CN101352438A - Uses of deferiprone and formulation thereof in preparing medicament for preventing and treating cardiotoxicity induced by anthracyclines - Google Patents
Uses of deferiprone and formulation thereof in preparing medicament for preventing and treating cardiotoxicity induced by anthracyclines Download PDFInfo
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Abstract
The invention belongs to the field of medicine, which relates to Deferiprone and a novel medicated purpose of a Deferiprone preparation, in particular to Deferiprone (1,2- dimethyl-3-hydroxide radical-4-pyridine, Deferiprone) and the application of the Deferiprone preparation in the prevention and curing of Anthracycline medicine heart toxicity. The invention researches the preventing and curing function of the Deferiprone to bandicoot heart toxicity caused by Adriamycin from the cell level, the tissue level and the whole level and prepares biodegradable type Deferiprone implant, Deferiprone troche, capsule, oral liquor and injection that can release medicine continuously. An experimental result proves that the Deferiprone and the Deferiprone preparation can not only improves the cardiac muscle shrinkage functions and protects the myocardial cell organ structure, but also complexes free iron ions directly, reduces the heart toxicity and other side and toxic effects caused by the Anthracycline medicine obviously and the mortality rate caused by the Anthracycline medicine.
Description
Technical field
The invention belongs to field of medicaments, relate to the medicinal new purposes of deferiprone and preparation thereof.Be specifically related to the application in control anthracene nucleus medicament cardiac toxicity of deferiprone (Deferiprone) and preparation thereof.
Background technology
Anthracene nucleus medicament occupies critical role in the chemotherapy of tumor, have wide spectrum, advantage efficiently, and its main mechanism is between the direct intercalation of DNA base pair, disturbs transcription, stops the formation of mRNA, suppresses the propagation of tumor cell.It not only suppresses the synthetic of DNA but also suppresses the synthetic of RNA, so all there is effect in each stage of cell cycle, is cell cycle nonspecific agent (CCNSA).Yet the dose accumulation cardiac toxicity of anthracene nucleus medicament has limited its clinical practice, and has increased patient's misery and burden.(Doxorubicin DOX) is example, and the myocardiac mortality rate of amycin is 40%, and the inductive congestive heart failure case fatality rate of amycin is up to 33%～70% with amycin.
Seeking myocardial protective agent at anthracene nucleus medicament heart toxicity mechanism is one of approach of control anthracene nucleus medicament cardiac toxicity.Existing research once adopted some medicines to be used to prevent the cardiac toxicity of anthracene nucleus medicament, and wherein the curative effect yea-sayer is very few.At present, only dexrazoxane (Dexrazoxane) obtains U.S. food drug surveilance office (FDA) and ratifies to be used for clinical prevention amycin cardiac toxicity.The dexrazoxane curative effect is more definite, but costs an arm and a leg, and can only be with slow quiet the pushing away in lactic acid solution dissolving back.In addition, dexrazoxane can increase the weight of the inhibition of amycin to bone marrow, and part patient can't tolerate, and therefore, still need research and develop determined curative effect, convenient drug administration, moderate myocardial protective agent.
Deferiprone (1,2-Dimethyl-3-hydroxypyrid-4-one, Deferiprone, DEF) be first oral iron ion chelating agent, 1999 through European Union's approval listing, is used for the incompatible thalassemia major patient of deferoxamine (Deferoxamine) treatment because of the often excessive treatment of ferrum due to the blood transfusion of need
[Brittenham GM.Iron chelators and irontoxicity[J] .Alcohol, 2003,30 (2): 151-158; Pierre TGS.Deferiprone versus desferrioxamine in thalassaemia, and T2
*Validation and utility[J] .The Lancet, 2003,361 (9352): 182-182; Kontoghiorghes GJ, AgarwalMB, Tondury P, et al.Deferiprone or fatal iron toxic effects? [J] .The Lancet, 2001,357 (9259): 882-883
]Deferiprone belongs to 3-hydroxyl-4-pyridine compounds, molecular weight 139.2, and pKa3.5, dissolubility is 16～18mg/ml in 24 ℃ of water.Under the condition of pH 7.4, deferiprone and Fe
3+With 3: 1 ratios in conjunction with forming complex (DEF-Fe
3+)
1Kontoghiorghes GJ.Comparative Efficacy and Toxicity of Desferrioxamine, Deferiprone and Other Iron andAluminum Chelating Drugs[J] .Toxicology Letters, 1995,80 (1-3): 1-18.
