CN102274160B - Method and preparation for treating resistance to antihypertensives and related conditions - Google Patents
Method and preparation for treating resistance to antihypertensives and related conditions Download PDFInfo
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Abstract
The invention relates to a medicinal preparation which contains melatonin and at least one antihypertensive compound, a method for treating patients with resistance to antihypertensives in the absence of melatonin, a method for decreasing nocturnal blood pressure of patients with blood pressure allorhythmia in the presence or absence of antihypertensives, and a method for providing patients with at least one of the following effects of: improvement of emotion and daytime insomnia, delay of cortisol peak level of patients, and potential preventive protection against harmful effect of ischemia on heart, wherein melatonin is applied with an effective amount and in an effective manner.
Description
The application is Chinese patent application number 00818153.5 divides an application, and original application is the China national phase application of International Application Serial No. PCT/IL00/00009.
Technical field
The present invention relates to for to when lacking melatonin to the antihypertensive function of anti-hypertension compound method and pharmaceutical preparation that drug-fast patient treats are arranged, be used under the condition that has or do not exist anti-hypertension compound exist the unusual patient of blood pressure rhythm reduce the blood pressure at night method, for reducing cortisol levels and avoid the method for cardiovascular event and melatonin in the purposes of producing the medicine that is used for above-mentioned purpose.
Background technology
In blood pressure, exist the variation (the diurnal blood pressure rhythm and pace of moving things) of every day, it is characterized in that the reduction at night and the rising on daytime.Old people and the patient that suffers from Cushing's syndrome, the patient of experience glucocorticoid treatment, there is hyperthyroidism, maincenter and/or periphery autonomic dysfunction (Shy-Drager syndrome, quadriplegia, diabetic or UN etc.), chronic kidney hypofunction, kidney or heart transplantation, congestive heart failure, faint from fear, sleep apnea syndrome, malignant hypertension, systemic artery is atherosis, patient (the Imai of the hypertensive cerebral organ injury that accelerates, Abe etc., Journal ofhypertension (supplement) 8:S125-132,1990) ((Portaluppi and among fatal familial insomnia's the patient, Cortelli etc., Hypertension 23:569-576,1994), reverse has occured in the normal mode of the diurnal blood pressure rhythm and pace of moving things.Although treat with antihypertensive, in some hyperpietics, still observed the blood pressure drops at night that is lower than normal value.The blood pressure drops at night that is lower than normal value is relevant with too high cardiovascular complication among the hyperpietic.The danger that exists the unusual patient (non-spoon type blood pressure patient) of blood pressure drops at night target organ damage to occur increases (1-4), has confirmed that the cardiovascular event that the non-spoon of women type blood pressure patient occurs will be more than spoon type blood pressure person (5).The mechanism of normal blood pressure drops and the pathophysiological mechanism relevant with shortage blood pressure drops at night are not illustrated yet fully in sleep procedure.
Glucocorticoid plays an important role in multiple body function.Under base state, glucocorticoid shows non-imposed effect to various body functions, for example keeps the homeostasis of normal and electrolyte and the water of blood pressure, blood glucose.In the mankind, hydrocortisone is that life is necessary.Usually, hydrocortisone is by acth secretion and be rhythmicity, reaches maximum haemoconcentration in the morning of every day, drops to half of peak value in the time of in the afternoon.Under stress state, the secretion of hydrocortisone increases to deal with the serious attack to whole health greatly.But the lasting rising of the hydrocortisone in the circulation is dealt with and stress adverse effect be arranged with the ability of disease immune system and body.The more important thing is that corticosteroid can be induced the neurodegenerative process of Hippocampus, cause the damage of memory and cognitive function.The Long Term Contact of brain and corticosteroid make its degeneration damage that is easy to be subject to be caused by ischemia and insane carbuncle (McEwen, Annals of the New York Academy of Science, 1994,746:145-154).Along with the aging of human body, the basal secretion of hydrocortisone increases by unknown mechanism, and the appearance in the morning of its peak value is also early than youngster (Moreley and Korenman compile, Blackwell Scientific Publications, 1992,70-91 page or leaf).Find in addition in the arteria coronaria patient, the cortisol levels at night be higher than suitable healthy individual of age (Brugger and Herold, Biological Rhythm Research, 1995,26:373).Between hypertension and high urocortisol value, exist and connect (Lichtenfeld each other, Hunt etc., Hypertension, 31:569-74,1998), can raise in the mode of dose dependent blood pressure (Kelly, Mangos etc. of oral hydrocortisone, Clin ExpPharmacol Physiol Supp125:S51-6,1998).Never it is relevant with shortage blood pressure drops at night to propose in the past too high cortisol levels.
