CN101843892B - Medicament composition comprising Enalapril quick-releasing part and felodipine slow-releasing part - Google Patents
Medicament composition comprising Enalapril quick-releasing part and felodipine slow-releasing part Download PDFInfo
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Abstract
The invention relates to a medicament composition preparation comprising an Enalapril quick-releasing part and a felodipine slow-releasing part. The medicament composition is a medical composition formed by mixing Enalapril and felodipine as medical active components with and pharmaceutically acceptable auxiliary materials. The composition preparation comprising comprises a slow-releasing part tablet core and a quick-releasing part coating, wherein the slow-releasing part tablet core is the felodipine, and the quick-releasing part coating is the Enalapril or Enalapril-acid addition salts. The composition can rapidly stabilize blood pressure and permanently keep the blood pressure steady.
Description
Technical field
The present invention relates to a kind of hypertensive drug combination preparation that is used for the treatment of, be specifically related to a kind of drug combination preparation that contains the immediate release section clothing layer of enalapril or enalapril-acid-addition salts and contain the slow-released part label of felodipine, belong to medical technical field.
Background technology
Enalapril is Angiotensin-Converting (ACE) inhibitor, is hydrolyzed into the dicarboxylic acids enalaprilat after oral in liver, and the strong inhibition Angiotensin-Converting reduces angiotensinⅡ content, causes systemic vasodilatation, blood pressure drops.Its usual amounts 5～10mg is for accelerating onset time the palpus intravenous injection.This medicine treatment moderate or severe hypertension, dosage must increase to 80mg/ days, and only having an appointment, 60% hyperpietic is alone to prove effective.Enalapril is developed by U.S. merck company at first, went on the market in the Germany in 1984, one of best-selling prescription drug of Ceng Zuowei European ﹠ American Market, but sales volume begins to descend after calendar year 2001, and main cause has: enalapril Patent expiry in 2000, and various countries are imitated one after another, similar new product constantly occurs, self have some problems: (1) efficacy of antihypertensive treatment has certain limit, and lot of documents report total effective rate only is about 60%, 40% invalid or curative effect is not remarkable; (2) target organ protection function is without clear superiority.And exploitation enalapril compound drug can overcome above-mentioned deficiency, improves the enalapril curative effect, reduces using dosage, reduces untoward reaction.
Felodipine is calcium antagonist class (CCB) antihypertensive drug, belongs to dihydropyridines.Arteria coronaria and peripheral blood vessel all there is dilating effect, thereby have the utilization that suppresses calcium in the calmodulin interference cell during high concentration concurrently, its characteristics are to small artery tool selectivity dilating effect, when therapeutic dose to cardiac muscle without negative inotropic action, prolonged application is conducive to the reverse of left ventricular hypertrophy; Water, sodium to renal tubules and collecting tubule heavily are absorbed with slight inhibitory action, to angina pectoris and the expansible coronary artery of patients with heart failure, increase myocardial oxygen delivery and reduce oxygen consumption; Felodipine is applicable to the treatment of each phase hypertension, especially be suitable for accompanying the patients with hypertension of renal hypofunction, raynaud's sign, asthma, gout and diabetes, also effective to pulmonary hypertension or renal hypertension, untoward reaction is light, is difficult for producing water, sodium retention phenomenon.The dosage form of using at present is ordinary tablet and slow releasing tablet, and the felodipine sustained-release tablets that carries out in suffering from the patient of essential hypertension research is found, uses separately said preparation treatment mild hypertension.