]The oral back of deferiprone absorbs rapidly from stomach, and plasma half-life does not wait from 0.8 hour by 2.3 hours, mainly through liver metabolism, discharges from urine with the form of gluconic acid or iron complex.There is research application magnetic resonance T2 imaging technique that the thalassemia patient's of life-time service deferiprone or deferoxamine myocardium iron content is monitored, found that deferiprone more can reduce myocardium iron content effectively than deferoxamine, the better cardiac function of deferiprone therapist, its cardiac ejection fraction (LVEF) is higher than the deferoxamine therapist
[Anderson LJ, Wonke B, Prescott E, et al.Comparison of effects of oral deferiprone and subcutaneousdesferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia[J] .Lancet, 2002,360 (9332): 516-520
]The cell in vitro result of the test shows, deferiprone and Fe thereof
3+Complex can prevent effectively that all ischemia-reperfusion is to hepatocellular damage
[Moridani MY, O ' Brien PJ.Iron complexes of deferiprone and dietaryplant catechols as cytoprotective superoxide radical scavengers[J] .Biochemical Pharmacology, 2001,62 (12): 1579-1585
], and can alleviate amycin to the isolated myocardium cells injury
[Link G, Tirosh R, Pinson A, et al.Roleof iron in the potentiation of anthracycline cardiotoxicity:Identification of heart cell mitochondria as a majorsite of iron-anthracycline interaction[J] .Journal of Laboratory and Clinical Medicine, 1996,127 (3): 272-278;
Barnabe?N，Zastre?JA，Venkataram?S，et?al.Deferiprone?protects?against?doxorubicin-induced?myocytecytotoxicity[J].Free?Radical?Biology?and?Medicine，2002，33(2)：266-275
]。But, relevant deferiprone external to the influence of caused by doxorubicin myocardial contraction damage and in vivo the influence of amycin cardiac toxicity is not appeared in the newspapers so far; Also do not see relevant with the report of deferiprone as the preparation research and development of chemotherapy myocardial protective agent.
Summary of the invention
The medicinal new purposes that the purpose of this invention is to provide deferiprone and preparation thereof.Be specifically related to the application in control anthracene nucleus medicament cardiac toxicity of deferiprone (Deferiprone) and preparation thereof.
The present invention at first from cellular level, organize level, integral level to study deferiprone to the toxic preventive and therapeutic effect of caused by doxorubicin rat heart; Secondly, prepared and to have continued 1 month deferiprone biodegradation type implant of release, estimated deferiprone preventive and therapeutic effect to the amycin cardiac toxicity in the rat body once more; At last, preparation deferiprone tablet, capsule, oral solution and injection.
Deferiprone English name of the present invention is Deferiprone, and chemical name is 1, and 2-dimethyl-3-hydroxyl-4-pyridone has the chemical constitution of formula (I):
Anthracene nucleus medicament of the present invention comprises amycin, epirubicin, idarubicin (idarubicin), mitoxantrone (metoxantrone), daunorubicin benzene track (rubida-zone), Carubicin (carminomycin), AD32 (AD-32), Aclacnomycin A (aclacinomycin A) or triferricdoxorubicin (quclamycin).Especially amycin.
Cardiotoxicity caused anthracycline drug rerum natura cardiomyopathy, the chronic cardiac insufficiency of comprising of described anthracene nucleus medicament.
The dosage scope of described deferiprone is 1～20mg/kg body weight/day, preferred 2.5mg/kg body weight/day.
Described preparation is tablet, capsule, oral solution, injection or implant, preferred tablet, capsule or injection, most preferably tablet or capsule.
Experimental result shows; the present invention utilizes the cardiac toxicity due to deferiprone (Deferiprone) and the preparation control anthracene nucleus medicament thereof; the preparation of making can not only improve myocardium shrinkage function, protecting myocardial cell device structure; and the direct complexation free iron ion of energy; remove oxygen-derived free radicals; alleviate peroxide injury of myocardium due to the anthracene nucleus medicament; alleviate the cardiac toxicity that the anthracene nucleus medicament chemotherapeutic period produces human body; thereby improve the therapeutic index of anthracene nucleus medicament, alleviate the misery of patients undergoing chemotherapy and reduce the mortality rate that anthracene nucleus medicament caused.