Melatonin is a kind of by the hormone of pinus in night secretion, occurs at human body reaching its peak level before the peak value of hydrocortisone.The production of melatonin descends with age.Equally, arteria coronaria patient's melatonin level at night also is lower than suitable healthy individual of age.But, the secretion that melatonin can affect hydrocortisone was under normal operation never proposed in the past.The Cardiovascular of the conventional melatonin that discharges
Melatonin (pineal hormone) usually play an important role in night secretion and in regulating circadian rhythm, biology of comprising sleep (Brzezinski, N Engl J Med 1997; 336:186-195, Penev and Zee, Ann Neurol 1997; 42:545-553).The external vasorelaxation action of in rabbit aorta, observing melatonin (under the high concentration of 10-1000 μ M) (Satake etc., Gen.Pharmacol., 1991,22:219-221 and 22:1127-1133).
Rodentine studies show that the ability that in some arteries, has melatonin receptor and regulate the rat smooth muscle tonicity (Capsoni etc., Neuroreport 1995; 6:1346-1348, Mahle etc., J Biol Rhythms 1997; 12:690-696).According to the kind of animal, this regulating action can show as vasodilation or vasoconstriction.
Melatonin is very complicated (Lusardi etc., Blood Press Monit 1997 on the impact of blood pressure and human cardiovascular system; 2:99-103, Cagnacci etc., 1998; 274:335-338, Arangino etc., Am J Cardiol 1999; 83:1417-1419; Terzolo etc., J.Pineal Research, 1990,9:113-124).The diastolic blood pressure that normotensive young individuals takes in the systolic blood drops that can cause in 4 weeks of melatonin (5mg) in whole 24 hours at h.d., be confined to the second half section at night descends, heart rate is in the daytime slight decline and at acceleration (Lusardi etc., the Blood Press Monit 1997 of second half section at night; 2:99-103).Can reduce systolic blood pressure and diastolic blood pressure (Cagnacci etc., 1998 after 90 minutes in administration to Youth Women or man's administration melatonin (1mg) by day; 274:335-338; Arangino etc., Am J Cardiol 1999; 83:1417-1419)).Unexpectedly increased their cortisol levels (Cagnacci, Soldani and Yen, L Pineal Res, 22:81-5,1997) to postmenopausal women's administration melatonin of old-age group at 08:00.
The people such as Terzolo studied long-term (2 months), low dosage (oral 2mg every day), regularly (18:00h) the administration melatonin on impact (the J.Pineal Research of adult male endocrine and cardiovascular variable element, 1990,9:113-124).After the treatment, be recorded to the average serum melatonin level of remarkable rising, and with circadian obvious improvement.Of 24 hours profiles demonstration hydrocortisones of hydrocortisone and testosterone shifted to an earlier date about 1.5 hours (not obvious) peak period in the morning, and testosterone has shifted to an earlier date 3 hours (obviously).The profile of prolactin antagonist and triiodothyronine and thyroxinic serum levels do not change.Equally, ((TSH), hydrocortisone, thyroliberin (ACTH) and aldosterone are also unaffected to the response of the irritant test of human chorionic gonadotropin for gonadotropin releasing hormone (GNRH), throtropin releasing hormone (TRH), thyroliberin (ACTH) and testosterone for metakentrin (LH), follicle stimulating hormone (FSH), prolactin antagonist, thyrotropin.Circadian rhythm to the cardiovascular variable element, be being controlled at not demonstrating any variation behind the melatonin treatment of systole and diastolic blood pressure, heart rate.
