CN100518743C - Compound digoxin preparation for treating chronic heart failure - Google Patents
Compound digoxin preparation for treating chronic heart failure Download PDFInfo
- Publication number
- CN100518743C CN100518743C CNB2007100521070A CN200710052107A CN100518743C CN 100518743 C CN100518743 C CN 100518743C CN B2007100521070 A CNB2007100521070 A CN B2007100521070A CN 200710052107 A CN200710052107 A CN 200710052107A CN 100518743 C CN100518743 C CN 100518743C
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- digoxin
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- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000002644 neurohormonal effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
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- 238000005453 pelletization Methods 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- 229960001999 phentolamine Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000003361 porogen Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 208000004124 rheumatic heart disease Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种用于治疗慢性心衰的复方地高辛制剂，每一制剂规格，按地高0.125mg、卡托普利12.5mg、氨酰心安6.25mg、氢氯噻嗪12.5mg、氨苯喋啶25mg的混合物分制成：4小时内释放的速释A丸，2～12小时内释放的缓释B丸，8～18小时内释放的缓释C丸；按氯化钾200mg、硫酸镁100mg的混合物制成8小时内释放的钾镁缓释D丸，A丸、B丸、C丸、D丸按1/3∶1/3∶1/3∶5.3的重量比混匀装入胶囊或者压成片剂。本发明通过将多种药选择性地复制成一粒，并设计合理小剂量，使治疗能同时作用于心衰的不同环节，结合分时段缓慢释放的制备方法，使疗效得以持续，药物不良反应大为降低，服用简化，这些因素使病人对治疗依从性大为提高。A compound digoxin preparation for treating chronic heart failure, each preparation specification is a mixture of 0.125 mg digoxin, 12.5 mg captopril, 6.25 mg acetolol, 12.5 mg hydrochlorothiazide, and 25 mg triamterene Divide into: quick-release A pills released within 4 hours, slow-release B pills released within 2-12 hours, and slow-release C pills released within 8-18 hours; prepared as a mixture of potassium chloride 200mg and magnesium sulfate 100mg Potassium and magnesium slow-release D pills released within 8 hours, A pills, B pills, C pills, and D pills are mixed in a weight ratio of 1/3:1/3:1/3:5.3 and packed into capsules or pressed into tablets agent. In the present invention, multiple drugs are selectively copied into one tablet, and a reasonable small dose is designed so that the treatment can act on different links of heart failure at the same time. Combined with the preparation method of slow release in time intervals, the curative effect can be sustained, and the adverse drug reactions are large. In order to reduce, taking simplified, these factors make the patient's treatment compliance greatly improved.
Description
Technical field
The present invention relates to the compositions and the medication preparation thereof of Folium Digitalis Purpureae, diuretic, angiotensin converting enzyme inhibitor and beta-blocker.
Background technology
Chronic heart failure (CHF) is the end stage eventually of development such as various heart diseases such as coronary heart disease, hypertension, cardiomyopathy, valvulopathy.
Along with the variation to this disease understanding, can divide three phases to the Drug therapy of CHF: bias toward from water-sodium retention understanding CHF 40-sixties of phase I, Folium Digitalis Purpureae and diuretic are mainly selected in treatment for use.70-eighties of second stage biases toward from hemodynamics angle understanding CHF, mainly selects vasodilation (as nitroglycerin, phentolamine, nitre Pu Na etc.) and variable force preparation (as dobutamine and amrinone etc.) for use.Since nineties phase III,, begun to bias toward, advocate and select angiotensin converting enzyme inhibitor (ACEI) and beta-blocker for use from nerve-hormone disturbance angle understanding CHF because cytobiology, molecular biology and endocrinology develop rapidly.