Description of drawings
Fig. 1 deferiprone is to the influence (n=12 of amycin heart failure rat body weight
*)
Wherein,
1P＜0.01,
3Compare with the blank group p＜0.05;
2P＜0.01,
4Compare with the amycin group p＜0.05,
Body weight: body weight; Week of experiment: experimental period (week);
CONT: the blank group, DOX: the amycin group, DEF-1: 1 group of deferiprone,
DEF-2: 2 groups of deferiprones, DEF-3: 3 groups of deferiprones, DEF-CONT: deferiprone matched group.
Fig. 2 tests the influence (n=6) of the 4th all deferiprones to amycin administration rat ultrasonic cardiography graph parameter,
Wherein, Chang: change percentage rate; EF: ejection fraction, LVFS: left ventricular ejection fraction,
LVEDD: diastasis left ventricular internal diameter, LVESD: the end-systole left ventricular internal diameter,
EDAWT: diastasis left ventricle antetheca thickness, ESAWT: end-systole left ventricle antetheca thickness,
EDPWT: diastasis left ventricular posterior wall thickness, ESPWT: end-systole left ventricular posterior wall thickness;
CONT: the blank group, DOX: the amycin group, DEF-1: 1 group of deferiprone,
DEF-2: 2 groups of deferiprones, DEF-3: 3 groups of deferiprones, DEF-CONT: deferiprone matched group.
Fig. 3 tests the influence (n=6 of the 9th all deferiprones to amycin heart failure rat ultrasonic cardiography graph parameter
*),
Wherein,
1P＜0.01,
3Compare with the blank group p＜0.05;
2P＜0.01,
4Compare with the amycin group p＜0.05.
Chang: change percentage rate; EF: ejection fraction, LVFS: left ventricular ejection fraction,
LVEDD: diastasis left ventricular internal diameter, LVESD: the end-systole left ventricular internal diameter,
EDAWT: diastasis left ventricle antetheca thickness, ESAWT: end-systole left ventricle antetheca thickness,
EDPWT: diastasis left ventricular posterior wall thickness, ESPWT: end-systole left ventricular posterior wall thickness;
CONT: the blank group, DOX: the amycin group, DEF-1: 1 group of deferiprone,
DEF-2: 2 groups of deferiprones, DEF-3: 3 groups of deferiprones, DEF-CONT: deferiprone matched group.
Fig. 4 tests the influence (n=6) of the 8th, 10 all deferiprones to amycin heart failure rat blood serum myocardium calcium protein T,
Wherein,
4Compare with the amycin group p＜0.05,
CTnT level: myocardium calcium protein level; 8: the eight weeks of Week, 10: the ten weeks of Week,
DOX: amycin group, DEF-1: 1 group of deferiprone, DEF-2: 2 groups of deferiprones, DEF-3: 3 groups of deferiprones.
Fig. 5 tests the influence (n=6) of the 8th, 10 all deferiprones to amycin heart failure rat blood serum blood urea nitrogen, creatinine,
Wherein,
3Compare with the blank group p＜0.05;
4Compare with the amycin group p＜0.05,
BUN: blood urea nitrogen, CRE: creatinine; 8: the eight weeks of Week, 10: the ten weeks of Week,
CONT: the blank group, DOX: the amycin group, DEF-1: 1 group of deferiprone,
DEF-2: 2 groups of deferiprones, DEF-3: 3 groups of deferiprones, DEF-CONT: deferiprone matched group.
Fig. 6 deferiprone is to the Ultrastructural influence of amycin heart failure rat left chamber myocardial cell,
Wherein, (A): the blank group; (B): the amycin group; (C): the deferiprone matched group; (D): 2 groups of deferiprones (A, B, C, D * 6000).
Fig. 7 deferiprone implant is to the influence (n=6 of amycin administration rat body weight
*),
Wherein, Body weight: body weight,
Time after the first DOX injection (Day): the time after the amycin administration for the first time (my god),
CONT: the blank group, DEF-I: the deferiprone group,
DOX-I: amycin group, DOX+DEF-I: amycin+deferiprone group.
Fig. 8 deferiprone implant is to the influence of amycin administration rat heart muscle organizational structure,
Wherein, (A): the blank group; (B): the amycin group; (C): amycin+deferiprone group (A, B, C * 100).
The external stripping (n=6) of Fig. 9 deferiprone ordinary tablet.
The release in vitro (n=6) of Figure 10 deferiprone slow releasing tablet.