Since nearly half a century, through clinical research for many years, it is found that most blood pressures can not be down to optimum level as giving initial blood pressure higher patient's single drug.A large amount of clinical researches show that single medication only can make patient's controlling of blood pressure arrival target blood pressure of 40～50%.And use two kinds of antihypertensive drugs curative effects greater than single medication, can make 70～80% hyperpietic's blood pressure obtain control (Yin Hongqian. Shandong medical industry, 2000,19 (6): 58～59).Therefore, when a kind of medicine that uses enough dose can not reach the blood pressure target, should add the medicine with a kind of other classifications.Most hyperpietics need two or more antihypertensive drug to reach the blood pressure target.International clinical trial proof drug combination has it to need and is worth, the dosage of every kind of medicine is little, collaborative or at least effect of addition of the therapeutical effect of medicine, its untoward reaction can be cancelled out each other or not overlapping at least or addition (Chinese hypertension prevention and control guide Drafting Committee.China's hypertension prevention and control guide.The hypertension magazine, 2000:8 (1) 94～102, and 103～112).Angiotensin converting enzyme inhibitor (ACEI)+calcium antagonist (CCB) is two kinds of drug regimens that metabolism had protective effect without any untoward reaction to the heart, kidney, used more and more by people: aspect the expansion blood vessel, calcium antagonist (CCB) has direct expansion artery effect, and angiotensin converting enzyme inhibitor (ACEI) reduces sympathetic activity by blocking-up renin-angiotensin system (RAS), can expand artery and vein, therefore Synergistic Hypotensive Effects is arranged; Because angiotensin converting enzyme inhibitor (ACEI) has the effect of the vein of expansion, still can offset the common ankle edema side effect of bihydropyridine type calcium antagonist (CCB); Two medicines share and also help to reverse target organ damages.In addition, aspect blood vessel wall localised protection and the heart, kidney protective effect, confirmed two kinds of medicines at antiproliferative, reduce the aspect such as urinaryalbumin synergism arranged.(Sha Chunming. combination of Chinese and Western medicine cardiovascular and cerebrovascular disease magazine, 2003,1 (7) 418-419).
Two kinds of medicines have been widely used in the treatment of cardiovascular disease; domestic have the compositions that contains dihydropyridine type calcium antagonists and angiotensin-convertion enzyme inhibitor medicine and a report (seeing CN101548973) of preparation method; but use two kinds of adjuvants as sustained-release matrix in this patent; must adopt complicated technique; must be with an organic solvent in the coating process; production cost is larger, and is unfavorable for large-scale production and environmental conservation.
As fully visible: enalapril and felodipine all are more satisfactory depressor, they are by different action pathway, reach the effect of blood pressure lowering, two kinds of Drug combinations are treated the camber severe hypertension, will well bring into play the effect of medicine cooperative compensating, for using single medicine to be difficult to control the patient of blood pressure, good effect, untoward reaction is few; Enalapril felodipine drug combination preparation is taken once every day, and an a slice has solved the inconvenience that present clinically needs of patients is taken respectively enalapril maleate sheet and Felodipine tablets.The applicant gropes through a large amount of tests, uses single framework material that felodipine is prepared into slow releasing preparation, can discharge fully stably; Adopt advanced technology, adopt conventional equipment, avoided in the coating process with an organic solvent obtaining enalapril felodipine drug combination preparation.
Summary of the invention
The purpose of this invention is to provide a kind of drug combination preparation take enalapril and felodipine as active component.Said preparation only need be taken once every day, greatly facilitates vast patient; The Drug combination of two kinds of different action pathway has been brought into play the effect of cooperative compensating greatly, is applicable to the patient that single medicine is difficult to control blood pressure, has greatly alleviated again patient's burden simultaneously; The said preparation medicine has adopted rapid release to add slow release design, both can the fast and stable blood pressure, and it is steady to keep lastingly blood pressure again, and untoward reaction is few, and patient dependence is strong.
Technical scheme of the present invention is summarized as follows:
The pharmaceutical composition that comprises enalapril immediate release section and felodipine sustained-release part; it is characterized in that said composition is comprised of slow-released part label, immediate release section coatings and/or optional external protection; wherein the slow-released part label contains felodipine, and the immediate release section coatings contains enalapril or enalapril-acid-addition salts.
Said composition is the form of preparation, and the content of enalapril or enalapril maleate is 2.5～25mg in each dosage unit, preferred 5～10mg; The content of felodipine is 2.5～25mg, preferred 5～10mg; More preferably enalapril or enalapril maleate content are 5mg, and felodipine content is 5mg.Preferably, said preparation is tablet.
The acid of enalapril-acid-addition salts is selected from pharmaceutically useful acid, preferably be selected from maleic acid, lactic acid, sulphuric acid, acetic acid, hydrochloric acid or the phosphoric acid one or both or two or more.
Aforementioned pharmaceutical compositions, the slow-released part label mainly comprises the mixture based on other adjuvant of the sustained-release matrix of 1～15% felodipine of slow-released part gross weight and 10～60% and surplus, and immediate release section clothing layer mainly comprises 5～50% enalapril or the coating material of enalapril-acid-addition salts and 50～95% or the mixture of rapid release substrate based on the immediate release section gross weight.
