CN105769759B - Ondansetron hydrochloride injecta composition and preparation method - Google Patents
Ondansetron hydrochloride injecta composition and preparation method Download PDFInfo
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- CN105769759B CN105769759B CN201610225573.3A CN201610225573A CN105769759B CN 105769759 B CN105769759 B CN 105769759B CN 201610225573 A CN201610225573 A CN 201610225573A CN 105769759 B CN105769759 B CN 105769759B
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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
- A61K9/08—Solutions
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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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
- A61K9/0012—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
Abstract
The present invention relates to ondansetron hydrochloride injecta composition and preparation methods.Specifically, being calculated as 1~3mg/ml comprising ondansetron hydrochloride and water for injection, the concentration of ondansetron hydrochloride with Ondansetron in the ondansetron hydrochloride parenteral solution of the present invention, the pH of the ondansetron hydrochloride parenteral solution is in the range of 3.0~4.0.The invention further relates to the preparation methods of the ondansetron hydrochloride parenteral solution.Ondansetron hydrochloride parenteral solution prepared by the present invention has the excellent properties of at least one aspect as used in the description.
Description
Technical field
The invention belongs to technology of pharmaceutical engineering field, specifically, being related to a kind of ondansetron hydrochloride product and its system
Method, more particularly to a kind of ondansetron hydrochloride injecta composition and its preparation method.
Background technology
At present, treating cancer is mostly using radiotherapy, chemotherapy, but the cancer patient for receiving radiation and chemotherapy will appear in various degree
Nausea and vomiting symptom.Nausea and vomiting caused by chemotherapy, refers in chemotherapy process, a kind of poison caused by chemotherapeutics
Property reaction.About 60% there is Nausea and vomiting symptom in chemotherapy patients, is divided into acute nausea and vomiting, delayed emesis and expected property
Vomiting.Caused by chemotherapeutic medicines Nausea and vomiting is mainly caused by several respects：1. chemotherapeutics stimulating gastrointestinal road mucous membrane is caused on mucous membrane
The chromaffin cell release neurotransmitters such as 5-HT3,5-HT3 combined with 5-HT3 receptors the nerve impulse of generation by vagus nerve and
Sympathetic nerve is passed to vomiting centre and causes to vomit；2. chemotherapeutics and its metabolite directly stimulate CTZ, then pass through DOPA
The a series of receptors such as amine, histamine, muscarine, 5-HT3 so be transferred to vomiting centre cause vomiting；3. feeling, the spiritual factor are straight
Connecing stimulation cerebral cortex access causes to vomit, and is more common in expected property vomiting.
Clinically used antiemetic mainly has：5-HT3 receptor antagonists, dopamine-receptor antagonist, steroids etc., with
The 5-HT3 receptor antagonists such as Ondansetron, Granisetron are the most commonly used.
Ondansetron hydrochloride (Ondansetron Hydrochloride, ODS), version in 2015《Chinese Pharmacopoeia》It has received
It carries, is provided with its dihydrate, structural formula, molecular formula, molecular weight are as follows：
Ondansetron hydrochloride is a kind of highly selective 5-hydroxytryptamine receptor antagonist.Clinic be mainly used in cancer radiation and
Nausea and vomiting symptom caused by chemotherapy and surgical operation.
Version in 2015《Chinese Pharmacopoeia》The ondansetron hydrochloride preparation recorded includes its tablet and injection with small volume.
Many draw however, it has been found that having about ondansetron hydrochloride injection with small volume when being used simultaneously with proton pump inhibitor
The document report for the problem of playing incompatibility.Such as Liu Chun equalitys (Liu Chun equalitys, nursing practice and research, 2010 years volume 7 the
22 the second half of the month phase version page 31) finding Pantoprazole sodium injection, there are incompatibility with ondansetron hydrochloride；Shao Ping (Shao Ping,
Shanxi Medicine magazine the second half of the month phase page 100 of volume 41 the 1st in January, 2012) also find that Pantoprazole is noted with ondansetron hydrochloride
Penetrating liquid, there are incompatibility；Liu Yan (Liu Yan, nursing practice and research, the 4th first half of the month phase version page 64 of volume 5 in 2008) has found
There are incompatibility with Omeprazole for ondansetron hydrochloride parenteral solution；
Therefore it provides a kind of ondansetron hydrochloride parenteral solution with excellent pharmaceutical properties for example it have high security example
Incompatibility and the method for preparing this parenteral solution can such as be avoided, be still that those skilled in the art expect very much, this for
It is very useful for clinical application.
Invention content
For this purpose, the purpose of the present invention is to provide a kind of new methods to prepare ondansetron hydrochloride parenteral solution, and phase
Treat ondansetron hydrochloride parenteral solution prepared by these methods have excellent pharmaceutical properties for example it have high security and for example may be used
Avoid incompatibility.Present inventors have surprisingly discovered that had using the ondansetron hydrochloride parenteral solution that the method for the present invention obtains
There are one or many aspects excellent properties.It finds and is accomplished the present invention is based on this.