Average blood drug level-time graph (n=6) after Figure 11 single oral dose deferiprone ordinary tablet and the slow releasing tablet.
The specific embodiment
1.1 the foundation of amycin heart failure model and the dosage of deferiprone are provided with test 10 weeks by a definite date, the 8th all drug withdrawals continue to observe for 2 weeks.Get 72 of rats, be divided into 6 groups at random by body weight, administration by the following method:
The amycin group: give amycin lumbar injection 2.5mg/kg (4.31 μ mol/kg), 1 time weekly, continuous 8 weeks.
The blank group: give equal-volume normal saline lumbar injection, administration is 5 days weekly, continuous 8 weeks.
Deferiprone treatment group: the administration 5 days weekly of the deferiprone of various dose, continuous 8 weeks.Wherein:
1 group of deferiprone: handle with the amycin group, and give low dosage deferiprone lumbar injection 1.71mg/kg.
2 groups of deferiprones: handle with the amycin group, and dosage deferiprone lumbar injection 6.85mg/kg in giving.
3 groups of deferiprones: handle with the amycin group, and give high dose deferiprone lumbar injection 13.71mg/kg.
The deferiprone matched group: give the deferiprone injection, dosage and dosing interval are with 3 groups of deferiprones.
1.2 general toxicity is observed
1～6 every day in week is observed rat diet in test, and active state is tested the beginning of the 7th week and observed 2 times until off-test every day.The record of weighing is weekly respectively organized rat body weight 1 time.Anatomic measurement ascites volume after dead rat is weighed.Test the 10th all every group of rat pentobarbital sodium anesthesia (36mg/kg), open breast rapidly and take out heart, electron microscopic observation is fixedly done in cold saline flushing back, measures the ascites volume simultaneously.
1.2.1 body weight change
The body weight of each treated animal sees Table 1 before the test, and each treated animal body weight change of duration of test is seen Fig. 1.
Behind the injection amycin, the body weight gain of amycin group and deferiprone treatment group all has to some extent and slows down.When testing for the 4th week (amycin accumulated dose 7.5mg/kg), the body weight gain of amycin group and deferiprone treatment group begins to be starkly lower than blank group and deferiprone matched group (p＜0.05); During the 9th week, i.e. amycin drug withdrawal 1 week back (the amycin accumulated dose reaches 20mg/kg), 2,3 groups of body weight of deferiprone begin greater than amycin group (p＜0.05); In the 10th when week,, i.e. after 2 weeks of amycin drug withdrawal, 1 group of body weight of deferiprone is in greater than amycin group (p＜0.05).
Obvious adverse reaction does not appear in the deferiprone control rats, and body weight gain is similar to the blank group.
Table 1 is the body weight (n=12) of each treated animal before the test, and each treated animal body weight change of duration of test is seen Fig. 1.
Table 1
1.2.2 symptom and sign and ascites volume
The amycin group the 7th week lethargy occurred, rolls up and alarm hair, rapid breathing in test; When testing for the 9th week (the amycin accumulated dose reaches 20mg/kg), obviously become thin; During off-test, visible liver, the obvious edema of kidney are a large amount of ascites.And the symptom of deferiprone treatment group is lighter, and 1,2 groups of ascites volumes of deferiprone are starkly lower than amycin group (p＜0.01 or 0.05).Obvious adverse reaction does not appear in blank group and deferiprone control rats, does not have liver, kiney edema and ascites during off-test.Table 2 is that test was respectively organized rat ascites amount and survival rate in the 10th week.
Table 2
2P＜0.01,
4Compare with the amycin group p＜0.05.
1.2.3 animal dis motility rate
Blank group, deferiprone matched group, deferiprone do not have animal dead for 2 groups, and survival rate is 100%.The amycin group has 3 rats dead respectively at the 8th, 9 and 10 weeks of test, and survival rate is 75%; Deferiprone respectively has 1 rat dead in the 10th week for 1,3 groups, and survival rate is 91.7% (table 2).
1.3 ultrasoundcardiogram monitoring
Respectively organize the rat cardiac function respectively at measuring in preceding 3 days of test and test the 4th week (the amycin accumulated dose reaches 7.5mg/kg), the 9th week (the amycin accumulated dose reaches 20mg/kg).
