CN110461325A - Treatment including oral or stomach application Edaravone - Google Patents
Treatment including oral or stomach application Edaravone Download PDFInfo
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- CN110461325A CN110461325A CN201880007105.6A CN201880007105A CN110461325A CN 110461325 A CN110461325 A CN 110461325A CN 201880007105 A CN201880007105 A CN 201880007105A CN 110461325 A CN110461325 A CN 110461325A
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Abstract
The present invention relates to the composition of liquid medicine for therapeutic treatment purposes, the composition of liquid medicine is the single phase aqueous solution of the 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) of non-complexing, it and include at least water and 0.2-9mg/mL Edaravone of 7 weight %, wherein treatment includes the composition of liquid medicine of oral or stomach application 10-250mL to provide the Edaravone of 30-300mg.
Description
Technical field
The present invention relates to purposes of the 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) in therapeutic treatment, institutes
Stating treatment includes the composition of liquid medicine that the application of oral or stomach includes water and Edaravone.
Background technique
ALS is a kind of Neurodegenerative conditions, influences the upper motor neurons being located in brain and is located at spinal cord and brain stem
In lower motor neuron.Upper motor neurons retrogression typically results in muscle cramp, and lower motor neuron retrogression
Lead to myasthenia, amyotrophia and twitch.
The early symptom of ALS generally includes the myasthenia of hand, arm, leg or foot, leads to these physical feeling inability or convulsion
Contraction.The disease itself causes to chew, talk, swallow and have difficulty in breathing there is likely to be in control speech or the muscle swallowed.
With the progress of disease, it can be diffused into other positions of body, lead to progressive myasthenia and paralysis.ALS patient finally loses
Them are gone to start and control all paleocinetic abilities, and neuromuscular respiratory failure makes breathing become more and more difficult.
The early symptom of the disease and development vary with each individual.
Sensory nerve and autonomic nerves system are unaffected, make the sense of hearing, vision, tactile, smell and the sense of taste and nonvoluntary
Flesh (such as those of control heartbeat, gastrointestinal tract, intestines and bladder function involuntary muscle) keeps complete.Cognitive function generally also not by
It influences.
Most of man-year ages for developing ALS are between 40 years old to 70 years old, but the disease is it can also happen that younger
Age.It has been found that illness rate increases with advancing age.Although ALS is classified as a kind of orphan disease, it is most often
The motor neuron disease seen.Annual 100, about one people or two human hairs open up ALS in 000 people, and the illness rate of ALS is estimated as often
About two in 100,000 populations, due to aging of population, number of patients is continuously increased.
Riluzole (Riluzole) is the currently the only approved drug for ALS.It is believed that its effect is its drop
The potentiality of hypoglutamatergic (neurotransmitter) signal transduction have been found in the human body with ALS with higher horizontal presence.
It has been found that the drug has limited beneficial effect to the symptom of ALS and the progress of disease.It will improve survival rate, but only
It is in certain degree.
In May, 2017, food and drug administration (U.S.Food and Drug Administration) approval
Radicava (Edaravone) treatment suffers from amyotrophic lateral sclerosis (ALS) (commonly known as Lu Jialei disease (Lou
Gehrig ' s disease)) patient.Radicava is the venoclysis given by health care professionals.That applies is first
Beginning treatment cycle be administered daily 14 days, followed by 14 days without drug period.Subsequent treatment cycle include 10 days of 14 days to
Medicine, then 14 days without drug.The function of Clinical Therapeutic Effects of Edaravone ALS is demonstrated in the clinical test in six months by a definite date that Japan carries out
Effect.In test, 137 participants, which are probabilistically assigned, receives Edaravone or placebo.At the 24th week, and receive placebo
Those patients compare, receive Edaravone patient decline in the clinical assessment of daily life function it is less.
Edaravone is a kind of intelligence development and neuroprotective agent, is used to help after acute cerebral ischemia and subsequent cerebral infarction
Nerve recovery.It is as a kind of effective antioxidant and strength removes free radical, to prevent oxidative stress and neuron
Apoptosis.
