preparation is approved by FDA in the United states and marketed in 2003, but due to poor water solubility and membrane permeability of aprepitant, the aprepitant oral preparation has poor oral absorption and low bioavailability. To ameliorate the deficiencies of oral formulations, Heron treatment developed aprepitant as a fat emulsion injection and obtained FDA approval for marketing in 2017.
Patent CN102379845A discloses an aprepitant microemulsion for injection and a preparation method thereof, which solves the problems of inconvenient clinical application, poor absorption, low bioavailability and the like of an aprepitant oral preparation and provides preparation methods of a small water injection, an infusion solution and a freeze-dried preparation of the aprepitant microemulsion.
Patent CN106852118A discloses an aprepitant emulsion containing 11% -15% of emulsifier, the ratio of oil to aprepitant is 10:1 to 15:1, the ratio of emulsifier to aprepitant is 15:1 to 30:1, and the ratio of emulsifier to oil is 1:1 to 3: 1. The aprepitant emulsion preparation provided by the aprepitant emulsion preparation can keep physical stability and chemical stability under certain storage conditions.
The American clinical tumor society takes aprepitant together with a 5-hydroxytryptamine 3(5-HT3) receptor antagonist and dexamethasone triple therapy as a recommended scheme, and the 2014 version of Chinese tumor treatment-related emesis prevention and treatment guideline released in China recommends that the triple scheme, namely aprepitant, a 5-HT3 antagonist and dexamethasone are combined to be used as a first-line treatment scheme for chemotherapy and antiemetic. In clinical use, aprepitant is often used simultaneously with a 5HT3 receptor antagonist and dexamethasone.
The aprepitant injection, the 5-HT3 receptor antagonist and dexamethasone are used in a compatible way, so that the liquid preparation step can be reduced, the possibility of drug contamination can be reduced, and the pain of clinical medication of patients can be greatly relieved. However, in the research of the preparation, not only the stability of each index of the preparation itself needs to be considered, but also the stability of the compatibility of the drug after long-term storage should be studied due to the complexity of clinical compatibility, so as to avoid the risk of clinical use. Therefore, the aprepitant injection provided by the application can still have good compatibility stability after long-term storage.
Disclosure of Invention
The invention provides an aprepitant injection with good compatibility stability after long-term storage.
In order to achieve the above object, the technical solution of the present invention is as follows:
the invention provides an aprepitant injection which contains aprepitant, phospholipid, ethanol, oil for injection and water for injection, wherein the phospholipid contains phosphatidylcholine and phosphatidylethanolamine, the phosphatidylcholine accounts for not less than 68% of the total weight of the phospholipid, and the phosphatidylethanolamine accounts for not more than 9% of the total weight of the phospholipid. When the aprepitant injection is compatible with 5-hydroxytryptamine antagonist and dexamethasone after being stored for 12 months, the content of aprepitant is not changed, PFAT5 is at a lower level, and the clinical safety is higher.
In the aprepitant injection, the phosphatidylethanolamine accounts for 3-9 wt% of the total amount of phospholipid.
In the aprepitant injection, the phosphatidylethanolamine accounts for 6-9 wt% of the total amount of phospholipid.
In the aprepitant injection, the weight percentage of the phosphatidylcholine in the total amount of the phospholipid is 72-85%.
In the aprepitant injection, the content of each component is as follows:
Figure BDA0001966338340000021
in the aprepitant injection, the weight ratio of the ethanol to the phosphatidylethanolamine is 1:1 to 7:1, preferably 1:1 to 5: 1.
In the aprepitant injection, the phospholipid is selected from natural phospholipid and salt thereof, synthetic or semisynthetic phospholipid and salt thereof or combination thereof. The natural phospholipid refers to phospholipid extracted from natural materials such as soybean and egg yolk.
In the aprepitant injection, the phosphatidylcholine is selected from natural phosphatidylcholine and salts thereof, synthetic or semi-synthetic phosphatidylcholine and salts thereof or any combination thereof; the synthetic or semi-synthetic phosphatidylcholine is selected from distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, didecanoylphosphatidylcholine, dilauroylphosphatidylcholine, erucylphosphatidylcholine, 1-stearoyl-2-oleoylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, 1-myristoyl-2-oleoylphosphatidylcholine, 1-stearoyl-2-palmitoylphosphatidylcholine, 1-stearoyl-2-myristoylphosphatidylcholine, 1-palmitoyl-2-stearoylphosphatidylcholine, 1-palmitoyl-2-myristoylphosphatidylcholine, 1-myristoyl-2-stearoyl phosphatidylcholine, 1-myristoyl-2-palmitoyl phosphatidylcholine, or a combination thereof.