Image acquisition: rat pentobarbital sodium i.p. anaesthetizes (36mg/kg), and dorsal position is fixed, the chest unhairing.See the capable M type of papillary muscles horizontal cavity footpath maximum ultrasonic examination (Philips Sonos5500 type multifunction supersonic diagnostic apparatus in the parasternal left-ventricular short-axis, the S12 probe, speed is 100mm/s), measure diastasis and end-systole left ventricular internal diameter (LVEDD and LVESD), diastasis and end-systole left ventricle antetheca thickness (EDAWT and ESAWT), diastasis and end-systole left ventricular posterior wall thickness (EDPWT and ESPWT).Instrument calculates left ventricle automatically and shortens mark LVFS (%)=(LVEDD-LVESD) * 100/LVEDD, and left ventricular ejection fraction (LVEF, Teichholz method)
[Bertinchant JP, Polge A, Juan JM, et al.[J] .Clinica Chimica Acta, 2003,329:39-51; Huang Guoqian, Liu Hong, Shu Xianhong, et al.[J]. Chinese ultrasonic image is learned magazine, 2004,13:848-852
]Off-line analysis after all data are all recorded a video, 3 cardiac cycles of numeration data continuous measurement are averaged.
With the ultrasonic cardiography graph parameter (Index before testing
0) be radix, calculate the variation percentage rate (%) of the 4th, the 9th weekly data (Index ') as follows:
The result shows that when reaching experiment the 4th week (the amycin accumulated dose reaches 7.5mg/kg) before the test, each organizes the echocardiographic parameters there was no significant difference (Fig. 2) of rat.
When testing for the 9th week, compare with the blank group, amycin group left ventricle shortens mark (LVEF) and left ventricular ejection fraction (LVFS) significantly reduces (p＜0.01), and diastasis and end-systole left ventricular internal diameter (LVEDD and LVESD) enlarge markedly (p＜0.01), and have 2 animals pericardial effusion (Fig. 3) to occur.
Each treatment group cardiac function of deferiprone has all obtained maintenance in various degree, tests the 9th Zhou Shijun and does not detect pericardial effusion.With the amycin group relatively, 2 groups of left ventriclies of deferiprone shorten marks (LVEF) and significantly rising of left ventricular ejection fraction (LVFS), LVESD significantly descend (p＜0.01); 1 group of end-systole left ventricular internal diameter of deferiprone (LVESD) is decline (p＜0.01) significantly; 3 groups of left ventricular ejection fractions of deferiprone (LVFS) are rising (p＜0.05) significantly.Every index of deferiprone matched group and blank group no significant difference more all have significant difference (p＜0.01) with the amycin group.
1.4 serum biochemistry index monitoring
The 10th week got blood respectively at 2h and test behind test the 8th all amycin lumbar injections, separation of serum detects myocardium calcium protein T (cTnT), blood urea nitrogen (BUN), creatinine (CRE) and triglyceride indexs such as (TG).
Myocardium calcium protein T detects: adopt the electrochemiluminescence method, checkout equipment is an ELECSYS-2010 type fully automatic electric chemical illumination immunity analysis instrument (Roche, Japan), and reagent is Roche company product.Reference value＜0.1ng/ml.
Blood urea nitrogen, creatinine, triglyceride detect: by VITROS-950 type automatic clinical chemistry analyzer (Johnson ﹠amp; Johnson, the U.S.) detect, reagent is Johson ﹠ Johnson's product.
1.4.1 serum myocardium calcium protein T monitoring result
The serum that blank group and deferiprone matched group are tested the 8th week, the 10th week does not all detect myocardium calcium protein T (detectability: 10ng/L).Amycin group the 8th all serum myocardium calcium protein Ts raise, and then are increased to 11.31 times of the 8th week during the 10th week, p＜0.05 (Fig. 4).
The deferiprone treatment is organized the 10th all serum myocardium calcium protein Ts and is all raise than the 8th week, but there was no significant difference.With the amycin group relatively, 2 groups of deferiprones, 3 group of the 10th all serum myocardium calcium protein T of deferiprone significantly descend (p＜0.05).
1.4.2 serum urea nitrogen, the creatinine monitoring result
2h behind the 8th all amycin drug administration by injection, each organizes the rat blood serum blood urea nitrogen, creatinine there was no significant difference (Fig. 5).
During the 10th week, blank group and deferiprone matched group blood urea nitrogen and creatinine are not seen obvious rising.With the blank group relatively, amycin group blood urea nitrogen and creatinine significantly raise (p＜0.05).With the amycin group relatively, 2 groups of deferiprones, deferiprone 3 group of the 10th all blood urea nitrogens, creatinine significantly descend (p＜0.05).