It is intended to make the life better to the other medicines that ALS patient opens and quality and alleviates the symptom of ALS, such as crick and convulsion
Contraction, constipation, fatigue, salivation and phlegm is excessive, pain, depression and sleeping problems.
EP-A1 405 637 describes purposes of the Edaravone in treatment motor neuron disease (including ALS).
EP-A1 714 960 be related to Edaravone treatment ALS in purposes, wherein have during treatment time one or
Multiple drug holidays.
EP-A2 754 440 describes the purposes of ALS of the Edaravone for treating specific group of patients, wherein passing through weight
Multiple 14 days application phases and 14 days drug holidays, or the application phase by establishing initial 14 days and the vacation of initial 14 days drugs
Phase, then the repetitive administration phase continues 10 days and 14 days drug holidays in 14 days to apply the reagent.
WO 2012/019381 describes the combination of oral medication containing Edaravone and cyclodextrin, wherein Edaravone
Weight ratio with cyclodextrin is 1:6-100.Preparation method the following steps are included:
Beta-cyclodextrin or the cyclodextrin mixt containing beta-cyclodextrin are mixed with the water of 1-5 times of weight,
Edaravone or its solution in organic solvent are added in cyclodextrin solution,
Grinding or stirring, and
In the at a temperature of evaporation water not higher than 60 DEG C, by being dried under reduced pressure.
In the prior art highly recognition be Edaravone oral administration biaavailability it is low, and research has been carried out
To provide the oral preparation of the Edaravone for the oral administration biaavailability for realizing improvement.
Rong et al. (Hydroxypropyl-Sulfobutyl- β-Cyclodextrin Improves the Oral
Bioavailability of Edaravone by Modulating Drug Efflux Pump of Enterocytes,
Journal of Pharmaceutical Sciences (2013), DOI 10.1002/jps.23807,1-13) describe one
Item research, wherein having studied hydroxypropyl-sulfonylurea-beta-cyclodextrin to the bioavilability of Edaravone and the influence of intestinal absorption.
It was found that Edaravone-cyclodextrin clathrate complex improves the water solubility of Edaravone and improves Edaravone in rat
Intracorporal bioavilability." original (raw) " Edaravone that the display of table 2 of this article is administered orally is (outstanding with 0.5%CMC-Na
It is floating) absolute bioavailability (Fabs) it is only 5.23% (the 100% bioavilability phase with the Edaravone intravenously applied
Than).Table 2 is also shown, by the way that the oral administration biaavailability of Edaravone and cyclodextrin, Edaravone can be enhanced 10 times
More than.
Parikh et al. (Development of a novel oral delivery system of edaravone
for enhancing bioavailability,International Journal of Pharmaceutics 515
(2016) 490-500) discuss Edaravone oral delivery system exploitation.Author describes a kind of novel Edaravone
Oral delivery system (NODS), by Labrasol and the acidic aqueous system optimized based on solubility and stability study
Mixture be made.NODS delivery system contains the Edaravone of 30mg/mL.Using the equivalent dose of 30mg/kg Edaravone,
The oral bioavilability of NODS delivery system is had studied in adult rat.It was found that the oral bio of NODS delivery system
Availability is the oral bio benefit of the Edaravone suspension containing 30mg/mL Edaravone and 0.5% sodium carboxymethylcellulose
5.7 times (referring to tables 2) of expenditure.
Parikh et al. (Lipid-based nanosystem of edaravone:development,
optimization,characterization and in vitro/in vivo evaluation,Drug Delivery
24(1)；(2017), 962-978) describe one be intended to by develop the nanosystems (LNS) based on lipid make Yi Dala
That gives is administered orally the research being possibly realized.Component (including oil, surfactant and cosurfactant) based on LNS is in stomach
Come the potentiality of solubilising maximization, the glucuronidation for reducing it and raising transmembranal penetration to it
Selected.Preparation is in the liquid LNS (L-LNS) of microemulsion form, and it includes CapryolTMPGMC (oil),RH 40:: TPGS 1000 (1:0.8:0.2) (surfactant) and
P (cosurfactant).The microemulsion has characteristics that droplet size (16.25nm), polydispersity index (0.039), light transmission
Rate % (99.85%) and self-emulsifying time (32s).It was found that the oral administration biaavailability of L-LNS almost than containing 30mg/mL according to reaching
The oral administration biaavailability of the Edaravone suspension of La Feng and 0.5% sodium carboxymethylcellulose is high 11 times (referring to tables 3).
