Hypotensive agent

 

(57) Abstract:

Use: medicine for the treatment of hypertension. The inventive composition of the medicinal product: ACE inhibitor-9(S)-[1(S)-etoxycarbonyl-3-phenylpropylamine] -octahydro-10 - oxo-6H-Niigata-[1,2-a] -[1,2]-diazepine-1(S)-carboxylic acid /Cilazapril"/ in free base form, hydrate, or pharmaceutically acceptable salts and calcium antagonist [1S,2S] -2-[2-[[3-(2-benzimidazolyl)propyl] -methylamino] -ethyl-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-aftermatket. The mass ratio of the ACE inhibitor: calcium antagonist is 1:1-100 based on the free base. The preferred ratio of 1:2-20. 1 C.p. f-crystals, 3 ill.

The invention relates to a pharmaceutical combination of drugs for treating hypertension containing certain derivatives of tetrahydronaphthalene and pyridostigmine.

Contained in the claimed means derivative of tetrahydronaphthalene are calcium antagonists (EP-A 0268148) and is suitable for the treatment of hypertension (Clozel et. al. Cardiovasc. Drug Rev. a 9.4-17 (1991).

Contained in the claimed means pyridostigmine are known inhibitors of the enzyme that converts angiotensin (ACE), and therefore primeniajutsia ACE

derived methylpropionyl-L-Proline (Captopril) and calcium antagonist derived benodiazepine (Diltiazem) with increased antihypertensive effect (U.S. patent N 4871731).

However, there is a need to produce a combined pharmaceutical medicine to lower blood pressure, in which the doses of the individual components can be considerably reduced, and unwanted side effects, which occur when the required dosage, respectively, in monotherapy, can be suppressed.

The proposed anti-hypertensive agent, such a crucial task that contains the ACE inhibitor-9(S)-[1(S)-etoxycarbonyl-3 - phenylpropylamine]-octahydro-10-oxo-6H-peridot[1,2-a][1,2]-diazepine -1(S)-carboxylic acid (Cilazapril") in free base form, hydrate, or pharmaceutically acceptable salts and calcium antagonist[1S, 2S] -2-[2-[[3-(2-benzimidazolyl)propyl] methylamino] -ethyl]- 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-aftermatket when the mass ratio of the ACE inhibitor calcium antagonist 1:1-100 based on the free base.

In the framework of the invention were able to establish that the application of the proposed combination products containing these derivatives tetrahedron and amplified, that can significantly reduce the effective dose of both components.

In this regard, the proposed anti-hypertensive combination tool has the following advantages:

(a) a significant decrease in the content of the applied active substances;

b) the absence or substantial weakening of unwanted side effects;

C) biological half-lives of both components is equal to the length from 10 to 12 h for the treatment of hypertensie. Therefore, it is expected uniform nature of the action;

g) high medical and biological features of each component (80-100% in the case of derived tetrahydronaphthalene-dihydrochloride [1S,2S]-2- [2-[[3-2(benzimidazolyl)propyl] methylamino] ethyl]-6-fluoro-1,2,3,4-tetrahydro-isopropyl-2-naphthylenediamine, hereinafter referred to as compound a, and 70% in the case of 9(S)-[1(S)-etoxycarbonyl-3-phenylpropylamine]octahydro-10-oxo-6H-peridot[1,2-a][1,2]diazepine-1(S)-carboxylic acid (Cilazapril)]

New pharmaceutical combined preparation is intended for simultaneous, separate or with a time interval of administration in the treatment of hypertension.

It is advisable that the mass ratio derived tetrahydronaphthalene and peridotitic preferably 5-100 mg derived tetrahydronaphthalene and 1-5 mg pyridostigmine. Usually appointed day total dose derived tetrahydronaphthalene and pyridostigmine does not exceed 55 mg. In the case of hydrate or pharmaceutically acceptable salts of these values must be changed accordingly.

The proposed combination drug containing a small dose of the active substance, may provide an even prolonged hypotensive effect.

The advantages of the proposed combined drug, providing a significant reduction in blood pressure compared with both the components used individually, are illustrated by the following experience.

The hypotensive effect of combined drug researchers in awake dogs with high blood pressure in the kidneys. German shepherd dogs (weight 23-30 kg) caused a rise in blood pressure, acting by a known method: one Bud and wrap with cellophane, and in the renal artery of the contralateral kidney with the help of occludator create stenosis. The pressure is measured implanted in the abdominal aorta catheter, which is connected to the sensor in the abdominal cavity (telemetry).

In Fig. 1 shows the effect of cilazapril (10 mg/kg, belt receiving (3 dogs in the case of cilazapril and combined funds 4 dogs in the case of compound A). Only cilazapril did not effect the connection And lowered blood pressure (MAR) 10-20 mm RT.article the combined means operated more efficiently at any time of measurement.

The synergistic effect of the combined funds was evident in another series of experiments, which reduced the dosage of the components, namely: 3 mg/kg of cilazapril (oral administration) and 10 mg/kg compound A (oral intake) with the same number of animals. The results of this series of experiments is shown in Fig. 2.