1.5 myocardial ultrastructure is observed
Transmission electron microscope observing myocardial ultrastructure (Fig. 6), amycin group (B) myocardial cell edema, mitochondrial swelling, the sarcoplasmic reticulum expansion, sarcostyle is arranged loose.By contrast, 2 groups of (D) myocardial cell injurys of deferiprone are generally lighter, several no swelling of mitochondrion, and the cardiac muscle fiber marshalling, only indivedual sarcoplasmic reticulums are slightly expanded.Blank group (A) and deferiprone matched group (C) cardiac muscle are not seen obvious pathological changes.
The above experimental result of the present invention shows, deferiprone can alleviate amycin in vivo to the infringement of cardiac systolic function, to the damage of myocardial cell device, and can prevent the damage of caused by doxorubicin cardiac muscle persistence.
Accurately take by weighing deferiprone by a certain percentage, lactic acid-hydroxyacetic acid copolymer (PLGA) and/or polylactic acid (PLA) are dissolved in an amount of dichloromethane, and 37 ℃ of oil baths volatilize solvent, with the extrusion molding of self-control extruder.Room temperature vacuum tank inner drying is cut into the spillikin that diameter * length is 2mm * 20mm with it to constant weight, the preparation average weight is 84.23 ± 11.01mg, promptly gets implant of the present invention.
Deferiprone biodegradation type implant is to the toxic control experiment of caused by doxorubicin rat heart
3.1 grouping and administration
Test is divided into 4 groups, 30 days by a definite date.Table 3 is respectively to organize dosage regimen.
Table 3
Observe ordinary circumstance after the administration, record body weight change and survival rate.The animal of duration of test death is in time weighed, and dissects.The 30th day finishes test after the administration, record ascites volume regulating liver-QI, kiney edema situation behind the sacrificed by exsanguination animal; Tip left compartment muscle 10% formaldehyde fixed of coring is done the pathology inspection.
3.2 the deferiprone implant is to the influence of amycin administration survival of rats rate
The rat back wound does not have redness and oozes out after the implant surgery, the basic healing of 1 week of operation back, and wound healing is good.It is the influences to amycin administration survival of rats rate of deferiprone implant that the survival of rats rate the results are shown in Table 4.
Table 4
Amycin group and amycin+deferiprone group all has animal dead.The generation in the 1st～18 day behind the first dosage of amycin of amycin treated animal is dead, and administration is only deposited 2 after 30 days, and survival rate is 33.33%.Amycin+deferiprone treated animal took place dead after the amycin first administration on the 1st～12 day, administration after 30 days survival rate be 66.67%.All the other two treated animals are all survived to off-test.
3.3 the deferiprone implant is to the influence of amycin administration rat body weight
Weigh weekly behind the implantation preparation 2 times, the result shows, duration of test, and blank group and deferiprone group body weight increase in time, and do not have group difference.All the other two treated animal body weight all obviously descend.Test the 4th day (the amycin accumulated dose reaches 2.5mg/kg), amycin group and amycin+deferiprone group body weight begins to be lower than blank group (p＜0.05); The 16th day (amycin drug withdrawal 4 days, accumulated dose reaches 10mg/kg), amycin+deferiprone group body weight is greater than amycin group (p＜0.05).(Fig. 7)
3.4 the deferiprone implant is to the influence of amycin administration rat ascites
The result shows that liver appears in rat after the amycin administration, kiney edema merges serious ascites.From incidence of ascites, ascites all takes place in amycin group, amycin+deferiprone group, and with liver, kiney edema, but the AS occurrence of amycin+deferiprone group is lower; From the ascites degree, compare the ascites volume of amycin+deferiprone group less (p＜0.05) with the amycin group.
Table 5 is the influences (n=6) to amycin administration rat ascites of deferiprone implant.
Table 5
4Compare with amycin I group p＜0.01
3.5 the deferiprone implant is to the influence of amycin administration rat heart muscle organizational structure
The result shows, blank group (A) rat heart muscle, and the heart tissue morphosis is intact, myocardial cell clear layer, no abnormality seen pathological change (Fig. 8).
Myocardial cell hypertrophy in amycin group (B) the rat heart tissue, muscle fiber is loose, visible vacuolar degeneration in the part myocardial cell.Amycin+deferiprone group (C) rat heart lesion tissue degree and scope are light than the amycin group, visible a small amount of myocardial cell hypertrophy, and the muscle fiber short texture shows as slight vacuolar degeneration.