WO 2012/019381 describes the combination of oral medication containing Edaravone and cyclodextrin, wherein Edaravone
Weight ratio with cyclodextrin is 1:6-100.Preparation method the following steps are included:
Beta-cyclodextrin or the cyclodextrin mixt containing beta-cyclodextrin are mixed with the water of 1-5 times of weight,
Edaravone or its solution in organic solvent are added in cyclodextrin solution,
Grinding or stirring, and
In the at a temperature of evaporation water not higher than 60 DEG C, by being dried under reduced pressure.
CN 101 953 832 describes the combination of oral medication combined comprising cyclodextrin with Edaravone.The China is special
The embodiment of benefit application is described containing cyclodextrin-Edaravone complex compound tablet, capsule and granule.
CN 105 816 423 describes the various drug delivery systems based on lipid comprising Edaravone.The China is special
The embodiment of benefit application, which is described, applies Edaravone to Oral Administration in Rats using self-emulsifying microemulsion drug delivery system (SMEDDS)
(30mg.kg)。
Food and drug administration ratifies intravenous Edaravone and is transfused (RadicavaTM) treat with amyotrophic side
The patient of rope sclerosis (ALS).Radicava is applied by health care professionals.The initial treatment period of application is every
Day administration 14 days, followed by 14 days without drug period.Subsequent treatment cycle includes that 10 days of 14 days are administered, then 14 days nothings
Drug.
Intravenous application is a kind of less attracting administration method, because it needs the presence of doctor, and is not therefore permitted
Perhaps self is applied.In addition, many patients, which do not like, receives drug by injection.
Summary of the invention
In the various modes of drug delivery, oral delivery is still the most attractive and acceptable of active pharmaceutical ingredient
Administration method.Oral route is convenience, the high-caliber patient compliance of generation and long-term compliance preferably as it
Property, this transfers and increases the therapeutic value of drug.In most cases, it allow patient's self-administering drug without
The help of doctor.
Accordingly, it is desirable to provide the Edaravone dosage form that can be applied by oral route.However, traditional peroral dosage form is (all
Such as tablet and capsule) to the patient of dysphagia bring problem.Patient (such as ALS patient) with neurodegenerative disease is logical
Often it is particularly the case.
Inventor is it was unexpectedly observed that the aqueous solution of Edaravone has the oral bioavailability than being assumed so far
Spend much higher oral administration biaavailability.And the above-mentioned article of Rong et al. reports the exhausted of oral administration " original " Edaravone
It is only 5.23% to bioavilability, inventor observes molten when aqueous Edaravone of the invention is administered orally to human subjects
When liquid, absolute bioavailability is about 80%.In fact, the oral bio of the aqueous solution containing 0.2-9mg/mL Edaravone
Availability is very high, when aqueous solution is administered orally with the daily dosage for providing 30mg to 300mg Edaravone, has realized
The medical effect of meaning.
It is surprisingly possible that aqueous Edaravone solution of the invention realizes high oral administration biaavailability, and not make
Enhance with the Edaravone of form complexed, and not by incorporation micella or the lipid phase (nanoemulsions or microemulsion) of dispersion
The solubility of Edaravone.
Therefore, the purposes the present invention relates to aqueous Edaravone solution in therapeutic treatment, the treatment include it is oral or
Stomach applies the single phase aqueous solution of the Edaravone of 10-250mL non-complexing to provide the Edaravone of 30-300mg, the list
Phase aqueous solution includes the Edaravone of at least water of 75 weight % and 0.2-9mg/mL.RadicavaTMBe can with dilution or
Example of the non-diluted form for the aqueous Edaravone solution of these oral or stomach treatments.