The objective of the invention is to reduce human cortisol levels, the peak value that particularly postpones hydrocortisone in the human hydrocortisone profile.Another object of the present invention is to be reduced in the blood pressure that when lacking melatonin the antihypertensive function of anti-hypertension compound is had drug-fast patient, particularly reduces the blood pressure at night in non-spoon type blood pressure patient.It is believed that these purposes can be potentially provide preventative protective effect for reducing blood pressure, the outbreak of prevention ischemia and to ischemia to the adverse effect of heart.According to following description, other purpose of the present invention will be apparent.
At U.S. Patent number 5,700, described a kind ofly by treat or reduce as much as possible the method for anoxia or ischemic brain injury to the administration melatonin that attacked by anoxia or ischemia in 828, described anoxia or ischemia are attacked and are defined as causing that the cerebripetal blood flow of stream lacks and/or the wound of large cerebral anoxia.This patent is not mentioned melatonin can prevent or improve anoxia or ischemia attack itself.
U.S. Patent number 5,849 has been described a kind of unit dosage form of the physiology's disease that is used for the treatment of vasoconstriction and causes thus in 338 (on August 26th, 1997 submitted), it contains Mg, vitamin C and E, folic acid, Se and melatonin.It comprises melatonin only be because when the applying date some characteristic of known it, these characteristics have been described in this patent.
The full text of these United States Patent (USP)s all is incorporated herein by reference.
Summary of the invention
Can realize above-mentioned purpose by the present invention, on the one hand, the invention provides a kind of pharmaceutical preparation, this pharmaceutical preparation contain at least a carrier, diluent or adjuvant and:
At the antihypertensive function for the anti-hypertension compound of when not having melatonin, using the melatonin that improves or prevent to occur the hypertension symptom effective dose among the drug-fast patient is arranged; With at least a can be at the anti-hypertension compound that in the patient of the described treatment of needs, produces the effective dose of antihypertensive function in the presence of the melatonin.
The present invention also provides melatonin producing for the purposes in the medicine that drug-fast patient's prevention or treatment hypertension symptom are arranged at the antihypertensive function for the anti-hypertension compound of using when not having melatonin, and there are among the drug-fast patient method of prevention or treatment hypertension symptom, the method comprise to use to described patient at the antihypertensive function for the anti-hypertension compound of when not having melatonin, using and improve or the melatonin of hypertension symptom effective dose appears in prevention in this patient.
On the other hand; the invention provides melatonin in the purposes that produce to be used for providing to the patient medicine of at least a following effects: improve emotion and daytime the insomnia, postpone patient's hydrocortisone peak level and to the potential preventive protection effect of ischemia to the heart illeffects, described medicine is to contain the pharmaceutical preparation that the effective dose of at least a above-mentioned effect melatonin can be provided.
On the other hand; the present invention also provides the method that at least a following effects is provided to the patient: improve emotion and daytime the insomnia, postpone patient's hydrocortisone peak level and to the potential preventive protection effect of ischemia to the heart illeffects, the method comprises to the patient uses melatonin with amount and the mode that can effectively reach described at least a effect.
Term herein " improve emotion " and refer to avoid may with conventionally form, be that the form of non-controlled release is used relevant being in a very depressed state of melatonin.
Surprisingly, as if can reduce the variation of discharge rate and every day to the human administration melatonin.In addition, there are differences between controlled release and the conventional melatonin that discharges, the form of controlled release can change and postpone hydrocortisone in the daytime profile, and conventional form can only suppress and can not make the time of peak value occur obviously to move.
The specific embodiment
The form that medicine/pharmaceutical preparation with the form of any routine, for example is suitable for oral, rectum, parenteral or percutaneous dosing can be carried out administration.It can be unit dosage form for example.In a specific embodiment, melatonin is the form of controlled release preparation, and wherein, melatonin preferably discharges with predetermined speed control.
At least a carrier, diluent or adjuvant can comprise for example at least a acrylic resin.
The amount that is used for prevention and treats hypertensive melatonin of considering at present should be that this purpose is effectively measured, think at present, in the situation of oral administration, for more than the every day 0.5mg and be no more than 100mg, 0.5-50mg for example, preferred 2.5-20mg, and for parenteral or percutaneous dosing, 0.1 and 50mg between.According to the present invention, can the antihypertensive of the melatonin of effective dose and effective dose is formulated together.Medicine/pharmaceutical preparation of the present invention can also contain at least a melatonin receptor regulator and/or melatonin profile regulator.