Preferred ultra-high efficiency of the proposed combined funds compared to both the individual components, if known involution due to chronic high blood pressure, hypertrophy of the internal environment in large muscular arteries in the treatment of high blood pressure ACE inhibitors and other common therapies [Hypertension 9, 178-187 (1987)] can be illustrated by the example described below experience.

The influence of individual components and their combination on blood vessels was studied on rats and male lines RoRo (weight of about 400 g, the age of 4-5 months. data Instichina group on the principle of randomization. The duration of treatment was 15 days. Cilazapril was added to the feed in an amount such that the daily intake averaged 10 mg/kg, and compound a (30 mg/kg) was administered via a stomach tube. Animals of the control group received the same laboratory food without additives.

After 15 days the rats were given ether anesthesia and by perfusion of fixative (2,5% glutaraldehyde in 0.1 - molar buffer solution phosphate, pH 7,4) recorded carotid artery. Through the left ventricle into the ascending aorta was injected probe (input), through the right ventricle into the atrium has introduced a second probe (output). The vascular system is first washed with 10 ml buffer isotonic saline and then fixed by introducing a retainer for 15 min under pressure of 11.7 kPa. In conclusion, I learned the right carotid artery was freed from the surrounding tissue and to further lock was placed in 2.5% glutaraldehyde. Each artery from the distal end to the proximal divided into five vascular segments were obezvozhivani and was placed in the substance EPON 12 (a registered trademark of the company "shell AG). The middle segment was used for morphological studies. Cross-sectional half-thickness (1 μm) were stained with the banking system DlASYS (Computing laboratory Heinz Mayer, SN-3367, Teigen).

The area studied environments was in control animals 89000 5000 μm2. Treatment of individual drug no results (84000 11000 μm2in the case of cilazapril and 87000 4000 μm2you the case of compound A) (see also Fig. 3, the numbers in the bars indicate the number of animals in the respective groups). Combined use of components reduced area by 15% to 74000 4000 μm2(statistically enough; p<0,05 according to t-test the T-test).

Reduction of the area of the environment as a result of the combined application components confirmed second series of experiments.

Obviously, between ACE-inhibitors and calcium antagonists there is a kind of mechanical impact. It is known that the use of a calcium antagonist and observed as a result of this reduction in blood pressure lead to a compensatory stimulation system the renin-angiotensin. This compensation is in turn suppressed with the use of ACE-inhibitors.

The results indicate unexpectedly preferred properties offer combined drugs. The value of the prior art did not allow to expect that the combination of proizvodi the th optimal anti-hypertensive effect.

The proposed combination drug typically prescribed for oral administration, for example, in the form of tablets, pills in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions. Possible and rectal administration of the drug, for example, in the form of suppositories, or parenterally, e.g. in the form of solutions for injection.

To obtain tablets, tablets in the shell, coated tablets and hard gelatin capsules offer the combined means is processed with pharmaceutically inert inorganic and organic materials, which are, for example, in the manufacture of tablets, coated tablets and hard gelatin capsules can be used lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.

Auxiliary materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc., depending on the properties of the active substance, soft gelatin capsules can be manufactured without any additional materials.

To obtain solutions and syrups are suitable as auxiliary materials, for example, water, polyhydric speech materials, as water, alcohols, polyols, glycerol, vegetable oils, etc.

For candles as auxiliary materials are suitable, for example, natural or hydrogenated oils, waxes, fats, semi-liquid or liquid polyols etc.,

Dosage forms can also contain preservatives, substances that contribute to the dissolution, stabilizers, wetting, emulsifying, sweet substances, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, substances to obtain a shell or antioxidants. In their composition may also contain other therapeutic substances.

The following drugs explain the invention.

Example 1.

Getting tablets in the shell of the following composition:

The basis of the tablets in the shell:

Connection And 29,07 mg (= 25 mg base)

Cilazapril 1.25 mg

Lactose anhydrous 70,18 mg

Corn starch white 30,00 mg

Polyvinylpyrrolidone 5,00 mg

Talc 5,00 mg

Fumarate sodium 1,50 mg

The mass of the basics of tablets in the shell 142,00 mg

Shell (lacquered finish)

The hypromellose of 4.00 mg

Polyethylene glycol 6000 1.00 mg

Titanium dioxide 1.60 mgne.

The method of obtaining basics coated tablet.

Cilazapril consistently and portions mixed with anhydrous lactose until a homogeneous mixture and then sift. After that add the connection And corn starch and polyvinylpyrrolidone, all components are quickly mixed, sieved over a certain time moisturize in a planetary mixer. The wetted mass granularit through the appropriate sieve, dried, and finally milled using a suitable screen. Here add after sifting talc and sodium fumarate and stirred to obtain a homogeneous mass. From ready-mix by pressing receive the tablets of the desired shape and size of the shell (with groove for dividing or without) weight 142,0 mg.