Detailed description of the invention
Therefore, the present invention relates to the composition of liquid medicine for therapeutic treatment, the composition of liquid medicine is non-network
The single phase aqueous solution of the 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) of conjunction, and include at least 75 weight %
Water and 0.2-9mg/mL Edaravone, wherein the treatment includes the liquid medicine of oral or stomach application 10-250mL
Compositions are to provide the Edaravone of 30-300mg.
As used herein term " Edaravone " refers to substance 3-methyl-1-phenyl-2-pyrazolin-5-one.
As used herein term " aqueous solution of Edaravone " refers to that wherein Edaravone is completely dissolved in water
Homogeneous mixture.
As it is used herein, term " single-phase " related with aforementioned aqueous solution refers to without two or more not
With the liquid composition of phase.Therefore, composition of liquid medicine of the invention is not lotion (such as microemulsion, nanoemulsions or glue
Beam suspension/solution).
As used herein term " Edaravone of non-complexing " refer to Edaravone not with complexing agent (such as β-ring
Dextrin) complex form be present in composition of liquid medicine.
As used herein term " treatment " includes therapeutic and pregnancies with conservative treatment.
Term " stomach application ", which refers to, to be applied to via pipe by the pipe (PEG tube) in nasal passage (NG pipe) or abdomen
Stomach.
Composition of liquid medicine of the invention is preferred for treating mammal, is more preferably used for the treatment mankind.
During the time that treatment according to the present invention is preferably incorporated at least 2 weeks, more preferably at least 4 weeks time
Period, at least once a day to patient is oral or stomach applicating liquid pharmaceutical composition.
Composition of liquid medicine is preferably to provide the amount of 50-200mg Edaravone, more preferably to provide 80-160mg
The amount of Edaravone is oral or stomach is applied.
The invention also includes the wherein treatments of two doses of application or more composition of liquid medicine daily.Preferably, it takes orally
Or the total amount of Edaravone of stomach application is no more than 300mg Edaravone daily, is more preferably no more than 200mg daily according to reaching
La Feng is most preferably no more than 160mg Edaravone daily.
In some cases, it is proposed that adjust Edaravone dosage by patient's weight.In general, to provide 0.4-4mg Yi Dala
/ the amount of kg body weight/day is given, more preferably to provide 0.8-3.7mg Edaravone/kg body weight/day amount, most preferably to provide
1-3.5mg Edaravone/kg body weight/day amount applies composition of liquid medicine of the invention.
According to a preferred embodiment of the invention, with the amount of 40-250mL, more preferably with the amount of 80-200mL, most
Preferably using the amount application of 100-150mL as the composition of liquid medicine of diluted Edaravone solution.In general, the dilution
Edaravone solution contain the Edaravone of 0.3-1mg/mL, more preferably containing the Edaravone of 0.4-0.8mg/mL.It is dilute
The Edaravone solution released can be molten by the Edaravone with waterborne liquid dilution concentration shortly before oral or stomach is applied
Liquid or the Edaravone preparation by will dry are mixed with waterborne liquid to prepare.
In another preferred embodiment, with the amount of 20-150mL, more preferably with the amount of 30-100mL, with concentration
The form of Edaravone solution carrys out applicating liquid pharmaceutical composition.The Edaravone solution of concentration usually contain 1-9mg/mL according to
Da Lafeng, more preferably containing the Edaravone of 1.1-7mg/mL, even more preferably containing the Yi Dala of 1.15-4mg/mL
It gives, most preferably containing the Edaravone of 1.2-2mg/mL.
In another preferred embodiment that the present invention treats, patient is in oral or stomach applicating liquid pharmaceutical composition
Fasting before at least 1 hour.
The water content of composition of liquid medicine is preferably at least 85 weight %.
In addition to Edaravone and water, composition of liquid medicine preferably contains one or more other components.It is such
The example of other components includes antioxidant, pH adjusting agent, preservative and sodium chloride.