When understood the concept of using melatonin treatment or prophylaxis of hypertension according to the present invention after, need not performing creative labour determine the scope for the melatonin effective dose of various route of administration for the object of the invention.When pharmaceutical preparation contained at least a antihypertensive, described antihypertensive can be selected from diltiazem
Captopril, atenolol, Benazepril, enalapril, valsartan, metoprolol, terazosin, prazosin, minoxidil, clonidine, ramipril and officinal salt thereof.In following table, provided every daily dose that the anti-hypertension compound that exemplifies is used for oral administration:
Table 1: anti-hypertension compound
By following examples the present invention is illustrated.
Embodiment 1
Prepare controlled release tablet with the following ingredients mixing and with mixture pressure tabletting with 2.5 tons in the cylindrical punch press of 7mm: the Eudragit of captopril (12.5mg/ sheet), melatonin (5mg/ sheet) and about 1.1 weight ratios
TMRS 100 acrylic resin carriers (Rohm Pharma) and lactose.Although said preparation should be taken, think that at present it should be suitable that these two kinds of tablets hour are taken in the first two of going to bed under doctor's guidance.
Embodiment 2
Prepare controlled release tablet with the following ingredients mixing and with mixture pressure tabletting with 2.5 tons in the cylindrical punch press of 7mm: diltiazem
The Eudragit of (180mg/ sheet), melatonin (5mg/ sheet) and about 2: 1: 2.5 weight ratios
TMRSPO acrylic resin carrier (Rohm Pharma), lactose and calcium hydrogen phosphate.Although said preparation should be taken, think that at present it should be suitable that these two kinds of tablets hour are taken in the first two of going to bed under doctor's guidance.
Experiment 1
In the test crowd who is formed by 52 hypertension and 130 normotensive gerontal patients, measured the impact of melatonin on blood pressure.All patients that suffer from the insomnia are diagnosed according to DSMIV.They are comprised of 86 male and 96 women, and the age is 72 ± 9 years old.With at random, the mode of double blinding before going to bed 2 hours to experimenter's administration every day 1,2 or 5mg melatonin controlled release preparation (Circadin
TM, Neurim Pharmaceuticals, Israel) or 3 weeks of placebo of identical appearance.In last week for the treatment of phase, measure in the morning blood pressure and between placebo or melatonin treatment and baseline, compare.The result is shown in table 2 and 3.
Table 2: the as a result hyperpietic of experiment 1 (the systole BP of baseline＞140mmHg)
Normotensive patient (the systole BP of baseline＜140mmHg)
Conclusion
The melatonin of administration of exogenous can reduce systole and the diastolic blood pressure on daytime in hypertensive old experimenter at night.Beat all is to use controlled release preparation (1-5mg) and have no significant effect in normotensive experimenter.Can notice, when the decline that when normotensive experimenter uses antihypertensive drug, can cause blood pressure, and use the conventional melatonin (5mg) that discharges within the whole 24 hours time, to reduce blood pressure normal young experimenter's blood pressure (Lusardi etc., Blood Press Monit 1997 at night; 2:99-103) experiment 2
16 gerontal patients that suffer from essential hypertension are studied.Measure all patients' 24 hours exercise blood pressure.Be divided into a spoonful type group (n 2 8) or non-spoon type group ((n=8) according to general who has surrendered patient under the night of mean arterial pressure.Collecting at twice 24 hours urine, once is by day, once is at night.Measure in duplicate the homaluria of the major metabolite 6 one sulfato oxygen base melatonins (6SMT) of melatonin by the elisa assay method.Two groups is similar aspect age and sex.In spoon type group, mean arterial pressure has descended 10.2% at night, and has increased by 8% in the patient of non-spoon type group.In spoon type group, 6SMT has increased by 240% in sleep procedure, 8.19 ± 1.68 (units) (p＜0.05) at night have been increased to from 3.28 ± 0.87 (units) in the daytime, and in non-spoon type group, remain unchanged (be 2.31 ± 0.68 (units) in the daytime, be 2.56 ± 0.79 (units) night).The result is as shown in table 3.