Aforementioned pharmaceutical compositions, sustained-release matrix comprise or are selected from hypromellose, polyvinylpyrrolidone, ethyl cellulose, hyprolose, hexadecanol, octadecanol, Rikemal B 200, stearic acid, glyceryl monostearate, carmethose, polyvinyl alcohol, polyvinylpolypyrrolidone, castor oil hydrogenated, stearic acid, the cellulose acetate one or more.
Aforementioned pharmaceutical compositions, the coating material of coatings or rapid release substrate comprise or are selected from hypromellose, hydroxypropyl cellulose, Polyethylene Glycol, wherein one or more of microcrystalline Cellulose.One or more waters preparation coating solutions in these materials, the part by weight of coating material and water are within preparation contains the proportion of commonly using in the field of medicaments of various pharmaceutical dosage forms of coatings and are that those skilled in the art are known.
In addition, preferably use in the present invention Opadry (OPADRY) or microcrystalline Cellulose or the mixture that formed by microcrystalline Cellulose and lactose as rapid release substrate or the coating material (if preparation coated tablet) of this drug combination preparation.Opadry is the thin film coating material (being film coating pre-mix dose) that contains polymer (cellulose derivative), plasticizer and pigment (color lake) of Shanghai Ka Lekang (Colorcon) packaging technique company limited production.
Generally speaking; enalapril of the present invention (or enalapril-acid-addition salts)-felodipine sustained-release preparation has three parts: namely slow release label, rapid release coatings and and/or optional external protection form; here; the rapid release coatings that is in slow release label top layer is comprised of enalapril (or enalapril-acid-addition salts) and rapid release substrate; it has consisted of immediate release section, and the slow release label becomes slow-released part.
In the preferred case, the slow release label mainly comprises based on the sustained-release matrix of 1～15% felodipine of label gross weight and 10～60% and other adjuvant of surplus.The rapid release coatings mainly comprises based on 5～50% enalapril (or enalapril-acid-addition salts) of coatings gross weight and 50～95% coating material.Protective layer mainly comprises coating material or forms (being the coating material that protective layer comprises 100wt%) by coating material.
Coating material (or claiming the coating preparaton) is Opadry in preferred embodiments.Preferably, other adjuvant is selected from one or both or the two or more combinations in lactose, microcrystalline Cellulose, Pulvis Talci, magnesium stearate, castor oil hydrogenated and the polyvidone class (for example PVP K30).
Technical scheme of the present invention is summarized as follows:
1, the pharmaceutical composition that comprises enalapril immediate release section and felodipine sustained-release part; it is characterized in that said composition is comprised of slow-released part label, immediate release section coatings and/or optional external protection; wherein the slow-released part label contains felodipine, and the immediate release section coatings contains enalapril or enalapril-acid-addition salts.
2, above 1 described pharmaceutical composition is characterized in that enalapril-acid-addition salts is enalapril maleate.
3, above 1 described pharmaceutical composition is characterized in that the content of enalapril in each dosage unit or enalapril-acid-addition salts is 2.5～25mg, and the content of felodipine is 2.5～25mg.
4, above 3 described pharmaceutical compositions is characterized in that the content of enalapril in each dosage unit or enalapril-acid-addition salts is 5～10mg, and the content of felodipine is 5～10mg.
5, above 4 described pharmaceutical compositions is characterized in that the content of enalapril in each dosage unit or enalapril-acid-addition salts is 5mg, and the content of felodipine is 5mg.
6, above 1 described pharmaceutical composition, it is characterized in that, the slow-released part label is to comprise based on the sustained-release matrix of 1～15% felodipine of slow-released part gross weight and 10～60% and other adjuvant of surplus, and immediate release section clothing layer is to comprise based on 5～50% enalapril of immediate release section gross weight or coating material or the rapid release substrate of enalapril-acid-addition salts and 50～95%.
7, above 6 described pharmaceutical compositions, the sustained-release matrix that it is characterized in that described pharmaceutical composition comprise or are selected from hypromellose, polyvinylpyrrolidone, ethyl cellulose, hyprolose, hexadecanol, octadecanol, Rikemal B 200, stearic acid, glyceryl monostearate, carmethose, polyvinyl alcohol, polyvinylpolypyrrolidone, castor oil hydrogenated, stearic acid, the cellulose acetate one or more.
8, above 6 described pharmaceutical compositions is characterized in that consisting of the coating material of coatings of described pharmaceutical composition or rapid release substrate and comprise or be selected from hypromellose, hydroxypropyl cellulose, Polyethylene Glycol, wherein one or more of microcrystalline Cellulose.