An embodiment according to the present invention, composition of liquid medicine have been made into ready-to-liquid composition.According to
Preferred embodiment, the instant composition of liquid medicine contain molar ratio be 1:2 to 2:1 alkali metal bisulfite and
Edaravone, it is highly preferred that molar ratio is 2:3 to 3:2, alkali metal bisulfite is selected from sodium hydrogensulfite, potassium bisulfite
And their combination.Most preferably, alkali metal bisulfite used in composition of liquid medicine is sodium hydrogensulfite.
According to other preferred embodiments, it is 1:5 to 1:1 that ready-to-liquid composition, which contains weight ratio, more preferably
Weight ratio is the L-cysteine and Edaravone of 1:4 to 1:2.
The pH of ready-to-liquid composition is generally in the range of 3.0 to 9.0, more preferably 3.0 to 6.0.In instant liquid
In the case that body composition is concentrate solution, as previously mentioned, pH ranges preferably from 3.0 to 4.5.It is in ready-to-liquid composition
In the case where dilute solution, as previously mentioned, the pH of composition ranges preferably from 3.5 to 6.0.
Ready-to-liquid composition in the form of concentrate solution preferably has the infiltration pressure-volume of 250-320mOsm/L range
Measure molar concentration.
In another preferred embodiment, ready-to-liquid composition does not include nonionic surfactant.Even
It is highly preferred that ready-to-liquid composition is free of surfactant.
Ready-to-liquid composition is preferably sterile solution.
In another embodiment of the present invention, by the way that the dry of Edaravone will be included before the application of oral or stomach
Dry particle Edaravone preparation mixes fresh to prepare composition of liquid medicine with waterborne liquid.
It was unexpectedly observed that in the presence of basifier, the rate that Edaravone dissolves in water dramatically increases inventor.Cause
This, preferably before the application of oral or stomach by will the dry particle pharmaceutical composition containing Edaravone and basifier with
Waterborne liquid mixes to prepare composition of liquid medicine.
Preferably, freshly prepared liquid composition contains 0.3-9mg/mL, more preferably contains 0.5-4mg/mL, and
The most preferably water-soluble alkali agent containing 0.8-2mg/mL.Water-soluble alkali agent is preferably chosen from: the oxide of alkalinous metal
And hydroxide；The oxide and hydroxide of alkaline-earth metal；Al(OH)3；Fe2O3；The salt of weak organic acid and weak inorganic acid, alkali
Property amine；Basic amino acid and their combination.
The oxide and hydroxide of alkalinous metal are preferably chosen from NaOH, KOH, LiOH and their combination.Alkaline earth
The oxide and hydroxide of metal are preferably chosen from Ca (OH)2、CaO、Mg(OH)2MgO and their combination.Weak organic acid
Carbonate, bicarbonate, borate, carboxylate (such as lactate, citrate, second are preferably chosen from the salt of weak inorganic acid
Hydrochlorate, formates and oxalates), phosphate, sulfate and their combination.Basic amine is preferably chosen from three (methylol) ammonia
Methylmethane, ethanol amine, diethanol amine, triethanolamine, N- methyl-glucamine, gucosamine, ethylenediamine, diethylamine, triethylamine,
Isopropylamine, diisopropylamine, ammonia and their combination.Basic amino acid be preferably chosen from arginine, histidine, lysine and
Their combination.The present invention includes using the above-mentioned water-soluble alkali agent in the form of pharmaceutically acceptable salt and hydrate.
According to particularly preferred embodiment, water-soluble alkali agent be selected from three (methylol) aminomethanes, phosphate (such as
Na3PO4) and their combination.
Freshly prepared liquid composition preferably pH is at least 6.0, more preferably at least 6.5, more preferably at least
6.8.The pH of freshly prepared liquid composition is typically not greater than 9.0, no more than 8.8, and does not surpass most preferably
Cross 8.5.
According to another preferred embodiment, freshly prepared liquid composition contains 5-40mg/mL, more preferably contains
Have a polyalcohol of 6-25mg/mL, the polyalcohol be selected from mannitol, D-sorbite, xylitol, maltitol, lactitol and
Their combination.