For this purpose, first aspect present invention provides a kind of ondansetron hydrochloride parenteral solution, wherein including：Ondansetron hydrochloride
And water for injection.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein ondansetron hydrochloride
Concentration is calculated as 1~3mg/ml with Ondansetron.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein ondansetron hydrochloride
Concentration is calculated as 1.5~2.5mg/ml with Ondansetron.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein ondansetron hydrochloride
Concentration is calculated as 1.75~2.25mg/ml with Ondansetron.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein ondansetron hydrochloride
Concentration is calculated as 2mg/ml with Ondansetron.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, pH is in 3.0~4.0 ranges
Interior, preferably its pH is in the range of 3.25~3.75.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, in order to adjust the need of pH value
Will, wherein acid-base modifier can also be included.In one embodiment, the acid-base modifier is hydrochloric acid or hydroxide
Sodium, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.In one embodiment, the dosage of the acid-base modifier be so that
The pH of the parenteral solution is in the range of 3.0~4.0, and preferably its pH is in the range of 3.25~3.75.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention is by including walking as follows
What rapid method was prepared：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, are added in suitable water for injection, stirring dissolves drug；
(2) into step (1) acquired solution in terms of medicine liquid volume addition 0.05~0.2% needle-use activated carbon, mixing is equal
It is even, then with the pH of acid-base modifier regulating liquid medicine in the range of 6.5~7.5, liquid is stirred at room temperature 30~60 minutes；
(3) by mixed liquor filtering decarbonization obtained by step (2), with the pH of acid-base modifier regulating liquid medicine in 3.25~3.75 models
In enclosing, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.25~3.75；
(4) by step (3) prepare liquid aseptic filtration, be filled into vial, seal, carry out pressure sterilizing to get.
It is injected in the ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (1)
It is the 50~90% of prescription full dose, particularly 60~80% with the dosage of water.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, used in water for injection
Water temperature below 40 DEG C.
Needle is used in the ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (2)
The addition of activated carbon is 0.05~0.15%.
Needle is used in the ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (2)
The addition of activated carbon is 0.1%.
The middle acid of the ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (2)
The pH of alkali conditioning agent regulating liquid medicine is in the range of 7.0~7.5.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (2) Chinese medicine liquid
Liquid is stirred at room temperature 30~45 minutes.
It is mixed in the ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (3)
Liquid filtering decarbonization is operated according to following manner：It is first filtered with filter paper, the stud for being then 1um with aperture filters, then use
The polyether sulfone filter core of 0.45um is by liquid coarse filtration.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (2) and step
(3) in, acid-base modifier used be selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate,
Dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combination.In one embodiment, the acid-base modifier is salt
Acid solution either sodium hydroxide solution particularly such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein described in step (3)
Benefit inject water to prescription full dose refer to add water for injection until activity component concentration for 1~3mg/ml (such as 1.5~
2.5mg/ml, such as 1.75~2.25mg/ml, such as 2mg/ml) amount.
The ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein described in step (4)
Aseptic filtration is to carry out aseptic filtration using the polyether sulfone filter core of 0.22um.
Hot pressing in the ondansetron hydrochloride parenteral solution of any embodiment according to a first aspect of the present invention, wherein step (4)
Sterilization treatment is sterilization treatment 30 minutes at 121 DEG C.
In addition, second aspect of the present invention provides, to prepare ondansetron hydrochloride parenteral solution such as first aspect present invention any
The method of ondansetron hydrochloride parenteral solution, includes the following steps described in embodiment：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, are added in suitable water for injection, stirring dissolves drug；
(2) into step (1) acquired solution in terms of medicine liquid volume addition 0.05~0.2% needle-use activated carbon, mixing is equal
It is even, then with the pH of acid-base modifier regulating liquid medicine in the range of 6.5~7.5, liquid is stirred at room temperature 30~60 minutes；
(3) by mixed liquor filtering decarbonization obtained by step (2), with the pH of acid-base modifier regulating liquid medicine in 3.25~3.75 models
In enclosing, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.25~3.75；
(4) by step (3) prepare liquid aseptic filtration, be filled into vial, seal, carry out pressure sterilizing to get.
The dosage of water for injection is place in the method for any embodiment according to a second aspect of the present invention, wherein step (1)
The 50~90% of Fang Quanliang, particularly 60~80%.
The method of any embodiment according to a second aspect of the present invention, used in water for injection water temperature 40 DEG C with
Under.
The addition of needle-use activated carbon in the method for any embodiment according to a second aspect of the present invention, wherein step (2)
It is 0.05~0.15%.
The addition of needle-use activated carbon in the method for any embodiment according to a second aspect of the present invention, wherein step (2)
It is 0.1%.
In the method for any embodiment according to a second aspect of the present invention, wherein step (2) medicine is adjusted with acid-base modifier
The pH of liquid is in the range of 7.0~7.5.
The method of any embodiment according to a second aspect of the present invention, wherein step (2) Chinese medicine liquid stirs medicine at room temperature
Liquid 30~45 minutes.
Mixed liquor filtering decarbonization is to shine in the method for any embodiment according to a second aspect of the present invention, wherein step (3)
Following manner operation：It is first filtered with filter paper, the stud for being then 1um with aperture filters, then the polyether sulfone filter core with 0.45um
By liquid coarse filtration.
In the method for any embodiment according to a second aspect of the present invention, wherein step (2) and step (3), acid used
Alkali conditioning agent is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, salt
Acid, phosphoric acid, nitric acid, sulfuric acid, or combination.In one embodiment, the acid-base modifier is hydrochloric acid solution or hydrogen
Sodium hydroxide solution, particularly such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
It mends and injects water to described in the method for any embodiment according to a second aspect of the present invention, wherein step (3)
Prescription full dose refer to add water for injection until activity component concentration for 1~3mg/ml (such as 1.5~2.5mg/ml, such as
1.75~2.25mg/ml, such as 2mg/ml) amount.
Aseptic filtration described in the method for any embodiment according to a second aspect of the present invention, wherein step (4) is to use
The polyether sulfone filter core of 0.22um carries out aseptic filtration.
Pressure sterilizing processing is 121 in the method for any embodiment according to a second aspect of the present invention, wherein step (4)
Sterilization treatment 30 minutes at DEG C.
The method of any embodiment according to a second aspect of the present invention, obtained by ondansetron hydrochloride parenteral solution in it is living
The concentration of property ingredient is calculated as 1~3mg/ml with Ondansetron.