In fact, the medicament categories of treatment CHF is various, and only cardiac tonic, diuretic, ACEI and beta-blocker four class medicines just reach hundreds of.Clinically, all be to take multiple medication combined treatment.How to select in numerous similar medicines, how to arrange in pairs or groups with inhomogeneous medicine, different doctors often fall far short, and same outpatient may be in treatment continuously in the uncertain therapeutic scheme; The patient who receives treatment, owing to need take the medicine of multiple varying number (have once nearly surplus in the of 10 slice), different number of times for a long time, therefore, except that while in hospital Shang Keyou nurse unified make up a prescription send out medicine on time and can guarantee to treat, leave hospital the back just normal because of can not adhere to taking medicine on time, decrement or withdraw (often because of some poison of drug side effect stimulation, some medicine too expensive etc.) voluntarily, sb.'s illness took a turn for the worse to cause heart failure, is in hospital once more repeatedly.Patient is poor to the compliance of medicine, takes place the compensatory single modal reason of acute mistake except that becoming patient CHF, also because of morbidity repeatedly, causes very heavy financial burden for individual family and society.
In addition, in the medicine of current treatment CHF, some important drug dose is higher, since the side effect that medicine itself exists, the situation that toxic reaction takes place or be difficult to tolerate among the user that is everlasting.For example, the oral medicine that digoxin is a Folium Digitalis Purpureae class purity height, effect is strong, rapid-action, curative effect is sure, its consumption of past is emphasized the amount of reaching capacity 1.5mg in the short-term (2-3 days), changes maintenance dose later on into, is 0.25mg every day.This therapeutic dose often may produce the digitalism reaction in the patient who accepts the digoxin treatment.Severe patient can cause death.And for example, merge the patient of hypokalemia, because of the long-term oral potassium chloride of need, cause gastrointestinal reaction, many patients are difficult to tolerance and withdraw voluntarily, more increase the weight of electrolyte disturbance and cause severe arrhythmia.For the patient who suffers from CHF, the toxic reaction of medicine often occurs or be difficult to tolerance in long periods of treatment, drug withdrawal influences treatment so that sb.'s illness took a turn for the worse because of not being able on the one hand, also hits the confidence of patient on the other hand, make it to produce pessimistic hopeless downhearted emotion, hinder patients ' recovery.
Summary of the invention
Purpose of the present invention, provide that a kind of medicine optimum organization by existing treatment CHF forms, determined curative effect, clothes back interaction energy is balanced lasting, reduce even eliminate the untoward reaction of medicine, few side effects is beneficial to for a long time and takes, and patient takes not only economy but also convenient, can improve medicine---the compound digoxin preparation of patient to the compliance of treatment.
A kind of compound digoxin preparation provided by the present invention is obtained by following preparation method:
Each preparation specification medicinal ingredient, determine by digoxin 0.125mg, captopril 12.5mg, atenolol 6.25mg, hydrochlorothiazide 12.5mg, triamterene 25mg, potassium chloride 200mg, magnesium sulfate 100mg, with the capsule number of digoxin contents in each preparation specification * need preparation or sheet number as base unit weight 1, major ingredient digoxin, captopril, hydrochlorothiazide, atenolol, triamterene, potassium chloride, magnesium sulfate successively in the ratio of 1:100:100:50:200:1600:800, are determined major ingredient each component material amount;
Digoxin, captopril, hydrochlorothiazide, atenolol, 5 kinds of medicine mix homogeneously of triamterene in the major ingredient are made powder, and wherein digoxin is diluted to 128 times with the starch equivalent method of rising progressively, again with other 4 kinds of medicine mixing porphyrizes, with this powder be divided into 3 parts standby;