Found that compare with the amycin group, the light sickness rate of the ascites degree of amycin+deferiprone group is lower, ordinary circumstance is better, myocardium pathology damage is lighter, prompting deferiprone implant can be alleviated caused by doxorubicin rat heart toxicity to a certain extent.The prompting of this result of the test, deferiprone is continuing still can partly to alleviate rat amycin cardiac toxicity under the low blood drug level.
3.6 the deferiprone implant is to the influence of amycin administration rat heart muscle iron content
Get blank group, amycin group, amycin I group, the amycin+about 100mg of deferiprone I group rat apex left compartment muscle, adopt flame method to measure iron content, this content has comprised free iron content and non-free iron content.Technical specification is with reference to GB/T15337-94 atomic absorption spectroscopy general rule, and measurement range and accuracy are (190～900) nm ± 0.5nm.Table 6 is DEF implant results that influence to DOX administration rat heart muscle iron content.
Table 6
*During off-test, 4 death of amycin I group rat, amycin+deferiprone I organizes 2 death
Amycin group rat only has 2 to survive to off-test, and myocardium iron content is higher than other group.Blank group, amycin+deferiprone group rat heart muscle iron content do not have group difference.
Get deferiprone 500mg, be dissolved in 1000ml water for injection, add active carbon 2g, 100 ℃ were heated 5 minutes, and the coarse filtration decarburization is regulated pH to 7 with sodium hydroxide test solution, is filtered to clarification.Embedding was sterilized 30 minutes, and was promptly got injection of the present invention for 100 ℃.
Get deferiprone 500mg, add amylum pregelatinisatum 200mg, lactose 200mg, microcrystalline Cellulose 400mg, mixing is granulated, and dry, granulate promptly get granule of the present invention.
Get deferiprone 500mg, add amylum pregelatinisatum 200mg, lactose 200mg, microcrystalline Cellulose 400mg, mixing is granulated, and dry, granulate are encapsulated, promptly get capsule of the present invention.
Get deferiprone 500mg, add microcrystalline Cellulose 1300mg, magnesium stearate 10mg, mixing is granulated after adding the 60% ethanol moistening that contains 6%PVP, and drying, granulate, tabletting promptly get ordinary tablet of the present invention (every contains deferiprone 25mg).
Adopt the commentaries on classics basket method of Chinese Pharmacopoeia version regulation in 2005 to measure dissolution.The purified water 900mL that handles with the degassing is a release medium, and temperature is (37 ± 0.5) ℃, and rotating speed is 50r/min, respectively at 3,5,10,15,20,25min sampling 5mL (replenishing synthermal water 5mL simultaneously immediately) through 0.8 μ m filtering with microporous membrane, discards filtrate just, stays subsequent filtrate to be measured.After each point in time sampling finishes, adopt the UV working sample, get its external stripping curve (Fig. 9).
Get deferiprone 500mg, add hydroxypropyl emthylcellulose (HPMC) K100M 300mg, waxiness 888300mg, microcrystalline Cellulose 700mg, magnesium stearate 10mg, mixing, granulate after adding the 60% ethanol moistening that contains 6%PVP, drying, granulate, tabletting promptly get slow releasing tablet of the present invention (every contains deferiprone 25mg).
Adopt the commentaries on classics basket method of Chinese Pharmacopoeia version regulation in 2005 to measure release.The purified water 900mL that handles with the degassing is a release medium, and temperature is (37 ± 0.5) ℃, and rotating speed is 50r/min, respectively at 1,2,4,6,8,10,12h sampling 5mL (replenishing synthermal water 5mL simultaneously immediately) through 0.8 μ m filtering with microporous membrane, discards filtrate just, stays subsequent filtrate to be measured.After each point in time sampling finishes, adopt the UV working sample, get its release in vitro curve (Figure 10).