Table 3: the result of experiment 2
Conclusion
The hyperpietic of non-spoon type group shows blunt melatonin secretion at night.Therefore, ectogenic melatonin may work in the circadian rhythm of blood pressure.Melatonin is on the research of the impact of hydrocortisone profile and emotion
Interleaved mode with double blinding, placebo is carried out following experiment.Each patient accepts the tablet (placebo, conventional release and controlled release) of all three types, but order of administration is at random, and patient or staff all do not know its order.
Experiment 3
To 8 healthy elderlies of suffering from the insomnia with the form of controlled release preparation (SR-Mf) once a day (point in evenings 10) use melatonin (2mg) week, can cause the obvious increase of their Sleep efficiency but not increase Sleep latency.(Sleep efficiency is to be in the time quantum of sleeping soundly in the total time of going to bed; Sleep latency is from turning off the light for the first time the sleeping required time).On the other hand, melatonin (2mg) treatment of conventional delivery formulations (RM) form of identical individual body and function Sleep efficiency can not be improved, Sleep latency can be shortened but compare with identical experimenter with placebo treatment.These results can be by short making an explanation of the half-life of melatonin in blood.That is to say that controlled release preparation can reduce the blood levels of hormone for a long time, therefore, its effect may onset slowly but can become at night subsequently obvious.
Homaluria by hormone has been assessed cortisol levels among these patients with 2 hours interval within 24 hours time.In the placebo treatment group, the hydrocortisone rhythm and pace of moving things that the patient shows is for to reach its peak value at 8:36AM, then hydrocortisone is to descend in the individual known mode more than 40 years old for the age (referring to Sherman etc., Journal of Clinical Endocrinology and Metabolism 1985,61:439).In matched group, average 24 hour discharge rates/hour (it be similar to haemoconcentration) of hydrocortisone in urine be 3.2 micrograms/hour.The amplitude of the rhythm and pace of moving things (i.e. the maximum deviation of 24 hours meansigma methods and maximum or minimum discharge rate) is 1.8 μ g/ hours.
The melatonin treatment that discharges with routine is after one week, and the total amount that hydrocortisone is drained descends.24 hours average discharge rate was down to 2.5 μ g/ hours, and amplitude was down to 1.0 μ g/ hours.In addition, the time of peak value is mobile slightly backward, appears at 8:27AM.The observation that is expected at the hydrocortisone rhythm and pace of moving things used behind the conventional melatonin that discharges and Terzolo etc. conform to ((J.Pineal Research, 1990,9:113-124).But Terzolo does not observe 24 hourly average levels of the hydrocortisone rhythm and pace of moving things and the reduction of amplitude.
Find after one week at the melatonin treatment with controlled release, the same with the melatonin of routine, the secretion of hydrocortisone weakens (24 hours Mean Speed is 2.5 μ g/ hours) and amplitude (1.2 μ g/ hours) and conventional discharge similar, but peak value has obviously been postponed till daytime later, appears at 12:06PM.Therefore, use controlled release melatonin caused the postponement of peak value rather than remain unchanged or slight in advance.In treated one month patient with controlled release preparation, found identical hydrocortisone profile ((24 hours average drainage 2.5 μ g/ hours, amplitude 1.0 μ g/ hours, time to peak 12:08).
Conclusion
These results show that body is also not obvious to the reaction of melatonin: body can be read the profile of melatonin and be not only that it existed in certain time.What is interesting is, compare with older individuals that in less than 40 years old people, the rhythm and pace of moving things of hydrocortisone has also been postponed (Sherman etc., ibid).Therefore, after with the controlled release melatonin treatment, the hydrocortisone profile that produces in the old people is individual similar to youth.
Discuss
The melatonin at recent findings night in the arteria coronaria patient is very low and cortisol levels is very high (Brugger and Herold, Biological Rhythm Research, 1995,26:373).Should be noted that hydrocortisone is a kind of stress hormone, the increase of having a heart attack when its high-load in the morning the time may be with morning is relevant.This experiment shows, the melatonin of using conventional release can reduce the production of hydrocortisone, not only can reduce cortisol levels but use controlled release melatonin, but also can postpone its peak value, occur the danger of ischemia outbreak in the time of therefore can being reduced in morning potentially.