Get 1 part of described powder, with starch, lactose porphyrize mixing, get mixed powder, powder: starch: lactose=1:1:1.3, it is an amount of to leave and take this mixed powder, make binding agent with 5～10% polyvinylpyrrolidones (PVP K30) aqueous solution, to be left mixed powder with q.s and make soft material, cross 16 order nylon screens, repeatedly granulate, it is round as a ball that this wet granular is put into coating pan, dry, repeatedly alternately add mixed powder and the 5% polyvinylpyrrolidone aqueous solution of leaving and taking in the rolling granule again, drying is collected the tight piller of 16～20 orders, obtains obeying the rapid release A ball that discharges in back 4 hours;
Get 1 part of described powder, with lactose, starch, hydroxypropyl emthylcellulose (HPMC), ethyl cellulose (EC) porphyrize mixing, get mixed powder, powder: lactose: starch: hydroxypropyl emthylcellulose: ethyl cellulose=1:1:0.75:0.5:0.5, it is an amount of to leave and take this mixed powder, make binding agent with 80% ethanol, to be left mixed powder with q.s and make soft material, cross 16 order nylon screens, repeatedly granulate, it is round as a ball that this wet granular is put into coating pan, dry, repeatedly alternately add mixed powder and the described ethanol binding agent of leaving and taking in the rolling granule again, drying is collected the tight piller of 16～20 orders, the slow release B ball that discharges in 2～12 hours after obtaining obeying;
Get 1 part of described powder, with lactose, starch, hydroxypropyl emthylcellulose, ethyl cellulose porphyrize mixing, get mixed powder, powder: lactose: starch: hydroxypropyl emthylcellulose: ethyl cellulose=1:1:0.25:1:0.05, method of granulating and binding agent obtain obeying the slow release C ball that discharges in back 8～18 hours with slow release B ball;
With potassium chloride in the major ingredient and magnesium sulfate and ethyl cellulose porphyrize mixing, potassium chloride: magnesium sulfate: ethyl cellulose=2:1:1 with the method for making slow release B ball or C ball, obtains obeying the potassium magnesium slow release D ball that discharges in back 8 hours;
Press
Dress capsule or tabletting.
Usage and dosage: oral.Each one of serious symptom person, early, the evening each once; Each one of stable disease person, once-a-day.
Its indication:
1, chronic heart failure due to the various organic heart diseasies.
2, dilated cardiomyopathy.
3, chronic room is pounced on, atrial fibrillation tachycardia person.
4, original bradyarrhythmia is through the arrangement heart heartstart and with heart failure symptoms person.
5, stable chronic heart failure patient's keeps treatment.
Contraindication:
1, severe bradycardia, sick sinus syndrome, atrioventricular block.
2, bronchial asthma.
3, severe renal nonfunction person.
According to the progress of modern age to CHF pathophysiology understanding, the activation of sympathetic nervous system and renin angiotensin aldosterone system (RAAS) plays an important role in heart failure takes place.In the present invention, selected digoxin is removed and is suppressed myocardial cell membrane Na
+/ K
+-ATP enzyme and bringing into play outside the positive inotropic action also suppresses the Na of parasympathetic nervus centripetalis
+/ K
+-ATP enzyme, the sensitivity of pressurize sensor increases the quantity of inhibition afferent impulse, and then the sympathetic irritability that the central nervous system is assigned weakens, thereby reduces the sympatheticotonia degree; In addition, can also be to suppressing the Na of kidney
+/ K
+-ATP enzyme causes renin secretion to reduce and inhibition RAAS; Digoxin also has the excretory effect of the atrial natriuretic peptide of increasing, and the Gaoxin, old place also is counted as neurohormonal regulator; According to the RADIANCE evidence: the digoxin of stopping using, only take diuretic, ACEI, heart failure worsens and accounts for 25%, only accounts for 5% and continue to take the digoxin group, illustrate that ACEI can not replace digoxin, and Gaoxin need prolonged application explanatorily.The present invention takes the maintenance dose treatment, and with minimal effective dose 0.125mg and other medicines combination, every day, intake mostly was 0.25mg most, and minimum is 0.125mg, finds existing satisfactory effect, also can avoid digitalism.