Freshly prepared liquid composition is preferably containing 0.03-30mg/mL, more preferably containing 0.05-20mg/mL's
Surfactant.
According to particularly preferred embodiment, freshly prepared liquid composition contains at least 0.03mg/mL, more preferably
At least nonionic surfactant of 0.05mg/mL.Nonionic surfactant is preferably chosen from poloxamer, polysorbate
And their combination.Poloxamer is nonionic triblock copolymer, flanks two by center polyoxypropylene hydrophobic chain and gathers
Ethylene oxide hydrophilic chain composition.
According to preferred embodiment, composition of liquid medicine contains less than 3 weight %'s, preferably less than 1 weight %
Water-miscible organic solvent, the water-miscible organic solvent are selected from polyethylene glycol (such as PEG200-10,000), propylene glycol, the third three
Alcohol, diethylene glycol monoethyl ether (such as Transcutol HP, Transcuto lP), Emulsifier EL-60 (such as
Cremophor RH 40, Cremophor EL), polyoxyethylene glyceride (such as Labrasol), polyoxyethylene sorbitol acid anhydride
The vitamin E (such as TPGS1000) and ethyl alcohol of aliphatic ester (such as polysorbas20, Tween 80), water-soluble form.
Composition of liquid medicine preferably contains no more than 5 weight %, no more than 3 weight %, and even
The no more than organic substance in addition to Edaravone of 1 weight %.
Composition of liquid medicine of the invention is preferred for treating neurodegenerative disease；Cerebral amyloid angiopathy (CAA)；
Autoimmune disease；Myocardial infarction or cranial vascular disease.It is highly preferred that composition of liquid medicine is for treating nervus retrogression disease
Disease or cranial vascular disease.
According to particularly preferred embodiment, composition of liquid medicine is for treating neurodegenerative disease, more preferably
For treating the neurodegenerative disease for being selected from amyotrophic lateral sclerosis (ALS) and Alzheimer's disease.Most preferably, liquid
Body pharmaceutical composition is for treating ALS.
According to particularly preferred embodiment, the Current therapeutic of disease includes pregnancies with conservative treatment.
It is further illustrated by the following non-limitative examples the present invention.
Embodiment
Embodiment 1
A research is carried out, wherein willThe Edaravone solution contained in ampoule is oral and intravenously applies
For dog, to provide the Edaravone of 60mg single dose.
The research carries out in one group of 4 male beagle dogs.Two are included in animal single oral administration
Edaravone solution in ampoule bottle (each ampoule contains 30mg Edaravone/20ml solution).After 2 days elution phases, move
Object receives twoThe intravenous infusion (15 minutes Infusion Times) of ampoule.
Taken at regular intervals blood sample before administration and after application, and the Edaravone blood plasma for measuring each sample is dense
Degree.The average result of these measurements has been displayed in Table 1.The parameter for indicating relative bioavailability is presented in table 2.
Table 1
N.d.: undetermined
Table 2
| It is administered orally | Intravenous infusion | |
| Tmax(min) | 5 | 15 |
| Cmax(ng/ml) | 2310 | 4380 |
| AUClast(h.ng/ml)1 | 542 | 1600 |
| AUC0-inf(h.ng/ml)2 | 553 | 1630 |
1AUClastIt is from the face under the plasma concentration v. time curve that the time of application once can measure plasma concentration to the end
Product
2AUC0-infIt is the plasma concentration v. time area under a curve from administration time to (extrapolation) infinity
These results indicate that the Edaravone being administered orally shows quick absorption, wherein about 5min reaches after application
Peak value maximum concentration, and compared with intravenous infusion, the systemic bioavailability (F shownabs=34%).
Embodiment 2
Single dose, random, two phases, crossing research are carried out in 18 healthy male and female human subjects.