Experiment 4
This experiment is carried out in 10 ages are the healthy male of youth in 26-30 year.They accept a slice every day contains melatonin (controlled release of (2mg) (SR-Mf) or conventional (RM) tablet or the placebo that discharges has one day eccysis phase between different treatments.Take tablet and require the experimenter between the 12-15 point, to sleep at 11:00AM.Treating as source amount application form by Lader-Bond before and after sleep assesses emotion.The result shows that conventional melatonin (2mg) can obviously shorten the Sleep latency of nap and improve Sleep efficiency.Controlled release preparation also has similar effect.But conventional releasing pattern has produced hostile and has knocked the sensation of sleeping, and controlled release forms does not have negative impact to emotion.These data show that also melatonin depends on the profile that produces on the impact of emotion.Should be noted that does not have low making an explanation of melatonin concentration that impact can not produce by controlled release preparation to emotion in blood because a lot of research verified the melatonin of similar concentration (conventional) can sway the emotion and sleepiness.Therefore, the administration time of melatonin and mode of administration all are very important for affecting physiologic parameters.May produce different impacts in the different time or with the identical dosage of different pattern administrations.
Although above specific embodiments of the present invention is specifically described, should be appreciated that the present invention is not limited to this, can carry out multiple change and modification to it, this is apparent to a skilled reader.These change and modifications of not describing in detail in the text can be regarded as apparent equivalent of the present invention.For example, the analog that substantially can simulate the melatonin of melatonin function in human body can be regarded as the apparent chemical equivalent of melatonin.
Following content is corresponding to the original rights claim of female case application:
1. pharmaceutical preparation, it is characterized in that: this pharmaceutical preparation contains at least a carrier, diluent or adjuvant, and:
At the antihypertensive function for the anti-hypertension compound of when not having melatonin, using the melatonin that improves or prevent to occur the hypertension symptom effective dose among the drug-fast patient is arranged;
At least a anti-hypertension compound that can in the presence of melatonin, in the patient of the described treatment of needs, produce the effective dose of antihypertensive function.
2. 1 a described pharmaceutical preparation, it is further characterized in that: comprise at least a following feature:
(i) it is suitable for oral, parenteral or percutaneous dosing;
(ii) it is unit dosage form, and per unit dosage contains the melatonin of 2.5-20mg;
(iii) it is the controlled release preparation form, and melatonin wherein preferably discharges with predetermined speed control;
(iv) it also contains at least a melatonin receptor regulator and/or melatonin profile regulator;
(v) described anti-hypertension compound is selected from diltiazem
Captopril, atenolol, Benazepril, enalapril, valsartan, metoprolol, terazosin, prazosin, minoxidil, clonidine, ramipril and officinal salt thereof;
(vi) described carrier, diluent or adjuvant comprise at least a acrylic resin.
3. melatonin is being produced for the purposes in the medicine that drug-fast patient's prevention or treatment hypertension symptom are arranged at the antihypertensive function for the anti-hypertension compound of using when not having melatonin.
4. 3 described purposes, it is characterized in that: wherein said medicine is the form of pharmaceutical preparation, it contains at least a following supplementary element (a) and (b): (a) at least a carrier, diluent or adjuvant; (b) at least a anti-hypertension compound that can in the described treatment of needs patient, produce the hypotensive activity effective dose.
5. 4 described purposes, wherein said pharmaceutical preparation is further characterized in that: comprise at least a following feature:
(i) it is suitable for oral, parenteral or percutaneous dosing;
(ii) it is unit dosage form, and per unit dosage contains the melatonin of 2.5-20mg;
(iii) it is the controlled release preparation form, and melatonin wherein preferably discharges with predetermined speed control;
(iv) it also contains at least a melatonin receptor regulator and/or melatonin profile regulator;
(v) when existing, described anti-hypertension compound is selected from diltiazem
Captopril, atenolol, Benazepril, enalapril, valsartan, metoprolol, terazosin, prazosin, minoxidil, clonidine, ramipril and officinal salt thereof;
(vi) described carrier, diluent or adjuvant comprise at least a acrylic resin.