The method of any embodiment according to a second aspect of the present invention, obtained by ondansetron hydrochloride parenteral solution in it is living
The concentration of property ingredient is calculated as 1.5~2.5mg/ml with Ondansetron.
The method of any embodiment according to a second aspect of the present invention, obtained by ondansetron hydrochloride parenteral solution in it is living
The concentration of property ingredient is calculated as 1.75~2.25mg/ml with Ondansetron.
The method of any embodiment according to a second aspect of the present invention, obtained by ondansetron hydrochloride parenteral solution in it is living
The concentration of property ingredient is calculated as 2mg/ml with Ondansetron.
The method of any embodiment according to a second aspect of the present invention, obtained by ondansetron hydrochloride parenteral solution pH exist
In the range of 3.0~4.0, preferably its pH is in the range of 3.25~3.75.
In the step of above method of the present invention, although the specific steps of its description are in certain details or language description
Step different from described in the upper and example of following detailed description part, however, those skilled in the art according to
The detailed disclosure of full text of the present invention can summarize approach described above step completely.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary
When offering expressed meaning and the inconsistent present invention, it is subject to the statement of the present invention.In addition, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
Subject to the meaning stated.
In the present invention, if not otherwise indicated, using to reagent and raw material be to buy from the market.
According to either side of the present invention embodiment, wherein when preparing the ondansetron hydrochloride parenteral solution,
Also add paper pulp in the step of wherein (2) together with activated carbon, paper pulp additive amount with the dry weight of paper be calculated as activated carbon 40~
60%.It has been unexpectedly discovered that thus ondansetron hydrochloride parenteral solution made from mode with a variety of proton pump inhibitors
It is not in incompatibility during compatibility.For example, hydrochloric acid Ang Dan is stated according to the gentle Liu Yan literature methods investigations of Liu Chun described above respectively
The method for taking charge of fine jade parenteral solution and Pantoprazole sodium injection and injection omeprazole powder needle compatibility investigates ondansetron hydrochloride note
The compatibility situation of liquid and proton pump inhibitor is penetrated, the results show that 7 kinds of parenteral solutions of embodiment 1-7 inhibit with two class proton pumps
There is White Flocculus during agent compatibility, show that these parenteral solutions cannot be with the compatibility of proton pump inhibitor；But 8 institute of embodiment
7 kinds of parenteral solutions are obtained with not occurring the situation of above-mentioned incompatibility during two class proton pump inhibitor compatibilities.In addition, from the market
Not 4 batches of ondansetron hydrochloride parenteral solutions on sale are bought (to represent with the place of production and breviary Chinese medicines quasi-word number, respectively Chengdu 329, peace
Emblem 842, Shandong 029, Jiangxi 340), it as a result shows that four kinds of ondansetron hydrochloride parenteral solutions on sale pump respectively with two proton and inhibits
There is White Flocculus in mixed liquor during agent compatibility.But making us unaccountable is, for 7 kinds of parenteral solutions of embodiment 8,
If in the step of preparing them, will not be handled in the range of liquid adjusting to pH6.5~7.5 in step (2), but
It directly adjusts to being handled in the range of 3.0~4.0, even if being equally then that activated carbon is applied in combination with paper pulp in preparation process
There is different degrees of white flock when respectively with two proton pump inhibitor compatibilities in mixed liquor in 7 kinds of obtained parenteral solutions
Object, it is seen that the preparation process condition of paper pulp and pH are essential for obtaining the parenteral solution with advantageous property.
Ondansetron hydrochloride parenteral solution of the present invention is used to control nausea and vomiting caused by cancer chemotherapy and radiotherapy；Also
Suitable for prevention and postoperative nauseaand vomiting.For child patient, 4 years old or more children：Control cancer chemotherapy and radiotherapy are drawn
The nausea and vomiting risen；Less than 4 years old children：Nausea and vomiting caused by controlling cancer chemotherapy；2 years old or more children：Prevention and treatment
Postoperative nausea and vomiting.
Ondansetron hydrochloride parenteral solution of the present invention as caused by chemotherapy and radiotherapy during nausea and vomiting, can intramuscular injection and
Intravenous injection.Be grown up (nausea and vomiting as caused by chemotherapy and radiotherapy) when, initial treatment is used before usual radiation and chemotherapy
Dosage is 8mg, using as follows：Inject solution：Slow intravenous or intramuscular injection this product 8mg immediately before treatment.Certain cases (are caused using high
Spitting property Cytotoxic drugs and/or high prescribed dose；There are individual patient correlative factors, have such as previously carried out going out during Cytotoxic drugs treatment
The younger patient now vomitted, female patients, etc.) need higher predose.Spitting property chemotherapy, hydrochloric acid Ang Dansi are caused for height
Fine jade parenteral solution maximum initial dose is 16 milligrams, 15 minutes venoclysis time.16 millis are not to be exceeded in single intravenous injection dosage
Gram.Spitting property chemotherapy is caused for height, 20 milligrams of venoclysis single dose dexamethasone sodium phosphate, can enhance hydrochloric acid Ang Dansi before chemotherapy
The effect of fine jade parenteral solution.Ondansetron hydrochloride parenteral solution dosage, to 16 milligram hours, uses 0.9% higher than 8 milligrams before venoclysis
50-100 milliliters of physiological saline or 5% glucose solution are diluted, and Infusion Time is no less than 15 minutes.Ondansetron hydrochloride is noted
It penetrates 8 milligrams of liquid or less dosage not needing to dilute, (must not slowly can be less than 30 seconds) muscle or intravenous injection.In hydrochloric acid Ang Dansi
It is spaced 2 to 4 hours after fine jade parenteral solution first administration, 8 milligrams of 2 veins or intramuscular delivery or constant rate intravenous can be added
1 milli Grams Per Hour is transfused, continues 24 hours.During continual cure (prevention Delayed onset or Delayed emesis), every 12 hours of next day is oral
The oral preparations such as this product 8mg tablets 2-3 days, longest may be up to 5 days.