9, above 1 described pharmaceutical composition, the protective layer that it is characterized in that consisting of described pharmaceutical composition comprises or is selected from hypromellose, hydroxypropyl cellulose, Polyethylene Glycol, wherein one or more of polyvinyl alcohol.
10, above 1～9 described pharmaceutical composition, it is tablet.
11, prepare the method for any one described pharmaceutical composition in above 1～10, it is characterized in that it may further comprise the steps:
(1) will be based on the sustained-release matrix of 1～15% felodipine of slow-released part gross weight and 10～60% and other adjuvant of surplus, water or mass concentration are 10～95% the lower mix homogeneously of ethanol water existence, drying, then tabletting obtains the slow-released part label;
(2) be uniformly dispersed adding purified water to based on the coating material of 5～50% enalapril of immediate release section gross weight or enalapril-acid-addition salts and 50～95% or rapid release substrate, form the coating solution that contains medicine;
(3) get the coating solution of step (2) in the slow-released part label coating rapid release coating rete of step (1), drying; With
(4) randomly, prepare coating solution with coating material and water, on the product of step (3), further apply this coating solution to form protective layer.
12, prepare the method for any one described pharmaceutical composition in above 1～10, it is characterized in that it may further comprise the steps:
(1) will be based on the sustained-release matrix of 1～15% felodipine of slow-released part gross weight and 10～60% and other adjuvant of surplus, it is mix homogeneously in the presence of 10～95% the ethanol water in water or mass concentration, drying, then tabletting obtains the slow-released part label;
(2) be mix homogeneously in 10～95% the ethanol water with add water or mass concentration to based on the coating material of 5～50% enalapril of the gross weight of immediate release section coatings or enalapril-acid-addition salts and 50～95% or rapid release substrate, the wet soft material of preparation, then granulate, dry, granulate, add the lubricant mixing, obtain clothing layer granule;
(3) with pressed coated machine compacting clad sheet: prior to filling out clothing layer granule in the nib, again label is placed nib central authorities, add again clothing layer granule, then suppress clad sheet.
Beneficial effect of the present invention is: the pharmaceutical composition that the invention provides a kind of enalapril and felodipine, two kinds of Drug combination treatment camber severe hypertensions, the effect of performance medicine cooperative compensating, more more effective than the dosage that increases separately a kind of medicine, for using single medicine to be difficult to control the patient of blood pressure, good effect, untoward reaction is few.Use single framework material that felodipine is prepared into slow releasing preparation, can discharge fully stably; Avoid with an organic solvent in the coating process, enalapril is evenly dispersed in the film-coat layer, slow release adds the design of rapid release, both can the fast and stable blood pressure, and it is steady to keep lastingly blood pressure again, and patient dependence is strong.
The specific embodiment
Come enalapril felodipine Pharmaceutical composition of the present invention done further specifying by following instance, but be not limited in following instance.
Embodiment 1: enalapril maleate felodipine sustained-release tablets (1000 prescriptions)
Label:
Felodipine 2.5g
HPMC 65g
Lactose 200g
Pulvis Talci 2g
95% alcoholic solution 180g
Rapid release coatings prescription (being used for the preparation coating solution):
Enalapril maleate 2.5g
Opadry 50g
Purified water 1000g
Protective layer prescription (being mixed with coating solution):
Opadry 50g
Purified water 1000g
Preparation method:
Felodipine, HPMC cross respectively 100 mesh sieves, and lactose, Pulvis Talci are crossed 80 mesh sieves.With an amount of (amount that provides namely) alcoholic solution soft material processed, 16 mesh sieves are granulated behind raw material (being drug felodipine)/adjuvant mix homogeneously, oven dry, and 18 mesh sieve granulate add the Pulvis Talci mixing, tabletting; Enalapril maleate is added in the Opadry solution for preparing, make pastille coating solution, for subsequent use; Label is placed seed-coating machine, get pastille coating solution coating after, use the coating solution of being prepared by coating material to wrap protective layer in tablet surface, after the drying and get final product.