6. at the antihypertensive function for the anti-hypertension compound of when not having melatonin, using the method for preventing or treating hypertension symptom among the drug-fast patient is arranged, it is characterized in that the method comprises to described patient to be used improvement or prevent to occur the melatonin that hypertension symptom has sales volume in this patient.
7. 6 described methods is characterized in that: wherein said melatonin is with the form administration of pharmaceutical preparation, and it contains at least a following supplementary element (a) and (b): (a) at least a carrier, diluent or adjuvant; (b) at least aly can in the described treatment of needs patient, produce the anti-hypertension compound that hypotensive activity has sales volume.
8. 7 described methods, wherein said pharmaceutical preparation is further characterized in that: comprise at least a following feature:
(i) it is suitable for oral, parenteral or percutaneous dosing;
(ii) it is unit dosage form, and per unit dosage contains the melatonin of 2.5-20mg;
(iii) it is the controlled release preparation form, and melatonin wherein preferably discharges with predetermined speed control;
(iv) it also contains at least a melatonin receptor regulator and/or melatonin profile regulator;
(v) when existing, described anti-hypertension compound is selected from diltiazem
Captopril, atenolol, Benazepril, enalapril, valsartan, metoprolol, terazosin, prazosin, minoxidil, clonidine, ramipril and officinal salt thereof;
(vi) described carrier, diluent or adjuvant comprise at least a acrylic resin.
9. melatonin is being produced the purposes that is used for providing to the patient medicine of at least a following effects; it is characterized in that: improve emotion and daytime the insomnia, postpone patient's hydrocortisone peak level and to the potential preventive protection effect of ischemia to the heart illeffects, described medicine is to contain the pharmaceutical preparation that the effective dose of at least a above-mentioned effect melatonin can be provided.
10. 9 described purposes, pharmaceutical preparation wherein is further characterized in that: the feature that at least one is following:
(i) it is the controlled release preparation that is suitable for discharge melatonin within predetermined a period of time after the human patients administration;
(ii) it be suitable for according to simulation have in the human plasma of normal endogenous melatonin profile at night night profile profile discharge the controlled release preparation of melatonin;
(iii) it is the unit dosage form that every dosage unit contains 1mg to 80mg melatonin.
11. 10 a described purposes, preparation wherein is the controlled release preparation that contains the particle form of coated granule, and required controlled release characteristics reaches by at least one following feature, that is:
(a) granularity of change melatonin;
(b) use at least two kinds of different coating materials that in human body, dissolve with different rates; With
(c) change the thickness of coating material, thereby the melatonin of particle form is used the coating material coating that in human body, dissolves with different rates of different-thickness.
12. 11 a described purposes, it is characterized in that: preparation wherein contains the melatonin of the particle form of useful at least a polymer coating material coating.
13. 9 a described purposes, it is characterized in that: preparation wherein contains at least a other composition that is selected from melatonin receptor regulator and melatonin profile regulator.
14. 13 a described purposes, it is characterized in that: preparation wherein contains at least a benzene phenodiazine that is selected from
Melatonin receptor regulator, benzene phenodiazine
The other medicines of melatonin profile regulator, beta-Blocking agent, calcium channel blocker and 5-hydroxy tryptamine uptake inhibitor.
15. the method for at least a following effects is provided to the patient; it is characterized in that: improve emotion and daytime the insomnia, postpone patient's hydrocortisone peak level and to the potential preventive protection effect of ischemia to the heart illeffects, the method comprises to the patient uses melatonin with amount and the mode that can effectively reach described at least a above-mentioned effect.
16. 15 a described method, wherein melatonin is with the form administration of pharmaceutical preparation, and described pharmaceutical preparation contains melatonin and at least a pharmaceutical carrier, diluent or coating, and wherein said preparation is characterised in that: comprise at least a following feature:
(i) it is the controlled release preparation that is suitable for discharge melatonin within predetermined a period of time after the human patients administration;
(ii) it be suitable for according to simulation have in the human plasma of normal endogenous melatonin profile at night night profile profile discharge the controlled release preparation of melatonin;
(iii) it is suitable for being selected from the administering mode administration of oral, parenteral, rectum and percutaneous dosing;
(iv) it is the unit dosage form that every dosage unit contains 1mg to 80mg melatonin.