In terms of pharmacological action, Ondansetron is a kind of selectivity 5HT3 receptor antagonists, although the effect machine of Ondansetron
System is not studied also clear completely, but it is not dopamine-receptor antagonist.Chemotherapeutics and radiotherapy can cause small enteric release
5-HT via the vagal afferent limb of 5-HT receptor activations, triggers vomiting reflex.The excitement of Vagus-pressor responses branch can also draw
It plays the 5-HT positioned at fourth ventricle bottom back zone to discharge, so as to by central mechanism strengthen.Ondansetron can block this anti-
The triggering penetrated to Nausea and vomiting caused by chemotherapy, radiotherapy, may be located at the nerve of surrounding and nervous centralis part by antagonism
Member 5-HT3 receptors and play a role.
In terms of toxicological study, acute toxicity test shows that Ondansetron has no apparent systematicness and tissue specificity poison
Property.Oral administration 10mg/kg in rat studies does not observe any effect, when dosage increases as 80mg/kg, moderate occurs
Behavior change, but without animal dead.The maximum non-lethal dose of rat intravenous injection is 15mg/kg.Rat is continuously orally given
Only there is behavior change up to 18 months when high blood concentration reaches 1407ng/ml in medicine Ondansetron.It can be considered that in drug
It is non-toxic under therapeutic dose.
Show Ondansetron without mutagenicity in conventional mutagenicity test.Male and female rats oral administration Ang Dan
Si Qiongda 0.15mg/kg/ days (about recommend 3.8 times of human vein injection dosage, based on body surface area), show to male and
Female rats fertility or reproductive ability are without influence.It is high in Pregnant rats and rabbit vein drug administration by injection Ondansetron dosage
It is about to recommend human vein injection dosage (0.15mg/kg, 3 times a day, in terms of body surface area) respectively up to 4mg/kg/ days
1.4 and 2.9 times, display Ondansetron will not cause to damage to fetus.In the experimental studies in 2 years of rat and mouse, orally give
The dosage of medicine Ondansetron is up to 10 and 30mg/kg/ days, be equivalent to recommend human vein injection dosage (0.15mg/kg, daily 3
Secondary, based on body surface area) 3.6 and 5.4 times, as a result show no carcinogenesis.QT interval prolongations, clone human heart from
In subchannel experiment, the Ondansetron of Clinical practice dosage can block hERG potassium channels so as to influence the potential work of cardiac repolarisation
With.In comprehensive QT researchs of healthy volunteer, also observe that dose-dependent QT extends.It is tested in 58 healthy men and women's property
In double blind, random, placebo and positive drug (Moxifloxacin) control, crossing research that person participates in, Ondansetron list is had evaluated
The influence of secondary administration phase between QTc.The dosage of Ondansetron is 8mg and 32mg venoclysises 15 minutes.Giving highest
After studying dosage 32mg, the maximum average value (upper limit of 95%CI) of phase and placebo difference is 19.5 between QTcF after baseline correction
(21.8)msec.After minimum research dosage 8mg is given, the maximum average value of phase and placebo difference between QTcF after baseline correction
(upper limit of 95%CI) is 5.6 (7.4) ms.During this investigation it turned out, there are not QTcF values more than 480ms, also do not occur
QTcF, which extends, is more than 60ms.There is determining apparent exposure-effect relation between Ondansetron concentration and Δ Δ QTcF.According to
Established exposure-effect relation, (95%CI's is upper for prediction Ondansetron 24mg venoclysis 15min, Δ Δ QTcF average value
Limit) it is 14.0 (16.3) ms.Conversely, Ondansetron 16mg venoclysis 15min, Δ Δ QTcF average value (upper limit of 95%CI)
For 9.1 (11.2) ms.
In terms of pharmacokinetics, 4 milligrams of an intravenously administrable is administered, the peak serum concentration reached is about 65 in 5 minutes
Nanograms/milliliter.After 4 milligrams of administered intramusculars, after injection up to peak serum concentration (about 25 nanograms/milliliters) in 10 minutes.
After 4 milligrams of 4 milligrams of intramuscular injection and intravenous injection, system exposure is equivalent.Ondansetron takes orally, intramuscular injection or vein
Half-life period no significant difference after injection, half-life period are about 3 hours, and Vdss is about 140 liters.
The protein binding rate of Ondansetron is 70-76%.Ondansetron passes through different metabolic pathways, predominantly liver generation
It is removed in Xie Houcong cycles.The original shape dose discharged from urine is less than the 5% of intake dosage.Lacking enzyme CYP2D6, (debrisoquine is more
State property) pharmacokinetics of Ondansetron is not influenced.Its pharmacokinetics of repeat administration is also without change.
Healthy elderly I early stage, studies have shown thats phase have slight age related Ondansetron clearance rate to reduce and partly decline
Phase extends.But extensive inter-subject variability cause young subjects (<65 years old) the medicine generation between aged subjects (>=65 years old)
Kinetic parameter has substantial portion of overlapping, between the young cancer patient being included in CINV clinical tests and senile patients with cancer
Apparent safety and effective sex differernce is not observed, does not support the evidence of senile patients with cancer application various dose.
According to recent Ondansetron plasma concentration and exposure-effect model, compared with Young Adults, in >=75 years old patient
In contemplate that the QTcF effects of bigger.Special drug administration information is provided to over-65s patient and 75 years old or more patient.
The availability that Ondansetron can be observed has gender differences, and the absorption rate and degree after female oral are higher,
Whole body is removed and volume is distributed relatively low (being adjusted through weight).