Receiving shell (varnish coating).

From hydroxypropylmethylcellulose, polyethylene glycol 6000, titanium dioxide and talc are preparing an aqueous lacquer suspension, which cover the resulting tablets appropriately on the method of coating in the drageeing boiler or other installation up until the tablet shell will not reach a final weight of 150 mg.

Example 2.

Getting hard gelatin which 26,93 mg

Lactose crystal 60,00 mg

Microcrystalline cellulose 50,00 mg

Talc 10,00 mg

Fumarate sodium 1,50 mg

Weight of filler capsules 180,00 mg

The method of obtaining.

Cilazapril consistently and portions mixed with lactose powder to obtain a homogeneous mixture, sift, add after sifting connection And crystalline lactose and microcrystalline cellulose and again mix accordingly. Then add the sifted talc and sodium fumarate and stirred for the required time. Ready mix fill hard gelatin capsules of appropriate size and color.

Example 3.

Getting tablets in the shell CR (controlled release) of the following composition:

The basis of the tablets CR

Connection And 58,13 mg (=50 mg base)

Cilazapril 2,50 mg

Lactose anhydrous 45,37 mg

"Metozel" (a registered trademark of the company "Dow chemical company") 10,00 mg

Hydroxypropylcellulose 10,00 mg

Talc 4,00 mg

Fumarate sodium 2,00 mg

Weight basis tablets CR 132,00

Shell (lacquered finish)

The hypromellose of 4.00 mg

Polyethylene glycol 6000 1.00 mg

Douchey.

Getting the basics coated tablet.

Cilazapril consistently and portions mixed with anhydrous lactose until a homogeneous mixture and sift, in conclusion, add after sifting connection And, "metozel" and hydroxypropylcellulose, stirred until a homogeneous mixture and then condense properly on the roller compactor. Konektory material is screened through an appropriate sieve and mixed with the sifted mixture of talc and sodium fumarate to obtain a homogeneous mass, from which the pressing get tablets weighing 132 mg of the desired size and shape.

Receiving shell (varnish coating).

From hydroxypropylmethylcellulose, polyethylene glycol 6000, titanium dioxide and talc prepare a water lacquer suspension, which by the way varnishing cover obtained tablets in the drageeing boiler or other installation until the tablet reaches the final mass of 140 mg.

Example 4.

Obtaining granulated funds CR in hard gelatin capsules of the following composition:

Granules

Connection And 58,13 mg (= 50 mg base)

Cilazapril 2,50 mg

Microcrystalline cellulose 139,37 mg

Dibutylsebacate 4,00 mg

Mass lacquer/granules/capsule 20,00 mg

The total mass of CR granules in the capsule 220,00 mg

The method of obtaining.

Getting granular grains.

Connection And cilazapril and lactose anhydrous mixed properly to smooth, moisturize appropriately in the mixer and squeeze through the bars. Extruded mass is crushed in the granulator, give the particles a round shape and finally dried in a fluidized bed.

Obtaining a varnish covering.

The obtained granules in the ongoing process sprayed in a fluidized bed under appropriate conditions a layer of aqueous dispersion consisting of ethyl cellulose (dispersion AQUACOAT) and dibutylsebacate until the weight of the lacquer coating will not be 10% of the mass of granules. In conclusion, carry out the heat treatment of the granules CR with lacquer finish, after which they dispense 220 mg hard gelatin capsules of the desired size and color.

1. Hypotensive means, including an ACE inhibitor and calcium antagonist, characterized in that as an inhibitor of ACE it contains 9(S) - [1(S)

etoxycarbonyl-3-phenylpropylamine] -octahydro-10-oxo-6N-peridot-[1,2-a] [1,2] -diazepine-1(S) carboxylic calcium antagonist [1S, 2S-2- [2- [[ 3-(2-benzimidazolyl)propyl]-methylamino] -ethyl-6-fluoro 1,2,3,4-tetrahydro-1 - isopropyl-2-aftermatket in their mass ratio, respectively 1 1 100 based on the free base.

2. Means under item 1, characterized in that the mass ratio of the ACE inhibitor calcium antagonist is 1 2 20.

 

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< / BR>
where B is one of the divalent residues and) g)

< / BR>
and

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X Gruppen or, if B denotes the divalent residue (a), a nitrogen atom,

l integer 1, 2 or 3,

m is an integer 1 or 2,

n is an integer of 1 to 4,

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R2a hydrogen atom, an unbranched or branched alkyl with 1 to 8 carbon atoms, unbranched or branched alkenyl with 4 to 6 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms, substituted, phenyl, unsubstituted or substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1 to 3 carbon atoms in the alkyl part, unsubstituted or substituted at the fragrance stands or methoxy group or a halogen atom,

R3and R4the same or the difference is,

R5a hydrogen atom or a chlorine or methyl,

R6and R7the same or different and denote hydrogen atoms or alkali with 1 to 3 carbon atoms, and, in addition, R7may also indicate a halogen atom,

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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2 ex

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