Captopril is an ACEI class medicine.The mechanism of action of ACEI: (1) suppresses Ang I and is transformed into AngII, acts on kininase II, suppresses the degraded of Kallidin I, increases the prostaglandin level, thereby expands periphery small artery, Venous system, alleviates heart front and back load; (2) suppress the RAAS of cardiac muscular tissue, prevent that ventricular muscles from reinventing; (3) suppress sympathetic nervous system, reduce catecholamine levels in the circulation blood, beta-receptor density is raised; (4) help to correct CHF patient's hypokalemia, reduce the incidence rate of ventricular arrhythmia.Captopril is for containing sulphydryl activity type ACEI medicine, and precursor type ACEI such as enalapril, benazepril (lotensin), fosinopril need such as (MENGNUO) are converted into the active substance rear through liver and play a role, and onset is slow.The oral post-absorption of captopril is fast, and onset in 15 minutes reached the peak in 60～90 minutes, and effect was kept 6～8 hours, through long-term a large amount of clinical research confirmations, it can improve cardiac function, increases exercise tolerance, dwindles cardiothoracic ratio, alleviate the periphery edema, reduce arrhythmia, improve survival rate.In addition, the price of captopril, much cheap than other ACEI medicine, have higher potency ratio, can alleviate patient's financial burden, ACEI treatment CHF needs use throughout one's life indefinite duration, so, select captopril, except that above-mentioned treatment meaning, also be beneficial to patient and take for a long time.
Atenolol is β
1-receptor blocking agent.From Waagstein in 1975 etc. report the earliest beta-blocker to heart failure due to the dilated cardiomyopathy effectively since, certainly, it treats the effect of CHF to Chinese scholars at present, large-scale clinical trials such as MDC, CIBIS-II, COPERNICUS and MERIT-HF confirm that all beta-blocker can improve patient's CHF long term survival rate, reduce mortality rate, it can make heart rate descend, block sympathetic activation and catecholamine release, beta-receptor is raised, thereby improve cardiac function.Though the beta-blocker short application use has negativity muscular strength effect, it share with the digoxin with positive inotropic action, can alleviate or offset this ill effect.Prolonged application beta-blocker treatment (4 months to 1 year) can reduce left chamber myoplasm amount, reduces capacity, increases ejection fraction, obviously improves cardiac function.As share with ACEI, can prevent and reverse Myocardial Remodeling, can make and give further improvement of back long term.Atenolol is selectivity β
1-receptor blocking agent does not have inherent sympathetic activity, hydrophilic β
1-blocker, the gastrointestinal absorption rate is lower, and it is constant relatively the peak concentration of drug time to occur, and individual variation is little, and the half-life is long, is difficult for seldom producing central nervous system's side reaction by alveolar-capillary barrier.Belong to lipotropy β and act on identical metoprolol
1-receptor blocking agent easily absorbs from gastrointestinal, eliminates through hepatic metabolism, because liver " first-dose response " arrives blood level and has only 30～50%, action time is short than atenolol.It easily by blood brain barrier, can produce obvious central nervous system's side reaction (as nightmare, hallucination etc.).The atenolol of selecting for use in the prescription, except that having above-mentioned advantage, it also is the cheaper medicine of price, has higher potency ratio.
Hydrochlorothiazide and triamterene are diuretic.Diuretic is a containment heart failure water-sodium retention, reduces venous return, alleviates pulmonary venous pleonaemia, reduce preload and improve the medicine of cardiac function, and be indispensable ingredient in any heart failure therapeutic strategy.With it and Folium Digitalis Purpureae class, ACEI, beta-blocker use in conjunction, can act on a plurality of links of heart failure pathology simultaneously.Hydrochlorothiazide can suppress renal tubules to Na
+, Cl
-Absorption again, cause row Na
+, Cl
-Increase, and the performance diuresis, but because Na
+, K
+Exchange, so K
+Discharge and also increase.For reducing losing of potassium, hydrochlorothiazide often needs to share with Potassium-sparing diuretic, triamterene has row's sodium to protect the potassium effect, and long action time, can reach 8～12 hours, compared with other medicines in the Potassium-sparing diuretic, as spironolactone, it does not have because of taking for a long time and causes such as side effect such as hyperkalemia, low blood sodium, gastrointestinal reaction, masculine mastoplasias.Be beneficial to patient CHF that need take for a long time especially.The present invention selects hydrochlorothiazide and triamterene for use, and the two share, and except that strengthening diuresis, the former arranges potassium, the latter protects potassium, and the two share the adverse side effect of can cancelling out each other, and prevents that hypokalemia from taking place.