In an experiment, the children (n=19) at monthly age 1-4 month receive surgical site infections, through weight normalized medicine
Object clearance rate, than in the slow moon 30% of the children (n=22) of 5-24 months, but it is similar to the children of 3-12 Sui.Drug half-life,
The average out to 6.7 hours in the children at monthly age 1-4 month is 2.9 hours in the children of 5-24 months and the children of 3-12 Sui.
The otherness occurred for the monthly age in the pharmacokinetic parameter of the children of 1-4 months, it may be possible to because moisture accounts in baby
Percentage higher in totality, so water soluble drug, such as the distribution volume bigger of Ondansetron.
3-12 Sui child patient of progressive elective surgery and general anesthesia removes the absolute value with distribution volume
It is to decline compared with adult.Two groups of data are linearly increased with weight gain, and numerical value 12 years old is close to young adult's level.
After elimination factor and distribution volume is standardized with weight, numerical value is similar in all ages and classes group.It can be more by weight administration
The change of age related is mended, effectively makes the exposure standardization of child patient system.
Group's medicine has been carried out for power (including cancer patient, patient with operation and healthy volunteer) to 428 subjects
Credit is analysed.Subject age is 1 month to 44 years old, receives intravenous injection Ondansetron.Analysis result is shown, in addition to the monthly age is 1-
Outside the baby of 4 months, the drug system exposed amount (AUC) that Children and teenager took orally or injected Ondansetron is suitable with adult.
The drug distribution volume of this product is in age related, and the drug distribution volumetric ratio baby of adult and children are low.In addition to the monthly age is 1-4
Outside the baby of a month, clearance rate and the weight rather than age of this product are in correlation.Due to entering the subject of 1-4 month age groups
Quantity is very little, it is impossible to which whether the clearance rate of this product reduces in correlation with the age in baby or be only that research is solid in itself certainly
Some variations.Due to being single dose administration when the children of less than 6 months carry out the prevention and treatment of postoperative nauseaand vomiting, clearly
Except the reduction of rate does not have clinical correlation.
The patient (creatinine clearance rate 15-60ml/min) of moderate impaired renal function, system clearance rate and distribution volume drop
It is low.Elimination half-life period (T1/2 5.4 hours) can be caused to have increased slightly, but without clinical meaning.To the severe that regular blood is needed to dialyse
The pharmacokinetics of the studies have shown that of renal damage patient Ondansetron that the phase measures between haemodialysis is substantially without change.Tight
Weight hepatic lesion patient, Ondansetron systemic clearance are substantially reduced, and eliminate Increased Plasma Half-life to 15-32 hours.
The positive effect of the present invention is：The method of the present invention can be effectively used for preparing with excellent properties
Ondansetron hydrochloride parenteral solution has good market application foreground.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general
And/or specific description.Although to realize the present invention many materials used in purpose and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.Following embodiment further illustrates the present invention rather than limits this hair
It is bright.
Hereafter preparation process is for the purpose of citing, and the comparability based on each citing and make some specific description,
Those skilled in the art can therefrom summarize to obtain the present invention program according to existing knowledge completely.Preparing hydrochloric acid Ang Dansi below
Use is the same as a batch of ondansetron hydrochloride bulk pharmaceutical chemicals during fine jade parenteral solution.When preparing ondansetron hydrochloride parenteral solution below, with
Amount per 1ml lists prescription, but when actually feeding intake, each batches amount is the amount of 5000ml.
Below prepare ondansetron hydrochloride parenteral solution when, if not otherwise indicated, using to acid-base modifier be 1M salt
Acid solution or 1M sodium hydroxide solutions.
Embodiment 1：Prepare ondansetron hydrochloride parenteral solution
Formula：
Ondansetron hydrochloride (in terms of Ondansetron), 2mg/ml；
Water for injection in right amount, adds to 1ml.
Preparation method：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, add to amount of preparation 75% water for injection (40 DEG C hereinafter, under
In together), stirring dissolves drug；
(2) 0.1% needle-use activated carbon is added in terms of medicine liquid volume into step (1) acquired solution, is uniformly mixed, then
With the pH of acid-base modifier regulating liquid medicine in the range of 7.0~7.5, liquid is stirred at room temperature 45 minutes；
(3) by mixed liquor filtering decarbonization (maneuver obtained by step (2)：It is first filtered with filter paper, is then 1um's with aperture
Stud filters, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration), with the pH of acid-base modifier regulating liquid medicine 3.25~
In the range of 3.75, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is 3.25~3.75
In the range of；
(4) the polyether sulfone filter core aseptic filtration for the liquid 0.22um for preparing step (3), is filled into vial, seals
Mouthful, carry out pressure sterilizing (sterilization treatment 30 minutes at 121 DEG C) to get.
Embodiment 2：Prepare ondansetron hydrochloride parenteral solution
Formula：
Ondansetron hydrochloride (in terms of Ondansetron), 1mg/ml；
Water for injection in right amount, adds to 1ml.
Preparation method：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, add to amount of preparation 90% water for injection (40 DEG C hereinafter, under
In together), stirring dissolves drug；
(2) 0.05% needle-use activated carbon is added in terms of medicine liquid volume into step (1) acquired solution, is uniformly mixed, connects
The pH with acid-base modifier regulating liquid medicine in the range of 6.5~7.0, liquid is stirred at room temperature 30 minutes；
(3) by mixed liquor filtering decarbonization (maneuver obtained by step (2)：It is first filtered with filter paper, is then 1um's with aperture
Stud filters, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration), with the pH of acid-base modifier regulating liquid medicine 3.0~3.5
In the range of, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.0~3.5；
(4) the polyether sulfone filter core aseptic filtration for the liquid 0.22um for preparing step (3), is filled into vial, seals
Mouthful, carry out pressure sterilizing (sterilization treatment 30 minutes at 121 DEG C) to get.