In the aprepitant injection, the phosphatidylethanolamine is selected from natural phosphatidylethanolamine and salts thereof, synthetic or semi-synthetic phosphatidylethanolamine and salts thereof or any combination of the synthetic or semi-synthetic phosphatidylethanolamine and the salts thereof; the synthetic or semi-synthetic phosphatidylethanolamine is selected from distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, erucic phosphatidylethanolamine, dilauroyl phosphatidylethanolamine or a combination thereof.
The aprepitant injection further comprises a pH regulator, wherein the pH regulator is selected from sodium oleate, oleic acid, sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate or a combination thereof.
The aprepitant injection further comprises a tonicity adjusting agent, wherein the tonicity adjusting agent is selected from sucrose, sodium chloride, glycerol, glucose, mannitol, xylitol or a combination thereof.
In the aprepitant injection, the oil for injection is selected from soybean oil, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil, medium-chain monoglyceride, medium-chain diglyceride, medium-chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol diester, linoleic acid glyceride, polyethylene glycol lauric acid glyceride or a combination thereof.
The preparation method of the aprepitant injection comprises the following steps:
(1) taking aprepitant, phospholipid and ethanol, and heating to dissolve the aprepitant, the phospholipid and the ethanol;
(2) adding the mixture obtained in the step (1) into oil for injection, and heating and dissolving to obtain an oil phase;
(3) adding a tension regulator and a pH regulator into water for injection, and uniformly stirring to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Detailed Description
The amounts of ethanol in the comparative examples and examples of the present invention are the amounts of ethanol in the final product after considering the amount of ethanol evaporated in the preparation process.
Example 1
Composition (I) Dosage (g)
Aprepitant 7.2
Egg yolk lecithin 144
Soybean oil 94
Ethanol 30
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin was 80%, and the content of phosphatidylethanolamine was 3%. (the weight ratio of ethanol to phosphatidylethanolamine is 7:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Example 2
Figure BDA0001966338340000041
Figure BDA0001966338340000051
The content of phosphatidylcholine in the egg yolk lecithin is 80%, and the content of phosphatidylethanolamine is 6%. (the weight ratio of ethanol to phosphatidylethanolamine is 3.5:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Example 3
Composition (I) Dosage (g)
Aprepitant 7.2
Egg yolk lecithin 144
Soybean oil 94
Ethanol 30
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin was 80%, and the content of phosphatidylethanolamine was 7%. (the weight ratio of ethanol to phosphatidylethanolamine is 3:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Example 4
Composition (I) Dosage (g)
Aprepitant 7.2
Egg yolk lecithin 144
Soybean oil 94
Ethanol 30
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin was 80%, and the content of phosphatidylethanolamine was 9%. (the weight ratio of ethanol to phosphatidylethanolamine is 2.3:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Example 5
Composition (I) Dosage (g)
Aprepitant 7.2
Egg yolk lecithin 144
Soybean oil 94
Ethanol 30
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin was 80%, and the content of phosphatidylethanolamine was 2.1%. (the weight ratio of ethanol to phosphatidylethanolamine is 10:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Comparative example 1
Composition (I) Dosage (g)
Aprepitant 7.2
Egg yolk lecithin 144
Soybean oil 94
Ethanol 30
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin is 80%, and the content of phosphatidylethanolamine is 12%.
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Comparative example 2
Figure BDA0001966338340000071
Figure BDA0001966338340000081
The content of phosphatidylcholine in the egg yolk lecithin was 80%, and the content of phosphatidylethanolamine was 15%.
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Test example 1 compatibility stability study of aprepitant injection.
The aprepitant injections of examples 1 to 5 and comparative examples 1 to 2 were stored at 2 to 8 ℃ and subjected to compatibility examination at 0 month, 6 months and 12 months, respectively.
Stability test after compatibility with 5-HT3 antagonist injection and dexamethasone sodium phosphate injection