17. 16 a described method, it is characterized in that: preparation wherein is the controlled release preparation that contains the particle form of coated granule, and required controlled release characteristics reaches by at least one following feature, that is:
(a) granularity of change melatonin;
(b) use at least two kinds of different coating materials that in human body, dissolve with different rates; With
(c) change the thickness of coating material, thereby the melatonin of particle form is used the coating material coating that in human body, dissolves with different rates of different-thickness.
18. 17 a described method, it is characterized in that: preparation wherein contains the melatonin of the particle form of useful at least a polymer coating material coating.
19. 15 described methods is characterized in that: wherein at the simultaneous of melatonin administration to patient's melatonin receptor or melatonin profile or the adjusting of the two.
20. 19 described methods, it is further characterized in that: comprise at least an other feature (α) and (β):
(α) jointly use at least a benzene phenodiazine that is selected to the patient
Melatonin receptor regulator, benzene phenodiazine
The other medicines of melatonin profile regulator, beta-Blocking agent, calcium channel blocker and 5-hydroxy tryptamine uptake inhibitor;
(β) regulate patient's melatonin profile by the impact that before using melatonin, in the application or after using the patient is applied illumination.
21. 20 a described method, it is characterized in that: wherein said at least a other medicines are included in the pharmaceutical preparation that contains the melatonin of using to some extent.
22. the method for item 16, it is characterized in that: wherein said at least a pharmaceutical carrier, diluent or coating comprise at least a acrylic resin.
Claims (3)
1. melatonin is in the purposes that produce to be used for existing or not exist in the controlled release drug that exists the unusual non-spoon type blood pressure patient of blood pressure rhythm to reduce the blood pressure at night under the condition of anti-hypertension compound.
2. purposes claimed in claim 1, wherein said medicine feature also is to have at least one following characteristics:
(i) it is suitable for oral, rectum, parenteral or percutaneous dosing;
(ii) it is suitable for orally, and the amount of contained melatonin provides the daily dose of 0.5-100mg;
(iii) it is suitable for discharging melatonin with predetermined speed control;
(iv) it also contains at least a melatonin receptor regulator and/or the agent of melatonin profile adjustment.
3. claim 1 or 2 described purposes, it is characterized in that: described medicine is suitable for oral, and the amount of contained melatonin provides the daily dose of 0.5-50mg.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110195561 CN102274160B (en) | 2000-01-05 | 2000-01-05 | Method and preparation for treating resistance to antihypertensives and related conditions |
| HK12104848.2A HK1164136A1 (en) | 2000-01-05 | 2012-05-17 | Method and formulation for treating resistance to antihypertensives and related conditions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110195561 CN102274160B (en) | 2000-01-05 | 2000-01-05 | Method and preparation for treating resistance to antihypertensives and related conditions |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00818153A Division CN1414851A (en) | 2000-01-05 | 2000-01-05 | Method and formulation for treating resistance to antihypertensives and related conditions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102274160A CN102274160A (en) | 2011-12-14 |
| CN102274160B true CN102274160B (en) | 2013-10-30 |
Family
ID=45100109
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110195561 Expired - Lifetime CN102274160B (en) | 2000-01-05 | 2000-01-05 | Method and preparation for treating resistance to antihypertensives and related conditions |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102274160B (en) |
| HK (1) | HK1164136A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109862826B (en) * | 2016-08-18 | 2023-03-21 | 皇家飞利浦有限公司 | Blood pressure management |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2134108C1 (en) * | 1998-10-06 | 1999-08-10 | Заславская Рина Михайловна | Agent for treatment of patient with arterial hypertension, method of treatment of patient with arterial hypertension |
-
2000
- 2000-01-05 CN CN 201110195561 patent/CN102274160B/en not_active Expired - Lifetime
-
2012
- 2012-05-17 HK HK12104848.2A patent/HK1164136A1/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2134108C1 (en) * | 1998-10-06 | 1999-08-10 | Заславская Рина Михайловна | Agent for treatment of patient with arterial hypertension, method of treatment of patient with arterial hypertension |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102274160A (en) | 2011-12-14 |
| HK1164136A1 (en) | 2012-09-21 |
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