CN1981768A - Compound benazepril dropping balls and their production - Google Patents

Abstract

A dripping pill of compound benazepril for treating hypertension and heart failure is prepared from benazepril hydrochloride, hydrochrothiazide and matrix. Its preparing process is also disclosed.

Description

Compound recipe benazepril drop pill and preparation method thereof

Technical field

The invention belongs to the pharmaceutical technology field, particularly a kind of by medicinal chemicals benazepril hydrochloride (Benazepril Hydrochloride), hydrochlorothiazide (Hydrochrothiazide) and the formulated compound recipe benazepril drop pill of drop pill substrate.

Background technology

Hypertension is one of modal cardiovascular disease in the world today, is the dead and wounded or disabled primary cause of disease of adult.Because the raising of people's living standard, growing tension is striven in work unexpectedly, and the hypertension number of patients increases greatly.China's hypertension prevalence obviously rises, show according to the China's Statistical data, among Chinese 35 to the 74 years old crowd, hypertensive sickness rate is up to about 27 percent, patient's number is near 100,013,000, and annual with the speed increment more than 300 million peoples, China has become the most serious country of hypertension harm in the world.Hypertension can cause the damage of organs such as the heart, brain, kidney, serious threat human beings'health and life.

The hypertension philtrum has quite a few patient singly to use a kind of depressor, and blood pressure is reduced to normally, need just can make blood pressure normal with two or more depressor.So, for ease of clinical rational drug use, improving compliance of patients, the clinical practice of further opening up medicine improves the therapeutic effect of medicine, improves the toleration of medicine, and two kinds of depressor commonly used are put together, makes compound formulation.Compound recipe benazepril drop pill of the present invention is exactly the composite antihypertensive preparation of being made up of benazepril hydrochloride and hydrochlorothiazide.

Benazepril hydrochloride is called to benazepril, shellfish and is drawn Puli, lotensin, chemistry by name (1 ' S, 3S)-3-{[1 '-(carbethoxyl group)-3 '-phenylpropyl]-amino-2,3,4,5-tetrahydrochysene-2-oxygen-1H-1-benzo nitrogen Zhuo-1-acetic acid mono-hydrochloric salts.Benazepril is not for containing the angiotensin converting enzyme inhibitor of sulfydryl, be prodrug, be hydrolyzed to activated benazeprilat in vivo, become a kind of emulative angiotensin converting enzyme inhibitor, the prevention angiotensin i-converting is an Angiotensin II, vascular resistance is reduced, and the aldosterone secretion reduces, and plasma renin activity increases.Benazeprilat also suppresses the degraded of Kallidin I, and vascular resistance is reduced, and produces hypotensive effect.Benazepril expansion artery and vein reduce peripheral vascular resistance or cardiac afterload, reduce pulmonary capillary embedding pressure or cardiac preload, also reduce pulmonary vascular resistance, thereby improve cardiac output, make exercise tolerance and time lengthening.Benazepril mainly brings high blood pressure down by suppressing renin angiotensin aldosterone system, and the hyperpietic of low renin is also had hypotensive effect.Hypotensive effect is slow and lasting.Be used for the treatment of each phase hypertension and congestive heart failure clinically, as auxiliary treatment to the not good congestive heart failure patients (NYHA classification II-IV) of Folium Digitalis Purpureae and/or diuretic reaction.

Hydrochlorothiazide, another name Hydrochlorothiazide, hydrochlorothiazide, Hydrochlorothiazide, Hydrochlorothiazide, chemistry 6-chloro-3 by name, 4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1, the 1-dioxide is to imitate diuretic in one.Hydrochlorothiazide mainly suppresses medullary loop ascending branch cortex portion to Na+ and Cl ^-Absorption again, thereby promote kidney that the drainage of sodium chloride is produced diuresis.Also have hypotensive effect, and can strengthen the hypotensive effect of other depressor, use as basic depressor and other depressor compatibility clinically, become the drug combination basis of other antihypertensive drugs curative effect of sure reinforcement.When benazepril hydrochloride was used with hydrochlorothiazide, no matter the height of its plasma renin levels of hyperpietic has played synergism to blood pressure drops, efficacy of antihypertensive treatment obviously improved, simultaneously adverse reaction reduction.Be used for the treatment of hypertension, heart failure patient clinically.

The compound recipe benazepril oral formulations of using clinically is mainly tablet at present.Because shortcomings such as these conventional agent fabricating technologies and dosage form have, and make this class oral formulations exist disintegration time long, and onset is slow, and bioavailability is lower, thereby influence giving full play to of drug effect.Compound recipe benazepril drop pill bioavailability height of the present invention, disintegrate is molten loose fast, the dissolution height, steady quality, release fast, produce effects fast can sublingual administration, also can swallow, and is easy to carry and use.Associating blood pressure lowering treatment must be followed principle of individuation, but the drop pill administered in divided doses can be adjusted taking dose according to conditions of patients and age easily.Preparation process of the present invention is simple, and workshop does not have dust, uses supplementary product kind few, and production process is short, and cost is low.

Summary of the invention

The object of the invention provides a kind of medicaments compound benazepril drop pill and preparation technology thereof who is used for hypertension and heart failure patient.