1 piece of ondansetron hydrochloride injection (specification: 4mg/2ml), dexamethasone sodium phosphate injection (specification: 5mg/1ml) and the aprepitant injection of examples 1-5 and comparative examples 1-2 are compatible, 0.9% sodium chloride injection is adopted as a diluent, and the dilution volume is 150 ml. After the solution is mixed evenly, the appearance, the average particle size, the PFAT5 and the content of aprepitant are respectively detected within 0h and 3 h.
The chemical stability of the compatible solution is detected by taking the content of aprepitant in the compatible solution at 0h as 100%, and the content of aprepitant in the compatible solution at 3h is detected to be equivalent to the percentage content of aprepitant at 0 h.
The amount of PFAT5 in the formulated sample was determined by reference to USP729 second method (photoresistance method).
Appearance 5ml of the above compatible solution was sampled at each time point and placed in a clean and transparent 10ml Zener's cuvette for observation.
The results are shown in the following table:
Figure BDA0001966338340000091
Figure BDA0001966338340000101
note: + indicates a stable and unchanged appearance. -means that particles are observed.
According to the detection results, the aprepitant injection prepared in the examples 1-4 has stable and unchanged appearance when being compatible with the ondansetron hydrochloride injection and the dexamethasone sodium phosphate injection after long-term storage, the content of aprepitant is not influenced, and the PFAT5 is at a lower level (lower than 0.05%); the aprepitant injection prepared in example 5 can keep stable after 0 month and 6 months of compatibility, and the increase of PFAT5 is large after 12 months of compatibility; the aprepitant injection of the comparative examples 1-2 can keep stable indexes such as residual rate, pH value, average particle size and the like when being combined for 0-12 months, but PFAT5 is obviously deteriorated in 6 months and PFAT5 is obviously over 0.05% in 12 months along with the increase of storage time, so that the combination stability is obviously deteriorated, and potential safety hazards are brought to clinical use.
Example 6
Composition (I) Content (g)
Aprepitant 7
Egg yolk lecithin 140
Soybean oil 50g
Medium chain triglycerides 50g
Ethanol 28
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin was 85%, and the content of phosphatidylethanolamine was 5%. (the weight ratio of ethanol to phosphatidylethanolamine is 4:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil and medium chain triglyceride, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Example 7
Composition (I) Content (g)
Aprepitant 7.5
Egg yolk lecithin 130
Olive oil 45
Medium chain triglycerides 45
Ethanol 10
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin was 86%, and the content of phosphatidylethanolamine was 7.5%. (the weight ratio of ethanol to phosphatidylethanolamine is 1:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into olive oil and medium-chain triglyceride, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Example 8
Composition (I) Content (g)
Aprepitant 8
Egg yolk lecithin 150
Soybean oil 95
Ethanol 40
Sucrose 55.6
Sodium oleate 5.5
Water for injection Adding to 1000ml
The content of phosphatidylcholine in the egg yolk lecithin was 72%, and the content of phosphatidylethanolamine was 8.5%. (the weight ratio of ethanol to phosphatidylethanolamine is 3:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into soybean oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
Example 9
Figure BDA0001966338340000121
Figure BDA0001966338340000131
The content of phosphatidylcholine in the egg yolk lecithin was 89%, and the content of phosphatidylethanolamine was 3%. (the weight ratio of ethanol to phosphatidylethanolamine is 5:1)
The preparation method comprises the following steps:
(1) taking aprepitant, egg yolk lecithin and ethanol, and heating to dissolve the aprepitant, the egg yolk lecithin and the ethanol;
(2) adding the mixture obtained in the step (1) into olive oil, and heating and dissolving to obtain an oil phase;
(3) adding sucrose and sodium oleate into water for injection, and stirring uniformly to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
When the samples prepared in examples 6-9 were formulated with ondansetron hydrochloride injection and dexamethasone sodium phosphate injection after 12 months of storage, the appearance, pH, mean particle size and aprepitant content remained stable, with PFAT5 at a lower level (less than 0.05%).
The foregoing has described in detail preferred embodiments of the present invention. However, the present invention is not limited to the specific details of the above-described embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the respective technical features described in the above embodiments may be combined in any manner without contradiction. The invention is not described in detail in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as the idea of the present invention is not violated.