Potassium chloride and magnesium sulfate are used to keep electrolytical balance.Sick normal low potassium, the hypomagnesemia of merging of CHF.The electrolysis quality disorderly is to cause severe arrhythmia so that dead major reason.Common with the oral kalium replenishment of 10% potassium chloride, but its bitter and puckery flavor, the stimulating gastrointestinal road, many patients are difficult to tolerance and withdraw voluntarily.Magnesium ion replenishes with usual employing vein, and oral consumption at intestinal absorption and magnesium sulfate is inverse ratio, and the big more absorption of dosage is few more, so adopt low dose of magnesium sulfate salt oral in the prescription.The present invention allocates magnesium salt potassium salt into the ratio of 1:2, replenish K on the one hand
+, Mg
2+To prevent arrhythmia and digitalism, on the other hand because of being made into slow-release pill, reducing even having eliminated stimulates gastrointestinal, is beneficial to lasting treatment.The material that plays slow releasing function can not be absorbed by the body, and gets rid of with feces.
Advantage of the present invention is:
1, integrates Folium Digitalis Purpureae, diuretic, ACEI, beta-blocker, and select the appropriate single medicine of each apoplexy due to endogenous wind and potassium salt, magnesium salt compatibility, make compound preparation, act on the different links of heart failure simultaneously, bring into play between each medicine and cooperate complementary action, certain side effect of repealing by implication, curative effect comprehensively, reliable.
2, by taking, make treatment balanced continuing in drug administration process on the one hand, reduce the misery of patient's Intolerance reaction the selected multiple medicine preparation method of slow release in batches of dividing into groups.
3, owing to take different rate of release, quick-acting, middle effect, long-acting combining have avoided the drug level short-term sharply to raise, " peak valley " phenomenon of very fast decline subsequently, and protection is stable, and effect is lasting, has also reduced the untoward reaction of medicine simultaneously.
4, because the multiple medicine that acts on the different links of heart failure simultaneously reasonably is copied into one, and take to make its medicinal ingredient in the whole process of taking, to continue the preparation method that discharges, patient's take medicine kind and medicining times are greatly reduced, and it is convenient that medication treatment is simplified; Because medicine is to divide into groups slowly to discharge in batches, the toxic and side effects of medicine and zest are reduced, make patient accomplish easily to adhere to taking medicine; Because prescription of the present invention is paid attention to the potency ratio of medicine, can alleviate the financial burden of patient's medication, be beneficial to the long-term medication treatment of patient, these factors make the present invention have fine drug compliance.
5, the content of each component medicine adopts effectively low dose of combination, not only produces the obvious treatment effect, and the toxicity of medicine is reduced, and the side effect of long-term prescription is reduced, and also is convenient to according to state of an illness trace when increase and decrease.
In the clinical trial process after the present invention creates, the following up a case by regular visits to of volunteer of adhering to taking reached 3～8 years, this crowd takes (each one of maintenance dose of the present invention always, once-a-day), conscious good, quality of life improves, and adverse side effect do not occur, does not have or seldom is in hospital once more because of heart failure worsens.Also have a lot of patients oneself to discuss this medicine to clinical trial hospital.Can estimate that product of the present invention will be obtained the coml success if put on market.