Embodiment 3：Prepare ondansetron hydrochloride parenteral solution
Formula：
Ondansetron hydrochloride (in terms of Ondansetron), 3mg/ml；
Water for injection in right amount, adds to 1ml.
Preparation method：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, add to amount of preparation 50% water for injection (40 DEG C hereinafter, under
In together), stirring dissolves drug；
(2) 0.2% needle-use activated carbon is added in terms of medicine liquid volume into step (1) acquired solution, is uniformly mixed, then
With the pH of acid-base modifier regulating liquid medicine in the range of 6.5~7.0, liquid is stirred at room temperature 60 minutes；
(3) by mixed liquor filtering decarbonization (maneuver obtained by step (2)：It is first filtered with filter paper, is then 1um's with aperture
Stud filters, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration), with the pH of acid-base modifier regulating liquid medicine 3.5~4.0
In the range of, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.5~4.0；
(4) the polyether sulfone filter core aseptic filtration for the liquid 0.22um for preparing step (3), is filled into vial, seals
Mouthful, carry out pressure sterilizing (sterilization treatment 30 minutes at 121 DEG C) to get.
Embodiment 4：Prepare ondansetron hydrochloride parenteral solution
Formula：
Ondansetron hydrochloride (in terms of Ondansetron), 1.5mg/ml；
Water for injection in right amount, adds to 1ml.
Preparation method：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, add to amount of preparation 60% water for injection (40 DEG C hereinafter, under
In together), stirring dissolves drug；
(2) 0.15% needle-use activated carbon is added in terms of medicine liquid volume into step (1) acquired solution, is uniformly mixed, connects
The pH with acid-base modifier regulating liquid medicine in the range of 6.7~7.2, liquid is stirred at room temperature 40 minutes；
(3) by mixed liquor filtering decarbonization (maneuver obtained by step (2)：It is first filtered with filter paper, is then 1um's with aperture
Stud filters, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration), with the pH of acid-base modifier regulating liquid medicine 3.3~3.7
In the range of, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.3~3.7；
(4) the polyether sulfone filter core aseptic filtration for the liquid 0.22um for preparing step (3), is filled into vial, seals
Mouthful, carry out pressure sterilizing (sterilization treatment 30 minutes at 121 DEG C) to get.
Embodiment 5：Prepare ondansetron hydrochloride parenteral solution
Formula：
Ondansetron hydrochloride (in terms of Ondansetron), 2.5mg/ml；
Water for injection in right amount, adds to 1ml.
Preparation method：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, add to amount of preparation 80% water for injection (40 DEG C hereinafter, under
In together), stirring dissolves drug；
(2) 0.1% needle-use activated carbon is added in terms of medicine liquid volume into step (1) acquired solution, is uniformly mixed, then
With the pH of acid-base modifier regulating liquid medicine in the range of 6.7~7.2, liquid is stirred at room temperature 35 minutes；
(3) by mixed liquor filtering decarbonization (maneuver obtained by step (2)：It is first filtered with filter paper, is then 1um's with aperture
Stud filters, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration), with the pH of acid-base modifier regulating liquid medicine 3.5~3.8
In the range of, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.5~3.8；
(4) the polyether sulfone filter core aseptic filtration for the liquid 0.22um for preparing step (3), is filled into vial, seals
Mouthful, carry out pressure sterilizing (sterilization treatment 30 minutes at 121 DEG C) to get.
Embodiment 6：Prepare ondansetron hydrochloride parenteral solution
Formula：
Ondansetron hydrochloride (in terms of Ondansetron), 1.75mg/ml；
Water for injection in right amount, adds to 1ml.
Preparation method：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, add to amount of preparation 70% water for injection (40 DEG C hereinafter, under
In together), stirring dissolves drug；
(2) 0.15% needle-use activated carbon is added in terms of medicine liquid volume into step (1) acquired solution, is uniformly mixed, connects
The pH with acid-base modifier regulating liquid medicine in the range of 6.7~7.2, liquid is stirred at room temperature 55 minutes；
(3) by mixed liquor filtering decarbonization (maneuver obtained by step (2)：It is first filtered with filter paper, is then 1um's with aperture
Stud filters, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration), with the pH of acid-base modifier regulating liquid medicine 3.3~3.7
In the range of, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.3~3.7；
(4) the polyether sulfone filter core aseptic filtration for the liquid 0.22um for preparing step (3), is filled into vial, seals
Mouthful, carry out pressure sterilizing (sterilization treatment 30 minutes at 121 DEG C) to get.
Embodiment 7：Prepare ondansetron hydrochloride parenteral solution
Formula：
Ondansetron hydrochloride (in terms of Ondansetron), 2.25mg/ml；
Water for injection in right amount, adds to 1ml.
Preparation method：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, add to amount of preparation 75% water for injection (40 DEG C hereinafter, under
In together), stirring dissolves drug；
(2) 0.1% needle-use activated carbon is added in terms of medicine liquid volume into step (1) acquired solution, is uniformly mixed, then
With the pH of acid-base modifier regulating liquid medicine in the range of 7.0~7.5, liquid is stirred at room temperature 40 minutes；
(3) by mixed liquor filtering decarbonization (maneuver obtained by step (2)：It is first filtered with filter paper, is then 1um's with aperture
Stud filters, then with the polyether sulfone filter core of 0.45um by liquid coarse filtration), with the pH of acid-base modifier regulating liquid medicine 3.3~3.7
In the range of, benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.3~3.7；
(4) the polyether sulfone filter core aseptic filtration for the liquid 0.22um for preparing step (3), is filled into vial, seals
Mouthful, carry out pressure sterilizing (sterilization treatment 30 minutes at 121 DEG C) to get.