Claims (10)

1. An aprepitant injection contains aprepitant, phospholipid, ethanol, oil for injection and water for injection, and is characterized in that the phospholipid contains phosphatidylcholine and phosphatidylethanolamine, the phosphatidylcholine accounts for not less than 68% of the total weight of the phospholipid, and the phosphatidylethanolamine accounts for not more than 9% of the total weight of the phospholipid.
2. The aprepitant injection as claimed in claim 1, wherein the weight percentage of the phosphatidylethanolamine in the total amount of the phospholipids is 3-9%.
3. The aprepitant injection as claimed in claim 2, wherein the weight percentage of the phosphatidylethanolamine in the total amount of the phospholipids is 6-9%.
4. The aprepitant injection according to any one of claims 1-3, wherein the content of each component is:
0.7-0.8 wt/wt% of aprepitant
Phospholipid 13-15 wt/wt%
Ethanol 1-4 wt/wt%
9-10 wt/wt% of oil for injection
The water for injection is added to 100% wt/wt%.
5. Aprepitant injection according to claim 4, wherein the weight ratio of ethanol to phosphatidylethanolamine is 1:1 to 7:1, preferably 1:1 to 5: 1.
6. The aprepitant injection according to claim 1, wherein the phospholipid is selected from a natural source phospholipid and salts thereof, a synthetic or semi-synthetic phospholipid and salts thereof, or a combination thereof.
7. The aprepitant injection according to claim 1, wherein the phosphatidylethanolamine is selected from a natural source of phosphatidylethanolamine and salts thereof, a synthetic or semi-synthetic phosphatidylethanolamine and salts thereof, or any combination thereof; the synthetic or semi-synthetic phosphatidylethanolamine is selected from distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine, erucic phosphatidylethanolamine, dilauroyl phosphatidylethanolamine or a combination thereof.
8. The aprepitant injection according to any one of claims 1-7, further comprising a pH adjusting agent selected from the group consisting of sodium oleate, oleic acid, sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, or a combination thereof.
9. An aprepitant injection according to any one of claims 1-7 further comprising a tonicity modifier selected from sucrose, sodium chloride, glycerin, glucose, mannitol, xylitol or combinations thereof.
10. A process for the preparation of an aprepitant injection of any one of claims 1-9 comprising the steps of:
(1) taking aprepitant, phospholipid and ethanol, and heating to dissolve the aprepitant, the phospholipid and the ethanol;
(2) adding the mixture obtained in the step (1) into oil for injection, and heating and dissolving to obtain an oil phase;
(3) adding a tension regulator and a pH regulator into water for injection, and uniformly stirring to obtain a water phase;
(4) adding the oil phase in the step (2) into the water phase in the step (3), and shearing at high speed to obtain primary emulsion;
(5) homogenizing the primary emulsion in the step (4) under high pressure;
(6) filtering and filling.
CN201910104324.2A 2019-02-01 2019-02-01 Aprepitant injection Pending CN111514100A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910104324.2A CN111514100A (en) 2019-02-01 2019-02-01 Aprepitant injection