The invention is characterized in by medicinal chemicals benazepril hydrochloride, hydrochlorothiazide and drop pill substrate formulated.The weight ratio of each composition is:

Benazepril hydrochloride, the two weight sum of hydrochlorothiazide: drop pill substrate=1: 1～1: 10

The present invention can be achieved through the following technical solutions:

Get benazepril hydrochloride, hydrochlorothiazide, pulverize separately also sieves, benazepril hydrochloride mixes by 1: 1.25 with hydrochlorothiazide, mixes heating and melting with drop pill substrate by weight 1: 1～1: 10 by two kinds of crude drug weight sums again, stir, splash in dimethicone or other drop pill coolant, separate drop pill, absorb coolant, drying, promptly.

Utilize the drop pill of method preparation of the present invention, its main feature is:

1. the quick stripping of medicine, the dissolution height, rapid-action, the bioavailability height, side effect is little.Compound recipe benazepril drop pill is to utilize solid dispersion technology, to after medicine and the fusion of drop pill substrate medicine be dispersed in the substrate, solidify by system of dripping and quenching, medicine is scattered in the substrate with molecularity or superfine crystal state, help absorption of human body, bring into play curative effect rapidly, improve bioavailability, reduce side effect, safety is reliable.

2. increased administering mode, can swallow, but also sublingual administration.Sublingual administration has made things convenient for the patient of dysphagia for the patient of dysphagia provides a kind of new medication to select.

3. medicine stability is good.Dropping pill formulation by medicine and substrate heating and melting after, splash in the immiscible liquid coolant and make, reduce with the air contact area, be difficult for oxidation, substrate is non-water thing, is difficult for causing drug hydrolysis, stability of drug is increased, thereby guaranteed drug quality.

4. drop pill production technology, production equipment are simple, with short production cycle, the production efficiency height, and cost is low.

5. in the main production process of drop pill, used material all is to carry out under liquid state, has reduced dust pollution, helps labor protection and environmental protection, helps the GMP management.

6. associating blood pressure lowering treatment must be followed principle of individuation, but compound recipe benazepril drop pill administered in divided doses can adjust taking dose according to conditions of patients and age easily, and divided dose is accurate.

Compound recipe benazepril drop pill crude drug is benazepril hydrochloride, hydrochlorothiazide.Benazepril hydrochloride is chemical to be called (1 ' S, 3S)-3-{[1 '-(carbethoxyl group)-3 '-phenylpropyl]-amino }-2,3,4,5-tetrahydrochysene-2-oxygen-1H-1-benzo nitrogen Zhuo-1-acetic acid mono-hydrochloric salts.Hydrochlorothiazide chemistry 6-chloro-3 by name, 4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide.

Benazepril hydrochloride molecular formula: C ₂₄H ₂₈N ₂O ₅.HCl

Benazepril hydrochloride molecular weight: 460.96

Hydrochlorothiazide molecular formula: C ₇H ₈ClN ₃O ₄S ₂

Hydrochlorothiazide molecular weight: 297.74

The dissolve scattered time limit detection method and the result of drop pill:

1. dissolve scattered time limit detection method: check according to inspection technique disintegration (" Chinese Pharmacopoeia 2005 version two ones " appendix XA).

2. dissolve scattered time limit testing result:

Sample number	The molten diffusing time (branch)
		Embodiment 1	＜10
Embodiment 2	＜10
		Embodiment 3	＜10
Embodiment 4	＜10
		Embodiment 5	＜10
Embodiment 6	＜10

The specific embodiment

Further the present invention can be described by the following examples, but not limited by embodiment.

Embodiment: per 1000 compound recipe benazepril drop pill supplementary material proportionings

The embodiment sequence number	Benazepril hydrochloride	Hydrochlorothiazide	Polyethylene glycol 6000	Macrogol 4000	Carboxymethyl starch sodium	Poloxamer
							1	2.5g	3.125g	15g	5g		1g
2	2.5g	3.125g	40g
							3	2.5g	3.125g	20g		5g
4	5g	6.25g	35g	5g
							5	5g	6.25g	20g		5g	2g
6	5g	6.25g	25g			5g

Claims (4)

1. compound recipe benazepril drop pill and preparation technology thereof is characterized in that by medicinal chemicals benazepril hydrochloride (Benazepril Hydrochloride), hydrochlorothiazide (Hydrochrothiazide) formulated with drop pill substrate.The weight ratio of each composition is:

Benazepril hydrochloride, the two weight sum of hydrochlorothiazide: drop pill substrate=1: 1～1: 10

2. compound recipe benazepril drop pill according to claim 1, its crude drug is the compound medicine composition, is made up of benazepril hydrochloride, two kinds of medicines of hydrochlorothiazide.The weight ratio of two kinds of crude drug is:

Benazepril hydrochloride: hydrochlorothiazide=1: 1.25

3. according to claim 1 described compound recipe benazepril drop pill, it is characterized in that described drop pill substrate is polyethylene glycols, carboxymethyl starch sodium, poloxamer, a kind of or several compatibilities in sodium carboxymethyl cellulose, stearic acid, sodium stearate, the polyoxyethylene monostearate, the content of each compatibility composition all are not equal to zero.

4. according to claim 1,2 and 3 described compound recipe benazepril drop pill, it is characterized in that preparation method is as follows: get benazepril hydrochloride, hydrochlorothiazide, pulverize separately also sieves, and benazepril hydrochloride mixes by weight 1: 1.25 with hydrochlorothiazide, mixed by weight 1: 1～1: 10 with drop pill substrate by two kinds of crude drug weight sums again, heating and melting stirs, and splashes in dimethicone or other drop pill coolant, separate drop pill, absorb coolant, drying, promptly.