Embodiment 8：Prepare ondansetron hydrochloride parenteral solution
Formula and preparation method respectively refer to embodiment 1-7, and different is only that paper is also added together with activated carbon in step (2)
Slurry, paper pulp be calculated as with the dry weight of paper 40% (embodiment 1,2) of activated carbon, 50% (embodiment 3,4), 60% (embodiment 5,6,
7) 7 batches of parenteral solutions, are obtained, be calculated as respectively #81, #82, etc. the rest may be inferred.
Test example 1：Related substances separation, the assay of active constituent, the experiment of pH value inspection and method in parenteral solution
【Assay】
It is measured according to high performance liquid chromatography (four general rules 0512 of version Chinese Pharmacopoeia in 2015).
Chromatographic condition and system suitability：With cyanoalkysilane bonded silica gel be filler (Kromasil CN columns,
4.6mmX250mm 5um or the comparable chromatographic column of efficiency)；With 0.02mol/L sodium dihydrogen phosphates (with sodium hydroxide test solution tune
PH value is saved to 5.4)-acetonitrile (50:50) it is mobile phase；Detection wavelength is 310nm.Ondansetron peak retention time is about 11 points
Clock；Number of theoretical plate is calculated by Ondansetron peak not less than 2000.
Measuring method：Precision measure ondansetron hydrochloride parenteral solution it is appropriate, quantitatively diluted with mobile phase be made in every 1ml containing about
The solution of Ondansetron 80ug, as test solution, precision measures 10ul injection liquid chromatographs, records chromatogram；Separately take
Ondansetron hydrochloride reference substance, is measured in the same method.By external standard method with calculated by peak area, and by result be multiplied by 0.8895 to get.
Pharmacopeia usually requires that the hydrochloric Ondansetron of ondansetron hydrochloride parenteral solution is based on Ondansetron (C18H19N3O)
It calculates, should be the 93.0%~107.0% of labelled amount.
After measured, in example 1 above -8 all 14 kinds of parenteral solution active component contents the 98.0% of its labelled amount
In the range of~102.0%, and in step (2) plus or the equal indifference of paper pulp is not added with, such as 1 parenteral solution of embodiment is injected with #81
The content indifference of liquid.
【Related substance】
It takes ondansetron hydrochloride parenteral solution appropriate, mobile phase is added to be made in every 1ml containing about the solution of Ondansetron 0.5mg,
As test solution；Precision measures 1ml, puts in 100ml measuring bottles, is diluted to scale with mobile phase, shakes up, molten as compareing
Liquid.
In addition to Detection wavelength is 216mn and 328mn, according to the chromatographic condition under assay item, it is molten that precision measures test sample
Liquid and each 10ul of contrast solution, are injected separately into liquid chromatograph, 5 times of record chromatogram to principal component peak retention time.
Pharmacopeia usually requires that, under 216nm wavelength, in the chromatogram of ondansetron hydrochloride parenteral solution test solution if any
Impurity peaks, single impurity peak area are not greater than 0.2 times (0.2%) of contrast solution main peak area, the sum of each impurity peak area
It is not greater than 0.5 times (0.5%) of contrast solution main peak area.Under 328nm wavelength, ondansetron hydrochloride impurity I is (opposite to protect
It is about 1.5 times (1.5%) that peak area 0.6) is not greater than contrast solution main peak area to stay the time.Wherein ondansetron hydrochloride
Impurity I is -4 (9H) -one of 9- methyl -3- methylene -2,3- dihydro -1H- carbazoles.
After measured, all the related substance of 14 kinds of parenteral solutions is satisfied by wanting for above-mentioned pharmacopeia routine in example 1 above -8
It asks, for example, under 216nm wavelength, the impurity peaks in the chromatogram of ondansetron hydrochloride parenteral solution test solution, single impurity
Peak area is respectively less than 0.08%, each impurity peak area and respectively less than 0.26%；Under 328nm wavelength, ondansetron hydrochloride is miscellaneous
Matter I is respectively less than 0.43%；And in step (2) plus or the equal indifference of paper pulp is not added with, such as 1 parenteral solution of embodiment is injected with #81
The related substance indifference of liquid.
【PH value inspection】Directly measure the pH value of parenteral solution.
After measured, pH value of the pH value of whole 14 kinds of parenteral solutions with being set in its preparation process in example 1 above -8
It is identical；And add in step (2) or be not added with the equal indifference of paper pulp, such as the pH value indifference of 1 parenteral solution of embodiment and #81 parenteral solutions
It is different.
Test example 2：The stability test of parenteral solution and method
Take parenteral solution, put 40 DEG C of dark places and place 6 months, measure active component content of the parenteral solution at 0 month and June,
Related substance, pH value.For active component content change, each parenteral solution calculate its at June content relative to its 0 month when contain
The percentage of amount, as remaining percentage composition, typically the remaining percentage composition of drug should be greater than 90% and be only to think qualified
's.
Whole 14 kinds of parenteral solutions in example 1 above -8, after measured, their related substances and pH value at June exist
In the range of States Pharmacopoeia specifications；Such as under 216nm wavelength, the single impurity of ondansetron hydrochloride parenteral solution is respectively less than 0.13%, each miscellaneous
Mass peak area and respectively less than 0.41%；Under 328nm wavelength, ondansetron hydrochloride impurity I is respectively less than 0.65%；They are 6
The pH value during moon is in the range of 3.0-4.0.
Whole 14 kinds of parenteral solutions in example 1 above -8, after measured, their active constituent remnants percentages at June contain
Amount shows that whole parenteral solutions are respectively provided with excellent stability in the range of 96~98%.
