CN101836982A - Medicinal composition for curing hypertension - Google Patents

Abstract

The invention provides a medicinal composition for curing hypertension, which comprises lercanidipine and enalapril. The composition has the advantages of high solubility and stability, easy operation, transportation and storage, wide application range, and suitability for scale production.

Description

The hypertensive Pharmaceutical composition of a kind of treatment

Technical field

The invention belongs to field of pharmaceutical preparations, relate to the hypertensive Pharmaceutical composition of treatment of lercanidipine and enalapril.

Background technology

Lercanidipine (lercanidipine) is a third generation dihydropyridine calcium channel blocker, reversibly blocks the Ca of vascular smooth muscle cell film L type calcium channel ²⁺In stream, expansion peripheral blood vessel and reduce the blood medicine.This product has the unique two benzene ring side chains and the stereo molecule structure of larger volume; it is one of the highest calcium ion antagonist of applied so far film attachment coefficient; its protonated amino group makes its particle exchange between blood plasma and tissue wall become more easy; therefore lercanidipine can be transferred to the arteries wall rapidly from blood plasma; and enter cell membrane lipid bilayer smoothly; and in double-layer of lipoid, assemble; near the calcium channel receptor; simultaneously its from cell membrane dissociate and stream to take off speed very slow, and persistent clinical hypotensive effect is arranged.

Enalapril (Enalapril) is an angiotensin converting enzyme inhibitor.Be hydrolyzed into enalaprilat after oral in vivo, hypertensinase is played the strong inhibition effect, reduce the content of angiotensin, cause systemic vasodilatation, blood pressure drops is used for the treatment of hypertension.It is similar with captopril that this product is treated hypertensive effect, but stronger than captopril, and effect slowly and lastingly.

Usefulness and the safety of these two kinds of medicine single-dose preparations of lercanidipine and enalapril in treatment Arterial Hypertention and other cardiovascular disease extensively confirmed.Clinical practice proves, compares with single agent medication, adopts that fixed mixing ratio type composite antihypertensive preparation curative effect improves relatively, side effect minimizing, taking convenience.In addition, lercanidipine and enalapril belong to the inhomogeneous medicine that antihypertensive function is arranged, so the two can act on more than one blood medicine regulatory mechanism simultaneously in conjunction with administration.But,, therefore absorb comparatively difficulty by oral administration because lercanidipine lipotropy height is almost insoluble in the medium of the pH 1～8 that is similar to the gastro-intestinal Fluid environment.And hydrolysis and dehydration degradation reaction, less stable may take place in enalapril.

Summary of the invention

The invention provides the hypertensive Pharmaceutical composition of a kind of treatment, have good stripping and stability.

Described Pharmaceutical composition is characterized in that: contain Lercanidipine hydrochloride 10mg and enalapril maleate 10mg or 20mg, and acceptable accessories.

Described pharmacy acceptable auxiliary is characterized in that comprising in filler, binding agent, stabilizing agent, solubilizing agent and the disintegrating agent one or more.

The invention provides the hypertensive pharmaceutical composition of a kind of treatment, be specially 1～10% Lercanidipine hydrochloride and 5～15% enalapril maleates, 60～85%% filleies, 10～40% binding agents, 1～20% stabilizing agent, 0～6% solubilizing agent and 2～15% disintegrating agents.

Wherein said filler is selected from lactose, mannitol, starch, pre-paying starch and the microcrystalline Cellulose one or more.

Described binding agent is selected from water, ethanol, polyvinylpyrrolidone, hyprolose, hydroxypropyl potassium cellulose, the starch one or more.

Described stabilizing agent is selected from sodium bicarbonate, the disodiumedetate one or both.

Described solubilizing agent is selected from sodium lauryl sulphate, the Polyethylene Glycol one or both.

Described disintegrating agent is selected from one or more of carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch.

The present invention also provides a kind of preparation technology of hypertensive Pharmaceutical composition, and concrete grammar is as follows:

1) Lercanidipine hydrochloride and enalapril maleate are dissolved in the binding agent;

2) filler, stabilizing agent, solubilizing agent and/or part disintegrating agent are mixed;

3) with the binding agent that obtains among the A with the soft material of the mixture system among the B, 18 mesh sieves are granulated;

4) this particle drying to moisture less than 2%;

5) 24 mesh sieve granulate;

6) add lubricant and residue disintegrating agent mix homogeneously;

7) this granule compress tablet coating, or be packed in capsule or the pouch.

The present invention also provides a kind of preparation technology of hypertensive Pharmaceutical composition, and concrete grammar is as follows:

1) with the Lercanidipine hydrochloride micronization;

2) enalapril maleate and stabilizing agent are dissolved in the binding agent;

3) with micronization Lercanidipine hydrochloride and filler, solubilizing agent and/or part disintegrating agent mix homogeneously;

4) with the binding agent that obtains among the A with the soft material of the mixture system among the C, 18 mesh sieves are granulated;

5) this particle drying to moisture less than 2%;

6) 24 mesh sieve granulate;

7) add lubricant and residue disintegrating agent mixing;

8) this granule compress tablet coating, or be packed in capsule or the pouch.

The present invention also provides a kind of preparation technology of hypertensive Pharmaceutical composition, and concrete grammar is as follows:

1) with the Lercanidipine hydrochloride micronization;

2) filler and part disintegrating agent are mixed;

3) with binding agent with the soft material of the mixture system among the B, 18 mesh sieves are granulated;

4) this particle drying to moisture less than 2%;

5) 24 mesh sieve granulate;

6) add micronization Lercanidipine hydrochloride, enalapril maleate, stabilizing agent, solubilizing agent, lubricant and/or residue disintegrating agent mixing;

7) this granule compress tablet coating, or be packed in capsule or the pouch.