What object was received:
140mg Edaravone (p.o) contains the new of 1.5 grams of drying agent as shown in table 3 with 100mL
The solution form of fresh preparation
60mg Edaravone (intravenous 60 minutes), uses two bottles(30mg is according to reaching in 20mL solution for ampoule
La Feng)
Table 3
| Weight % | |
| Edaravone (micronization) | 9.3 |
| Mannitol | 56.8 |
| Sodium orthophosphate | 33.3 |
| Lauryl sodium sulfate | 0.5 |
| It amounts to | 100.0 |
Before administration with taken at regular intervals blood sample after application, and the Edaravone blood plasma for measuring each sample is dense
Degree.The average result of these measurements has been displayed in Table 4.The parameter for indicating relative bioavailability is presented in table 5.
Table 4
N.d.: undetermined
Table 5
| It is administered orally | Intravenous infusion | |
| Tmax(hr) | 0.25 | 1 |
| Cmax(ng/ml) | 2936 | 1030 |
| AUClast(h.ng/ml)1 | 2389 | 1292 |
| AUC0-inf(h.ng/ml)2 | 2413 | 1304 |
1AUClastIt is from the face under the plasma concentration v. time curve that the time of application once can measure plasma concentration to the end
Product
2AUC0-infIt is the plasma concentration v. time area under a curve from administration time to (extrapolation) infinity
These results indicate that the Edaravone being administered orally shows quickly to absorb, wherein about 15min reaches after application
Peak value maximum concentration, and compared with intravenous infusion, the systemic bioavailability (F shownabs=79%).
Claims (18)
1. being used for the composition of liquid medicine of therapeutic treatment, the composition of liquid medicine is 3- methyl-1-phenyl-of non-complexing
The single phase aqueous solution of 2- pyrazolin-5-one (Edaravone), and include the water and 0.2-9mg/mL of at least 75 weight %
Edaravone, wherein the treatment includes the composition of liquid medicine of oral or stomach application 10-250mL to provide 30-
The Edaravone of 300mg.
2. the composition of liquid medicine according to claim 1 for treatment, wherein to provide 50-200mg Edaravone
Amount apply the composition of liquid medicine.
3. it is according to claim 1 or 2 for treatment composition of liquid medicine, wherein with provide be no more than 300mg according to
Da Lafeng/day amount applies the composition of liquid medicine.
4. the composition of liquid medicine according to any one of the preceding claims for treatment, wherein to provide 0.4-
4mg Edaravone/kg body weight/day amount applies the composition of liquid medicine.
5. the composition of liquid medicine according to any one of the preceding claims for treatment, wherein the liquid medicine
Composition is the diluted Edaravone solution containing 0.3-1mg/mL Edaravone, applies the dilution with the amount of 40-250mL
Edaravone solution.
6. the composition of liquid medicine described in any one of -4 for treatment according to claim 1, wherein the liquid medicine
Composition is the Edaravone solution of the concentration containing 1-9mg/mL Edaravone, applies the concentration with the amount of 20-150mL
Edaravone solution.
7. the composition of liquid medicine according to any one of the preceding claims for treatment, wherein the liquid medicine
Composition contains the water of at least 85 weight %.
8. the composition of liquid medicine according to any one of the preceding claims for treatment, wherein the liquid medicine
Composition contains the alkali metal bisulfite and Edaravone that molar ratio is 1:2 to 2:1, the alkali metal bisulfite choosing
From sodium hydrogensulfite, potassium bisulfite and their combination.
9. the composition of liquid medicine according to any one of the preceding claims for treatment, wherein the liquid medicine
Composition contains the L-cysteine and Edaravone that weight ratio is 1:5 to 1:1.
10. the composition of liquid medicine according to any one of the preceding claims for treatment, wherein the liquid medicine
Compositions are free of nonionic surfactant.
11. the composition of liquid medicine described in any one of -7 for treatment according to claim 1, wherein in oral or stomach
By will include that the dry particle Edaravone preparation of Edaravone mixes with waterborne liquid and to prepare the liquid before application
Pharmaceutical composition.
12. the composition of liquid medicine according to claim 11 for treatment, wherein the dry particle Edaravone
Preparation includes basifier.