The animal drug disposition dynamic behavior comparative test of deferiprone ordinary tablet and slow releasing tablet
Adopt binary cycle two preparation trial design, 6 bull beasle dogs are weighed, and are divided into two groups at random, and one group for being subjected to the reagent group, and another group is a reference medicine group, 3 every group.Behind the fasting 12h, oral test preparation deferiprone slow releasing tablet 25mg of animal subject difference or reference preparation deferiprone ordinary tablet 25mg.The test preparation blood sampling time for take medicine preceding and take medicine the back 20,40,60,90,120,180,240,300,360,420,480,540,600,720min; The reference preparation blood sampling time for take medicine preceding and take medicine the back 10,15,20,30,45,60,90,120,180,240,300,360,480,720min.By forelimb venous blood collection 3mL, 37 ℃ of water-bath 30min, the centrifugal 15min of 3000r/min gets upper serum, puts-20 ℃ and is stored to mensuration.After one week of drug withdrawal, carry out cross matching, method is the same.
Average blood drug level-time graph after 6 beasle dog single oral dose deferiprone ordinary tablets and the slow releasing tablet is asked the pharmacokinetic parameter of calculation as shown in figure 11 with the rectangle method.
Table 7 be behind beasle dog single oral dose deferiprone slow releasing tablet and the ordinary tablet pharmacokinetic parameters (x ± s, n=6).
Table 7
Annotate: t
1/2: biological half-life, t
Max: peak time, C
Max: peak concentration, AUC
0-720: from 0 up to 720 minutes lower area of blood concentration-time curve, AUC
0～∞: from 0 when the infinity blood drug level-time song
Area under the line, MRT
0-∞: mean residence time, F%: relative bioavailability.
The result shows, the degree of absorption bioequivalence of deferiprone slow releasing tablet and deferiprone ordinary tablet; Slow releasing tablet biological half-life (t
1/2), peak time (t
Max) and mean residence time (MRT) prolongation, peak concentration (C
Max) reduce, show that slow releasing tablet has tangible sustained releasing character.
Experimental drug thing of the present invention is commercial, and used laboratory animal is available from laboratory animal portion of former Shanghai Medical Univ.
Claims (8)
1, the deferiprone of formula (I) structure and preparation thereof the purposes in preparation control anthracene nucleus medicament cardiac toxicity medicine,
2, purposes according to claim 1 is characterized in that described anthracene nucleus medicament is selected from amycin, epirubicin, idarubicin, mitoxantrone, daunorubicin benzene track, Carubicin, AD32, Aclacnomycin A or triferricdoxorubicin.
3, purposes according to claim 1 is characterized in that described anthracene nucleus medicament is an amycin.
4, purposes according to claim 1 is characterized in that described anthracene nucleus medicament cardiac toxicity is anthracycline drug rerum natura cardiomyopathy or anthracycline drug rerum natura chronic cardiac insufficiency.
5, purposes according to claim 1, the dosage scope that it is characterized in that described ferrum ketone is 1～20mg/kg body weight/day.
6, purposes according to claim 5, the dosage that it is characterized in that described ferrum ketone is the 2.5mg/kg body weight/day.
7, purposes according to claim 1 is characterized in that described preparation is selected from tablet, capsule, oral solution, injection or implant.
8, purposes according to claim 7 is characterized in that described preparation is selected from tablet or capsule.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100442079A CN101352438A (en) | 2007-07-25 | 2007-07-25 | Uses of deferiprone and formulation thereof in preparing medicament for preventing and treating cardiotoxicity induced by anthracyclines |
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| CNA2007100442079A CN101352438A (en) | 2007-07-25 | 2007-07-25 | Uses of deferiprone and formulation thereof in preparing medicament for preventing and treating cardiotoxicity induced by anthracyclines |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017199073A1 (en) * | 2016-05-18 | 2017-11-23 | Karimian, Khashayar | Effervescent deferiprone tabelt |
| US10780055B2 (en) | 2017-10-25 | 2020-09-22 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
-
2007
- 2007-07-25 CN CNA2007100442079A patent/CN101352438A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017199073A1 (en) * | 2016-05-18 | 2017-11-23 | Karimian, Khashayar | Effervescent deferiprone tabelt |
| US10780055B2 (en) | 2017-10-25 | 2020-09-22 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
| US10940115B2 (en) | 2017-10-25 | 2021-03-09 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
| US10940116B2 (en) | 2017-10-25 | 2021-03-09 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
| US11357731B2 (en) | 2017-10-25 | 2022-06-14 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
| US11458103B2 (en) | 2017-10-25 | 2022-10-04 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
| US11607389B2 (en) | 2017-10-25 | 2023-03-21 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
| US11723874B2 (en) | 2017-10-25 | 2023-08-15 | Chiesi Farmaceutici S.P.A. | Delayed release deferiprone tablets and methods of using the same |
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