For ease of being familiar with the present invention better, be illustrated compound digoxin preparation is used for clinical observation of curative effect report below:
Object: from January, 1998 to 2000 year December, the patients with congestive heart failure that intracardiac section of one hospital is in hospital in Jingzhou City is selected at random, 120 examples are compound digoxin preparation treatment group, man's 70 examples, woman's 50 examples, 28-80 years old ages, mean age 60.9 ± 13.2, average 11.7 ± 3.1 years of the heart course of disease, those selected all carefully fills in a form and registers the situation of in the past being in hospital.The cause of disease: hypertension, coronary heart disease 65 examples, rheumatic heart disease 29 examples, DCM (dilated cardiomyopathy) 21 examples, other 5 examples.Cardiac function is pressed NHYHA classification III level 70 examples, IV level 50 examples.Picked at random heart failure same period patient 200 examples are the conventional therapy group.
Usage and time: each 1 of compound digoxin preparation 2 times on the 1st morning, evening, treat after the stable disease 1 time 1 time on the 1st 1, as the heart failure severe patient can use low dose of cedilanid temporarily, furosemide is quiet pushes away, the edema severe patient can increase hydrochlorothiazide and triamterene consumption in addition.1 year to 3 years medicine time.In patient's drug administration process because of heart failure worsen due to dead person; Or producing violent dry cough, the patient can not anti-receptor; Severe bradycardia heart rate＜55 time/minute or accompany two, the third degree A-V block person, promptly stop the compound digoxin preparation treatment.
Observation index: patient's laboratory examinations such as laggard promoting the circulation of blood routine urinalysis, electrolyte, hepatic and renal function, blood fat, blood glucose of being admitted to hospital.Electrocardiogram, X line and cardiac function (Color Sonography, machcardiogram) be the check in March before using compound digoxin preparation and after the medication, patient's while in hospital symptom takes a turn for the better, leave hospital after cardiac function improves and continue to take compound digoxin preparation maintenance dose every day 1 time, each 1, outpatient service regularly is with examining.
Curative effect judging standard: the cardiac function progress is a produce effects for 2 grades, and 1 grade of cardiac function progress is effectively, 1 grade of cardiac function progress less than or worsen dead person for invalid.
Statistical procedures:, measure medication front and back cardiac function and add and subtract standard deviation, row t check with mean with SPSS software kit MICROCOMPUTER PROCESSING; Compound digoxin preparation treatment group and conventional therapy group case fatality rate adopt X
2Check.The result
Cardiac function: use compound digoxin preparation front and back row Color Sonography cardiac inspection such as table 1.The machcardiogram cardiac inspection sees Table 2.Cardiac function significantly improves 2 grades of person's 65 examples, accounts for 54.16%, and improve 1 grade of person's 45 example and account for 37.5%, total effective rate 91.66%, nonresponder's 10 examples account for 8.33%.
Heart rate, blood pressure: heart rate is 100.96 ± 5.85 before the 120 example treatments, treatment back 78.24 ± 7.98, P＜0.001.Blood pressure: systolic pressure treatment is preceding 142.98 ± 26.41, is 128.39 ± 16.31P＜0.001 after the treatment; Before and after the diastolic pressure treatment is 83.77 ± 15.57, is 76.25 ± 11.92 after the treatment, P＜0.001.
The hospitalization number of times: it is 3.06 times/year that 120 examples are not used the preceding annual average time in hospital number of times of compound digoxin preparation treatment, after using the treatment of compound digoxin preparation and long term maintenance amount,, various factors influence (as drug withdrawal, infection, fatigue etc.) heart failure needs hospitalizing's average out to 0.82 time/year because of worsening.P＜0.01, there were significant differences.