Embodiment 2: enalapril maleate felodipine sustained-release tablets (1000 prescriptions)
Label:
Felodipine 5g
HPMC 50g
Lactose 100g
Microcrystalline Cellulose 55g
Magnesium stearate 2g
Castor oil hydrogenated 5g
Polyvidone k 30 6g
95% alcoholic solution 120g
Purified water 15g
Rapid release coatings prescription:
Enalapril maleate 5g
Opadry 10g
Purified water 200g
The protective layer prescription:
Opadry 10g
Purified water 200g
Preparation method:
Felodipine, HPMC cross respectively 100 mesh sieves, and microcrystalline Cellulose, lactose, polyvidone k30, magnesium stearate are crossed 80 mesh sieves.With an amount of (amount that provides namely) alcoholic solution soft material processed, 16 mesh sieves are granulated behind former/adjuvant mix homogeneously, drying, and 18 mesh sieve granulate add the magnesium stearate mixing, tabletting; Enalapril maleate is added in the Opadry solution, make pastille coating solution, for subsequent use; Label is placed seed-coating machine, get pastille coating solution coating after, use the coating solution of being prepared by coating material to wrap protective layer in tablet surface, after the drying and get final product.
Embodiment 3: enalapril maleate felodipine sustained-release tablets (1000 prescriptions)
Label:
Felodipine 10g
HPMC 80g
Lactose 60g
Microcrystalline Cellulose 70g
Silicon dioxide 2g
Magnesium stearate 1g
95% alcoholic solution 150g
Purified water 40g
Rapid release coatings prescription:
Enalapril maleate 10g
Opadry 20g
Purified water 400g
The protective layer prescription:
Opadry 5g
Purified water 200g
Preparation method:
Felodipine, HPMC cross respectively 100 mesh sieves, and microcrystalline Cellulose, lactose, silicon dioxide, magnesium stearate are crossed 80 mesh sieves.With an amount of alcoholic solution soft material processed, 16 mesh sieves are granulated behind former/adjuvant mix homogeneously, drying, and 18 mesh sieve granulate add magnesium stearate, silicon dioxide mixing, tabletting; Enalapril maleate is added in the Opadry solution, make pastille coating solution, for subsequent use; Label is placed seed-coating machine, get pastille coating solution coating after, use by the coating solution of coating material preparation in tablet surface and to wrap protective layer, after the drying and get final product.
Embodiment 4: enalapril maleate felodipine sustained-release tablets (1000 prescriptions)
Label:
Felodipine 15g
HPMC 45g
Lactose 60g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Polyvidone k 30 6g
95% alcoholic solution 100g
Purified water 25g
Rapid release coatings prescription:
Enalapril maleate 15g
Opadry 15g
Purified water 300g
The protective layer prescription:
Opadry 10g
Purified water 200g
Preparation method:
Felodipine, HPMC cross respectively 100 mesh sieves, and microcrystalline Cellulose, lactose, polyvidone k30, magnesium stearate are crossed 80 mesh sieves.With an amount of alcoholic solution soft material processed, 16 mesh sieves are granulated behind the supplementary material mix homogeneously, drying, and 18 mesh sieve granulate add the magnesium stearate mixing, tabletting; Enalapril maleate is added in the Opadry solution, make pastille coating solution, for subsequent use; Label is placed seed-coating machine, get pastille coating solution coating after, use by the coating solution of coating material preparation in tablet surface and to wrap protective layer, after the drying and get final product.
Embodiment 5: enalapril maleate felodipine sustained-release tablets (1000 prescriptions)
Label:
Felodipine 25g
HPMC 80g
Lactose 50g
Microcrystalline Cellulose 55g
Magnesium stearate 3g
Polyvidone k 30 6g
95% alcoholic solution 150g
Purified water 18g
Rapid release coatings prescription:
Enalapril maleate 25g
Opadry 15g
Purified water 300g
The protective layer prescription:
Opadry 15g
Purified water 300g
Preparation method:
Felodipine, HPMC cross respectively 100 mesh sieves, and microcrystalline Cellulose, lactose, polyvidone k30, magnesium stearate are crossed 80 mesh sieves.With an amount of alcoholic solution soft material processed, 16 mesh sieves are granulated behind the supplementary material mix homogeneously, drying, and 18 mesh sieve granulate add the magnesium stearate mixing, tabletting; Enalapril maleate is added in the Opadry solution, make pastille coating solution, for subsequent use; Label is placed seed-coating machine, get pastille coating solution coating after, use by the coating solution of coating material preparation in tablet surface and to wrap protective layer, after the drying and get final product.