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910104324.2A CN111514100A (en) 2019-02-01 2019-02-01 Aprepitant injection

Publications (1)

Publication Number Publication Date
CN111514100A true CN111514100A (en) 2020-08-11

Family

ID=71900584

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910104324.2A Pending CN111514100A (en) 2019-02-01 2019-02-01 Aprepitant injection

Country Status (1)

Country Link
CN (1) CN111514100A (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102379845A (en) * 2011-11-03 2012-03-21 南京优科生物医药有限公司 Aprepitant microemulsion for injection and preparation method thereof
CN104622806A (en) * 2015-02-04 2015-05-20 北京蓝丹医药科技有限公司 Propanidid-containing pharmaceutical composition and preparation method of pharmaceutical composition
US20160082013A1 (en) * 2014-09-19 2016-03-24 Heron Therapeutics, Inc. Emulsion formulations of aprepitant
CN105878250A (en) * 2014-10-29 2016-08-24 北京乐嘉宝医药科技有限责任公司 Aprepitant nano composition
US20170216205A1 (en) * 2016-02-01 2017-08-03 Heron Therapeutics, Inc. Emulsion formulations of an nk-1 receptor antagonist and uses thereof
CN107049942A (en) * 2016-12-30 2017-08-18 北京普德康利医药科技发展有限公司 A kind of alprostadil injection

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102379845A (en) * 2011-11-03 2012-03-21 南京优科生物医药有限公司 Aprepitant microemulsion for injection and preparation method thereof
US20160082013A1 (en) * 2014-09-19 2016-03-24 Heron Therapeutics, Inc. Emulsion formulations of aprepitant
CN105878250A (en) * 2014-10-29 2016-08-24 北京乐嘉宝医药科技有限责任公司 Aprepitant nano composition
CN104622806A (en) * 2015-02-04 2015-05-20 北京蓝丹医药科技有限公司 Propanidid-containing pharmaceutical composition and preparation method of pharmaceutical composition
WO2016124162A1 (en) * 2015-02-04 2016-08-11 北京蓝丹医药科技有限公司 Propanidid pharmaceutical composition and preparation method therefor
US20170216205A1 (en) * 2016-02-01 2017-08-03 Heron Therapeutics, Inc. Emulsion formulations of an nk-1 receptor antagonist and uses thereof
CN107049942A (en) * 2016-12-30 2017-08-18 北京普德康利医药科技发展有限公司 A kind of alprostadil injection

Similar Documents

Publication Publication Date Title
JP6896019B2 (en) Compositions containing lipid compounds, triglycerides and surfactants, and how to use them
EP4035657A1 (en) Drug composition containing abiraterone acetate, and preparation method therefor and application thereof
ITMI952411A1 (en) ORAL PHARMACEUTICAL PREPARATION
JP5847722B2 (en) Taxane pharmaceutical solution containing pH regulator and method for producing the same
CN104224711B (en) Paclitaxel submicron emulsion taking steroid compound as intermediate vector
EP3292860B1 (en) Cabazitaxel fat emulsion injection, and preparation method and use thereof
JP2017519820A (en) Application in fat emulsion with freeze-thaw resistance of high concentration glycerin
CN101829052B (en) Self-emulsifying preparation of taxane compound and preparation method thereof
CN114796110A (en) Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution
EP2903435B1 (en) Non-aqueous taxane nanodispersion formulations and methods of using the same
WO2019197961A1 (en) Pharmaceutical composition of nintedanib esylate
JP2001501192A (en) Pharmaceutical composition comprising amisulpride and its therapeutic application
CN109010269B (en) Aprepitant fat emulsion injection
CN112168781B (en) Tacrolimus self-microemulsion composition and preparation method thereof
CN111514099A (en) Aprepitant injection
CN111514100A (en) Aprepitant injection
EA001905B1 (en) Gelatine encapsulated solution dosage forms of sertraline
JP2019210222A (en) Oil-in-water type emulsion composition and method for producing the same
CN108619088A (en) A kind of florfenicol residues
TW201141538A (en) Taxane pro-emulsion formulations and methods making and using the same
CN103784405B (en) A preparation for improving oral bioavailability of risedronate sodium and a preparing method thereof
JP2973077B2 (en) Vitamin E preparation composition
CN102228431A (en) Self-emulsified medicinal composition for taxane compounds
EP2952207B1 (en) Oil based pharmaceutical compositions for oral administration
CN104523590B (en) A kind of Clevidipine butyrate fat emulsion injection

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20200811