Table 1 50 examples are used compound digoxin preparation treatment front and back heart B ultrasonic cardiac inspection (mean+SD)
Table 2 90 examples are used compound digoxin preparation treatment front and back machcardiogram cardiac inspection (mean+SD)
Case fatality rate: followed up a case by regular visits to CHF patient 2 years, 120 examples are used compound digoxin preparation treatment patient, dead 10 examples (wherein worsening 9 examples of dying that cause death, 1 example of dying suddenly) because of heart failure, and mortality rate is 8.33%; 200 routine conventional therapy persons, dead 34 examples (wherein because of dead 29 examples of heart failure carrying out property deterioration, 5 examples of dying suddenly), mortality rate is 17%, both have notable difference (P＜0.05).
Side effect: use compound digoxin preparation and bradycardia person's (＜60 times/minute) 5 examples in 120 examples, account for 4.16%; Zest dry cough person 5 examples 4.16%; Hypotensive's 4 examples 3.3%.Do not see that digitalism takes place, wherein 6 customary Folium Digitalis Purpureae determination of plasma concentration are 1.16ng/L.
Conclusion
Digoxin, diuretic, ACEI and the treatment of beta-blocker tetrad are adopted in the treatment of chronic heart failure (CHF), and this is a rational and effective therapeutic scheme.
Therefore CHF is a kind of progressive pathological changes, and the treatment to CHF transfers secular reparation strategy to from past short-term hemodynamics, pharmacology's measure, prevents and delays Myocardial Remodeling, and prolonged application ACEI and beta-blocker are useful.
Compound digoxin preparation in one, is not seen bibliographical information with the multiple drug regimen of four classes as yet, and its synergism is strong, effective dose is little, few side effects, take easyly, can improve the compliance of patient to Drug therapy.
The clinical observation compound digoxin preparation is treated 120 routine CHF patients and is obtained good result, doing well,improving not only, and quality of life improves, and has reduced admission rate, has reduced mortality rate.Therefore compound digoxin preparation prevents, controls to be an effective model to CHF.
The specific embodiment:
The invention will be further described for following surface function.
The compound digoxin preparation that is used for the treatment of chronic heart failure, dosage form can be capsule, can be tablet, in each preparation specification, medicinal component is: digoxin 0.125mg, captopril 12.5mg, atenolol 6.25mg, hydrochlorothiazide 12.5mg, triamterene 25mg, potassium chloride 200mg, magnesium sulfate 100mg, oral, each one of serious symptom person, early, the evening each once; Each one of stable disease person, once-a-day.
A kind of compound digoxin preparation provided by the present invention is obtained by such preparation method: each preparation specification, mixture branch by digoxin 0.125mg, captopril 12.5mg, atenolol 6.25mg, hydrochlorothiazide 12.5mg, triamterene 25mg is made: the rapid release A ball that discharges in 4 hours, the slow release B ball that discharges in 2～12 hours, the slow release C ball that discharges in 8～18 hours; Make the potassium magnesium slow release D ball that discharges in 8 hours by the mixture of potassium chloride 200mg, magnesium sulfate 100mg, A ball, B ball, C ball, D ball are pressed
:
:
: 5.3 weight ratio mixing incapsulates or is pressed into tablet.This preparation method can be undertaken by such technology:
With the capsule number of digoxin contents in each preparation specification * need preparation or sheet number as base unit weight 1, major ingredient digoxin, captopril, hydrochlorothiazide, atenolol, triamterene, potassium chloride, magnesium sulfate successively in the ratio of 1:100:100:50:200:1600:800, are determined major ingredient each component material amount;
Digoxin, captopril, hydrochlorothiazide, atenolol, 5 kinds of medicine mix homogeneously of triamterene in the major ingredient are made powder.Because digoxin content is little, at first get digoxin with starch " equivalent is risen progressively " method dilution 7 times to 128 times, again with other 4 kinds of medicine mixings porphyrizes (cross 100 mesh sieves, under together), with this powder be divided into 3 parts standby;