Embodiment 6: enalapril maleate felodipine sustained-release tablets (1000 prescriptions)
Felodipine 10g
HPMC 40g
Silicon dioxide 2g
Lactose 70g
PVP K30 15g
95% alcoholic solution 100g
Enalapril maleate 5g
Microcrystalline Cellulose 45g
Lactose 120g
Magnesium stearate 3g
Silicon dioxide 2g
Purified water 120g
Preparation method:
Felodipine, HPMC cross respectively 100 mesh sieves, and silicon dioxide, lactose are crossed 80 mesh sieves.Behind former/adjuvant mix homogeneously, with PVP K30 60% ethanol water soft material processed, 16 mesh sieves are granulated, oven dry, and 18 mesh sieve granulate add the silicon dioxide mixing, compressed cores; Enalapril maleate, microcrystalline Cellulose are crossed respectively 100 mesh sieves, and lactose, magnesium stearate are crossed 80 mesh sieves, and mixing is former/adjuvant, with purified water soft material processed.Granulate, drying, granulate adds magnesium stearate, silicon dioxide mixing, and is for subsequent use.With cored tablet machine compacting clad sheet.
Test:
With the pharmaceutical composition of the embodiment 2 preparation mainstream product as test usefulness, measure according to the method for the relevant requirements of the Pharmacopoeia of the People's Republic of China 2010 editions.
(1) dissolution determination
Get this product, put in the sedimentation basket, according to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia), take water 500ml as solvent, rotating speed is that per minute 50 turns, and in the time of 30 minutes, it is an amount of to get solution, filter, get subsequent filtrate and measure with the high performance liquid chromatogram method, the result is as shown in table 1.
Table 1 enalapril maleate dissolution determination result
(2) drug release determination
Get this product, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D first method), adopt the device of dissolution method the second method, [get sodium dihydrogen phosphate liquid (1mol/L) 206ml with 0.4% CTAB phosphate buffer (pH6.5), sodium hydrogen phosphate liquid (0.5mol/L) 196ml, cetyl trimethyl ammonium bromide 20.0g, adding water to 5000ml] 500ml is solvent, rotating speed is that per minute 200 turns, start about 30 seconds of rotation, get 6 of test samples, drop into respectively in 6 process containers, begin immediately timing.Get respectively solution 2ml at 1,4 and 7 hour and filter, and immediately in process container, replenish same solvent 2ml.Get subsequent filtrate and measure with the high performance liquid chromatogram method, the result is as shown in table 2.
Table 2 felodipine drug release determination result
Above test data shows: the pharmaceutical composition in the embodiment of the invention, in carrying out the vitro release test, drug release feature meets the regulation of the Chinese Pharmacopoeia relevant slow releasing preparation of version appendix in 2010, has obvious slow releasing function.
With the pharmaceutical composition of embodiment 2 preparation as being subjected to test preparation, take the domestic enalapril maleate sheet (5mg) that has gone on the market as reference preparation 1 with Felodipine tablets (5mg) reference preparation 2, healthier experimenter single and continuous several times under the empty stomach state are taken the pharmacokinetic parameter that is subjected to test preparation and reference preparation.
(1), felodipine: be subjected to the main pharmacokinetic parameter of test preparation to compare the 12nd day T of administration with the reference preparation that routine discharges
Max, DF and LnC
Ss-maxThere is significant difference (P＜0.05) in these 3 pairs of parameters, and all the other parameters are all without significant difference.Be subjected to the 1st day T of test preparation administration
Max(7.909 ± 3.590) h is than the 1st day T of reference preparation administration
Max(4.136 ± 1.951) h prolongs more than the 3h, C
MaxObviously reduce about 21%～39%, MRT
0-tProlong approximately 13%～15%, C
Ss-maxReduce approximately 39%, C
Ss-min49% (the seeing Table 3) that raise approximately illustrates obviously postponed by the peak time of the felodipine in the test preparation that blood concentration fluctuation significantly reduces, and the stable state peak concentration significantly reduces, and Steady state trough concentration obviously raises, and mean residence time is longer in the body.Result of the test shows, compared with reference preparation by test preparation, the biological property that is subjected to the felodipine in the test preparation to have slow releasing tablet.
(2), enalapril maleate: the main pharmacokinetic parameter that is subjected to test preparation is compared with the reference preparation that routine discharges, in 16 pairs of pharmacokinetic parameters of enalapril except the T of administration the 1st day and the 12nd day
MaxAnd the 1st day MRT of administration
0-tThere were significant differences outer (P＜0.05) for these 3 pairs of parameters, and all the other 13 pairs of parameters are all without significant difference.And the active metabolite of the enalapril of two kinds of preparations---between 20 pairs of pharmacokinetic parameters of enalaprilat all without significant difference (P＞0.05).Result of the test shows, compared with reference preparation by test preparation, and the pharmaco-kinetic processes that enalapril and active metabolite enalapril are pulled in the healthy young men subject is basically identical.