Industrial applicability
The invention belongs to medicine manufacture technology fields, are related to a kind of ondansetron hydrochloride product and its preparation method, particularly
It is related to a kind of ondansetron hydrochloride parenteral solution and its preparation method.Ondansetron hydrochloride parenteral solution according to the present invention,
The excellent effect of other aspects is also optionally presented.
Claims (16)
1. a kind of ondansetron hydrochloride parenteral solution, wherein including：Ondansetron hydrochloride and water for injection；Wherein ondansetron hydrochloride
Concentration 1.5 ~ 2.5mg/ml is calculated as with Ondansetron；The parenteral solution is prepared by a method comprising the following steps to obtain：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, are added in suitable water for injection, stirring dissolves drug；
(2) into step (1) acquired solution in terms of medicine liquid volume addition 0.05 ~ 0.2% needle-use activated carbon, while add paper pulp,
Paper pulp additive amount is calculated as the 40 ~ 60% of activated carbon with the dry weight of paper；It is uniformly mixed, then with the pH of acid-base modifier regulating liquid medicine
In the range of 6.5 ~ 7.5, liquid is stirred at room temperature 30 ~ 60 minutes；
(3) by mixed liquor filtering decarbonization obtained by step (2), with the pH of acid-base modifier regulating liquid medicine in the range of 3.25 ~ 3.75,
Benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.25 ~ 3.75；It is described mixed
Liquid filtering decarbonization is closed to operate according to following manner：It is first filtered with filter paper, the stud for being then 1um with aperture filters, then use
The polyether sulfone filter core of 0.45um is by liquid coarse filtration；
(4) by step (3) prepare liquid aseptic filtration, be filled into vial, seal, carry out pressure sterilizing to get.
2. ondansetron hydrochloride parenteral solution according to claim 1, the concentration of wherein ondansetron hydrochloride are calculated as with Ondansetron
1.75~2.25mg/ml。
3. ondansetron hydrochloride parenteral solution according to claim 1, the concentration of wherein ondansetron hydrochloride are calculated as with Ondansetron
2mg/ml。
4. ondansetron hydrochloride parenteral solution according to claim 1, pH is in the range of 3.25 ~ 3.75.
5. ondansetron hydrochloride parenteral solution according to claim 1, the acid-base modifier is hydrochloric acid or sodium hydroxide.
6. ondansetron hydrochloride parenteral solution according to claim 1, the dosage of water for injection is the 50 of prescription full dose in step (1)
~90%。
7. ondansetron hydrochloride parenteral solution according to claim 1, the dosage of water for injection is the 60 of prescription full dose in step (1)
~80%。
8. ondansetron hydrochloride parenteral solution according to claim 1, the water temperature of water for injection used is below 40 DEG C.
9. ondansetron hydrochloride parenteral solution according to claim 1, in step (2) addition of needle-use activated carbon for 0.05 ~
0.15%。
10. ondansetron hydrochloride parenteral solution according to claim 1, the addition of needle-use activated carbon is 0.1% in step (2).
11. ondansetron hydrochloride parenteral solution according to claim 1, the middle pH of acid-base modifier regulating liquid medicine of step (2) exists
In the range of 7.0 ~ 7.5.
12. ondansetron hydrochloride parenteral solution according to claim 1, wherein step (2) Chinese medicine liquid stir 30 ~ 45 points at room temperature
Clock.
13. ondansetron hydrochloride parenteral solution according to claim 1, the acid-base modifier is 1M hydrochloric acid solutions or 1M hydrogen
Sodium hydroxide solution.
14. ondansetron hydrochloride parenteral solution according to claim 1, aseptic filtration described in step (4) uses 0.22um
Polyether sulfone filter core carries out aseptic filtration.
15. ondansetron hydrochloride parenteral solution according to claim 1, pressure sterilizing processing is sterilized at 121 DEG C in step (4)
Processing 30 minutes.
16. the method for ondansetron hydrochloride parenteral solution described in claim 1 is prepared, the concentration of ondansetron hydrochloride in the parenteral solution
1.5 ~ 2.5mg/ml is calculated as with Ondansetron；It includes the following steps：
(1) the ondansetron hydrochloride bulk pharmaceutical chemicals of recipe quantity are taken, are added in suitable water for injection, stirring dissolves drug；
(2) into step (1) acquired solution in terms of medicine liquid volume addition 0.05 ~ 0.2% needle-use activated carbon, while add paper pulp,
Paper pulp additive amount is calculated as the 40 ~ 60% of activated carbon with the dry weight of paper；It is uniformly mixed, then with the pH of acid-base modifier regulating liquid medicine
In the range of 6.5 ~ 7.5, liquid is stirred at room temperature 30 ~ 60 minutes；
(3) by mixed liquor filtering decarbonization obtained by step (2), with the pH of acid-base modifier regulating liquid medicine in the range of 3.25 ~ 3.75,
Benefit injects water to prescription full dose, and the optional pH with acid-base modifier regulating liquid medicine is in the range of 3.25 ~ 3.75；It is described mixed
Liquid filtering decarbonization is closed to operate according to following manner：It is first filtered with filter paper, the stud for being then 1um with aperture filters, then use
The polyether sulfone filter core of 0.45um is by liquid coarse filtration；
(4) by step (3) prepare liquid aseptic filtration, be filled into vial, seal, carry out pressure sterilizing to get.
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| CN109464385A (en) * | 2018-12-20 | 2019-03-15 | 江西润泽药业有限公司 | Ondansetron hydrochloride and the composition of dexamethasone and preparation method thereof |
| CN109464386A (en) * | 2018-12-20 | 2019-03-15 | 江西润泽药业有限公司 | Ondansetron hydrochloride injection and preparation method thereof |
| CN114209648A (en) * | 2021-12-31 | 2022-03-22 | 贵州景峰注射剂有限公司 | Ondansetron hydrochloride injection and preparation method thereof |
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