Get 1 part of described powder, with starch, lactose porphyrize mixing, get mixed powder, powder: starch: lactose=1:1:1.3, it is an amount of to leave and take this mixed powder, make binding agent with 5～10% polyvinylpyrrolidones (PVP K30) aqueous solution, to be left mixed powder with q.s and make soft material, cross 16 order nylon screens, repeatedly granulate, it is round as a ball that this wet granular is put into coating pan, dry, repeatedly alternately add mixed powder and the 5% polyvinylpyrrolidone aqueous solution of leaving and taking in the rolling granule again, drying is collected the tight piller of 16～20 orders, obtains obeying the rapid release A ball that discharges in back 4 hours;
Get 1 part of described powder, with lactose, starch, hydroxypropyl emthylcellulose (HPMC), ethyl cellulose (EC) porphyrize mixing, get mixed powder, powder: lactose: starch: hydroxypropyl emthylcellulose: ethyl cellulose=1:1:0.75:0.5:0.5, it is an amount of to leave and take this mixed powder, make binding agent with 80% ethanol, to be left mixed powder with q.s and make soft material, cross 16 order nylon screens, repeatedly granulate, it is round as a ball that this wet granular is put into coating pan, dry, repeatedly alternately add mixed powder and the described ethanol binding agent of leaving and taking in the rolling granule again, drying is collected the tight piller of 16～20 orders, the slow release B ball that discharges in 2～12 hours after obtaining obeying;
Get 1 part of described powder, with lactose, starch, hydroxypropyl emthylcellulose, ethyl cellulose porphyrize mixing, get mixed powder, powder: lactose: starch: hydroxypropyl emthylcellulose: ethyl cellulose=1:1:0.25:1:0.05, method of granulating and binding agent obtain obeying the slow release C ball that discharges in back 8～18 hours with slow release B ball;
With potassium chloride in the major ingredient and magnesium sulfate and ethyl cellulose porphyrize mixing, potassium chloride: magnesium sulfate: ethyl cellulose=2:1:1 with the method for making slow release B ball or C ball, obtains obeying the potassium magnesium slow release D ball that discharges in back 8 hours;
Press
Dress capsule or tabletting, then each preparation specification has medicinal ingredient and content:
Digoxin 0.125mg
Captopril 12.5mg
Atenolol 6.25mg
Hydrochlorothiazide 12.5mg
Triamterene 25mg
Potassium chloride 200mg
Magnesium sulfate 100mg.
Used hydroxypropyl emthylcellulose is the hydrophilic gel framework material, and the disintegration form is the diffusion of gel layer and the corrosion of gel skeleton; Used ethyl cellulose for the hydrophobicity framework material, dissolves in ethanol, and can film forming.In pelletization, make binding agent with 80% ethanol, make ethyl cellulose dissolving or be partly dissolved, be able to combine and form skeleton with hydroxypropyl emthylcellulose.The hydrophobicity of ethyl cellulose and film property play retardation to the aquation of hydroxypropyl emthylcellulose, and dissolution rate and the diffusion velocity contained in the medicine of skeleton are reduced, and the release of medicine is slowed down reach the purpose of long duration of action.
Available fully similarly other framework materials are applied to the present invention, and importantly, fibrous root suitably regulates the ratio of adjuvant to reach the period that respectively discharges of the presently claimed invention according to used framework material.
Used lactose, starch, respectively as porogen, filler, can be in the use according to the practical situation adjustment.
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100521070A CN100518743C (en) | 2007-04-29 | 2007-04-29 | Compound digoxin preparation for treating chronic heart failure |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100521070A CN100518743C (en) | 2007-04-29 | 2007-04-29 | Compound digoxin preparation for treating chronic heart failure |
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| Publication Number | Publication Date |
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| CN101045061A CN101045061A (en) | 2007-10-03 |
| CN100518743C true CN100518743C (en) | 2009-07-29 |
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2007
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Non-Patent Citations (1)
| Title |
|---|
| 联合用药治疗充血性心力衰竭130例疗效观察. 杨学新等.长江大学学报（自科版），第2卷第3期. 2005 * |
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