The pharmacokinetic parameter of table 3 is subjected to test preparation (T) and reference preparation (R) multiple dosing the 1st day and the 12nd day
With the pharmaceutical composition contrast enalapril maleate sheet (10mg) of embodiment 2 preparation treat gently, Moderate Essential Hypertension curative effect and safety at random, double blinding, dual analog, positive drug parallel control, the phase clinical research of multicenter II.
(1), validity result:
II clinical trial phase result show use tested medicine enalapril maleate+felodipine pharmaceutical composition (from embodiment 2) and the treatment of control drug enalapril maleate sheet gently, Moderate Essential Hypertension 4, after 8 weeks, test group and matched group clinic SiDBP/seat systolic pressure (SeDBP/SeSBP), vertical position diastolic pressure/vertical position systolic pressure (ODBP/OSBP) all significantly reduce (P＜0.01) than baseline value, and tested medicine and control drug clinical efficacy are definite.Treatment 8 when week test group and matched group SiDBP (SeDBP) are than baseline value descend respectively 10.63mmHg ± 6.14mmHg, 7.65mmHg ± 7.34mmHg, and the blood pressure lowering total effective rate is respectively 80.87%, 63.64%; Covariance analysis shows that test group blood pressure drops level has statistical significant difference (P＜0.01) than matched group; The CMH check shows that also test group blood pressure lowering effective percentage has statistical significant difference (P＜0.01) than matched group.Enalapril maleate+clinical antihypertensive effect of felodipine pharmaceutical composition is better than the enalapril maleate sheet.
Ambulatory blood pressure monitoring (ABPM) result of the test shows that service test medicine enalapril maleate+felodipine medicine composite for curing is light, Moderate Essential Hypertension is after 4 weeks, baseline value significantly reduced (P＜0.001) before average clinic seat cuff diastolic pressure, systolic pressure were all treated, and the trial drug Clinical efficacy is definite.Through 24 hours dynamic blood pressure monitorings (ABPM) show enalapril maleate+felodipine pharmaceutical composition can continue 24 hours effectively reduction gently, Moderate Essential Hypertension patient's blood pressure, coincide with the clinic blood pressure measurement, the diastolic pressure, systolic pressure blood pressure lowering T/P of taking enalapril maleate+felodipine pharmaceutical composition every day for 1 time is than all greater than 50%.
(2), safety results:
Use that the treatment of tested medicine enalapril maleate+felodipine pharmaceutical composition (from embodiment 2) and control drug enalapril maleate sheet is light, Moderate Essential Hypertension is after 8 weeks, test group is similar with matched group adverse events/adverse reaction rate, untoward reaction is the most common to be the modal adverse events of ACEI class medicine, (test group accounts for 38.30%, 18/47 example in i.e. cough; Matched group accounts for 44.68%, 21/47 example).This test has no enalapril maleate+felodipine pharmaceutical composition has clinical remarkable harmful effect to the lab index such as experimenter's blood glucose, blood fat, hepatic and renal function and physical examination result.Trial drug and control drug clinical drug safety toleration are good.
Claims (2)
1. the pharmaceutical composition that comprises enalapril immediate release section and felodipine sustained-release part; said composition is that tablet form and said composition are comprised of slow-released part label, immediate release section coatings and external protection; wherein according to 1000 calculating, the employed prescription of pharmaceutical composition for preparing this tablet form is:
Label:
Rapid release coatings prescription:
Enalapril maleate 5g
Opadry 10g
Purified water 200g
The protective layer prescription:
Opadry 10g
Purified water 200g
The preparation method of the described compositions of tablet form comprises following process:
Felodipine, hypromellose are crossed respectively 100 mesh sieves, and microcrystalline Cellulose, lactose, polyvidone k30, magnesium stearate are crossed 80 mesh sieves;
The alcoholic solution soft material processed of the amount that provides more than using behind former/adjuvant mix homogeneously, 16 mesh sieves are granulated, drying, 18 mesh sieve granulate add the magnesium stearate mixing, tabletting;
Enalapril maleate is added in the Opadry solution, make pastille coating solution, for subsequent use; With
Label is placed seed-coating machine, get pastille coating solution coating after, use the coating solution of being prepared by coating material to wrap protective layer in tablet surface, after the drying and get final product.