13. the composition of liquid medicine according to claim 12 for treatment, wherein basifier is selected from: alkalinous metal
Oxide and hydroxide；The oxide and hydroxide of alkaline-earth metal；Al(OH)3；Fe2O3；Weak organic acid and weak inorganic acid
Salt, basic amine；Basic amino acid and their combination.
14. composition of liquid medicine described in any one of 1-13 according to claim 1, wherein the composition of liquid medicine
PH range is 6.0 to 9.0.
15. the composition of liquid medicine according to any one of the preceding claims for treatment, wherein the liquid medicine
Compositions are for treating neurodegenerative disease；Cerebral amyloid angiopathy (CAA)；Autoimmune disease；Myocardial infarction or brain
Vascular diseases.
16. the composition of liquid medicine for treatment as described in any one of the preceding claims, wherein the liquid medicine
Composition is for treating neurodegenerative disease or cranial vascular disease.
17. the composition of liquid medicine for treatment as described in any one of the preceding claims, wherein the liquid medicine
Composition is used to treat the neurodegenerative disease selected from amyotrophic lateral sclerosis (ALS) and Alzheimer's disease.
18. the composition of liquid medicine for treatment as described in any one of the preceding claims, wherein the treatment includes
It was at least taken orally once a day at least 2 weeks time or stomach applies the composition of liquid medicine.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP171517410 | 2017-01-17 | ||
| EP15017410 | 2017-01-17 | ||
| EPPCT/EP2017/067005 | 2017-07-06 | ||
| PCT/EP2017/067005 WO2018133957A1 (en) | 2017-01-17 | 2017-07-06 | Medical treatment comprising enteral administration of edaravone |
| EP171800873 | 2017-07-06 | ||
| PCT/EP2018/051097 WO2018134243A1 (en) | 2017-01-17 | 2018-01-17 | Treatment comprising oral or gastric administration of edaravone |
| EP18000873.2A EP3492653B1 (en) | 2017-11-30 | 2018-11-06 | Online cleaner for water-bearing systems or systems which come into contact with water |
Publications (1)
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| WO2022042644A1 (en) * | 2020-08-26 | 2022-03-03 | 上海博志研新药物技术有限公司 | Edaravone sustained-release pharmaceutical composition, preparation method, and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1449754A (en) * | 2003-04-16 | 2003-10-22 | 浙江震元制药有限公司 | Edaravone medicine composition and preparation thereof |
| EP1714960A1 (en) * | 2004-02-09 | 2006-10-25 | Mitsubishi Pharma Corporation | Novel therapeutic agent for amyotrophic lateral sclerosis (als) or disease attributable to als |
| CN105616405A (en) * | 2014-11-05 | 2016-06-01 | 中国人民解放军第三军医大学第三附属医院 | Use of edaravone in preparation of drug for preventing and treating cerebral amyloid angiopathy (CAA) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101953832B (en) * | 2010-08-10 | 2012-02-15 | 南京师范大学 | Oral drug composite of beta-cyclodextrin edaravone inclusion and preparation method thereof |
-
2017
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2018
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1449754A (en) * | 2003-04-16 | 2003-10-22 | 浙江震元制药有限公司 | Edaravone medicine composition and preparation thereof |
| EP1714960A1 (en) * | 2004-02-09 | 2006-10-25 | Mitsubishi Pharma Corporation | Novel therapeutic agent for amyotrophic lateral sclerosis (als) or disease attributable to als |
| CN105616405A (en) * | 2014-11-05 | 2016-06-01 | 中国人民解放军第三军医大学第三附属医院 | Use of edaravone in preparation of drug for preventing and treating cerebral amyloid angiopathy (CAA) |
Non-Patent Citations (2)
| Title |
|---|
| MAKOTO ISHIZAWA ET AL.: ""An antioxidant treatment potentially protects myocardial energy metabolism"", 《LIFE SCIENCES》 * |
| 贾萧铭: ""依达拉奉氯化钠注射液制备工艺及质量研究"", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022042644A1 (en) * | 2020-08-26 | 2022-03-03 | 上海博志研新药物技术有限公司 | Edaravone sustained-release pharmaceutical composition, preparation method, and application |
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