2. prepare the method for the pharmaceutical composition that comprises enalapril immediate release section and felodipine sustained-release part of claim 1, said composition is that tablet form and said composition are comprised of slow-released part label, immediate release section coatings and external protection, wherein
According to 1000 calculating, the employed prescription of pharmaceutical composition for preparing this tablet form is:
Label:
Rapid release coatings prescription:
Enalapril maleate 5g
Opadry 10g
Purified water 200g
The protective layer prescription:
Opadry 10g
Purified water 200g
The preparation method of the described compositions of tablet form comprises following process:
Felodipine, hypromellose are crossed respectively 100 mesh sieves, and microcrystalline Cellulose, lactose, polyvidone k30, magnesium stearate are crossed 80 mesh sieves;
The alcoholic solution soft material processed of the amount that provides more than using behind former/adjuvant mix homogeneously, 16 mesh sieves are granulated, drying, 18 mesh sieve granulate add the magnesium stearate mixing, tabletting;
Enalapril maleate is added in the Opadry solution, make pastille coating solution, for subsequent use; With
Label is placed seed-coating machine, get pastille coating solution coating after, use the coating solution of being prepared by coating material to wrap protective layer in tablet surface, after the drying and get final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010181421 CN101843892B (en) | 2010-05-18 | 2010-05-18 | Medicament composition comprising Enalapril quick-releasing part and felodipine slow-releasing part |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010181421 CN101843892B (en) | 2010-05-18 | 2010-05-18 | Medicament composition comprising Enalapril quick-releasing part and felodipine slow-releasing part |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101843892A CN101843892A (en) | 2010-09-29 |
| CN101843892B true CN101843892B (en) | 2013-03-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010181421 Active CN101843892B (en) | 2010-05-18 | 2010-05-18 | Medicament composition comprising Enalapril quick-releasing part and felodipine slow-releasing part |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105748422B (en) * | 2016-04-05 | 2019-02-22 | 广州白云山医药集团股份有限公司白云山制药总厂 | Pharmaceutical composition comprising enalapril and felodipine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1134665A (en) * | 1994-09-02 | 1996-10-30 | 阿斯特拉公司 | Novel pharmaceutical composition containing the ACE inhibitor ramipril and a dihydropyridine compound |
| CN1526398A (en) * | 2003-09-19 | 2004-09-08 | 启东盖天力药业有限公司 | Compound blood pressure reducing prepn containing angiotonin converzyme inhibitor, calcium ion agonist and Estazolam |
| CN101548973A (en) * | 2008-03-31 | 2009-10-07 | 扬州制药有限公司 | Composition containing dihydropyridine calcium channel blocker and preparation method thereof |
-
2010
- 2010-05-18 CN CN 201010181421 patent/CN101843892B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1134665A (en) * | 1994-09-02 | 1996-10-30 | 阿斯特拉公司 | Novel pharmaceutical composition containing the ACE inhibitor ramipril and a dihydropyridine compound |
| CN1526398A (en) * | 2003-09-19 | 2004-09-08 | 启东盖天力药业有限公司 | Compound blood pressure reducing prepn containing angiotonin converzyme inhibitor, calcium ion agonist and Estazolam |
| CN101548973A (en) * | 2008-03-31 | 2009-10-07 | 扬州制药有限公司 | Composition containing dihydropyridine calcium channel blocker and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 罗金德等.用HPMC直接压制骨架片.《现代应用药学》.1987,第4卷(第5期),45-47. * |
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|---|---|
| CN101843892A (en) | 2010-09-29 |
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Address after: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the Cloud Road No. 88 Patentee after: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS CO., LTD., BAIYUNSHAN PHARMACEUTICAL GENERAL FACTORY Address before: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the Cloud Road No. 88 Patentee before: Baiyunshan Pharmaceutical General Factory, Baiyunshan Pharmaceutical Co., Ltd, G |
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Effective date of registration: 20161110 Address after: No. twenty-eight Guangdong temeisi 515400 city of Jieyang province Jiexi County Road Patentee after: Baiyun Mountain Weiling Pharmaceutical Co. Ltd. Address before: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the Cloud Road No. 88 Patentee before: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS CO., LTD., BAIYUNSHAN PHARMACEUTICAL GENERAL FACTORY |