The Lercanidipine hydrochloride and the medication combined application of enalapril maleate of different blood pressure lowering mechanism have the side effect of minimizing, improve curative effect and take characteristics such as convenient.But the Lercanidipine hydrochloride water solublity is relatively poor, and is almost insoluble in the medium of the pH 1～8 that is similar to the gastro-intestinal Fluid environment.Hydrolysis and dehydration degradation reaction easily take place in the enalapril maleate less stable in the preparation process.And, interaction between the compound medicine can influence the stripping behavior and the stability of each folk prescription medicine, and make the stripping behavior of compound medicine and stability have uncertainty, so the present invention makes the good stripping of having of compound medicament composition by selecting different classes of adjuvant and Different Preparation for use, increase stability.

The specific embodiment

1 one kinds of tablets that contain lercanidipine and enalapril of embodiment

Prescription:

Supplementary material	Consumption (mg)
		Lercanidipine hydrochloride	??10
Enalapril maleate	??10
		Sodium bicarbonate	??20
Lactose	??185
		Microcrystalline Cellulose	??52
Carboxymethylstach sodium (in add)	??10
		Carboxymethylstach sodium (adding)	??10
Magnesium stearate	??3
		Opadry	In right amount

Preparation technology:

1. Lercanidipine hydrochloride and enalapril maleate are dissolved in the adequate amount of ethanol;

2. lactose and sodium bicarbonate, microcrystalline Cellulose, carboxymethylstach sodium (in add) are mixed;

3. utilize High Speed Stirring Machine, with the solution that obtains in 1 with the even product granulation that obtains in 2;

50 ℃ of this granules dry to moisture less than 2%;

5.24 mesh sieve granulate;

6. add magnesium stearate and carboxylic potassium sodium cellulosate mixing;

7. φ 9mm scrobicula stamping;

The weightening finish of 8.15% Opadry coating solution coating is to 3%.

9. two aluminum packings.

2 one kinds of tablets that contain lercanidipine and enalapril of embodiment

Prescription:

Supplementary material	Consumption (mg)
		Lercanidipine hydrochloride	??10
Enalapril maleate	??10
		Sodium bicarbonate	??5

Supplementary material	Consumption (mg)
		Lactose	??120
Starch	??32
		Cross-linking sodium carboxymethyl cellulose (in add)	??5
Cross-linking sodium carboxymethyl cellulose (adding)	??5
		Sodium lauryl sulphate	??10
Magnesium stearate	??3

Preparation technology:

1. with the Lercanidipine hydrochloride micronization;

2. with lactose, starch and cross-linking sodium carboxymethyl cellulose (in add) mix homogeneously;

3. water is with the even product granulation that obtains in 2;

50 ℃ of this granules dry to moisture less than 2%;

5.24 mesh sieve granulate;

6. add micronization Lercanidipine hydrochloride, enalapril maleate, sodium bicarbonate, sodium lauryl sulphate, cross-linking sodium carboxymethyl cellulose (adding) and magnesium stearate mix homogeneously;

7. φ 8mm scrobicula stamping;

8. two aluminum packings.

3 one kinds of granules that contain lercanidipine and enalapril of embodiment

Prescription:

Supplementary material	Consumption (mg)
		Lercanidipine hydrochloride	??10
Enalapril maleate	??20
		Sodium bicarbonate	??10
Lactose	??105
		Starch	??32
Low-substituted hydroxypropyl cellulose (in add)	??5
		Low-substituted hydroxypropyl cellulose (adding)	??5

Supplementary material	Consumption (mg)
		Polyethylene glycol 6000	??10
Magnesium stearate	??3

Preparation method:

1. Lercanidipine hydrochloride is carried out micronization;

2. enalapril maleate and sodium bicarbonate are dissolved in the adequate amount of ethanol;

3. micronization Lercanidipine hydrochloride and lactose, starch, low-substituted hydroxypropyl cellulose (in add) are mixed;

4. utilize High Speed Stirring Machine, with the solution that obtains in 1 with the even product granulation that obtains in 3;

50 ℃ of this granules dry to moisture less than 2%;

6.24 mesh sieve granulate;

7. add magnesium stearate, low-substituted hydroxypropyl cellulose (adding), polyethylene glycol 6000 mixing;

8. insert capsule No. two, two aluminum packings.

4 couples of embodiment of embodiment 1,2,3 carry out dissolution determination

Respectively embodiment 1,2,3 is carried out dissolution determination, and wherein dissolution employing " second method in 2005 editions second appendix X C of the Chinese pharmacopoeia dissolution method, dissolution medium is 0.5% sodium dodecyl sulfate solution, rotating speed is 50r/min.

5 couples of embodiment of embodiment 1,2,3 carry out accelerated stability test, and the related substance testing result is as follows:

Claims (10)

1. treat hypertensive Pharmaceutical composition for one kind, it is characterized in that: contain Lercanidipine hydrochloride 10mg and enalapril maleate 10mg or 20mg, and acceptable accessories.

2. adjuvant according to claim 1 is characterized in that comprising in filler, binding agent, stabilizing agent, solubilizing agent and the disintegrating agent one or more.

3. filler according to claim 2 is characterized in that comprising in lactose, mannitol, starch, pre-paying starch and the microcrystalline Cellulose one or more.

4. binding agent according to claim 2 is characterized in that comprising in water, ethanol, polyvinylpyrrolidone, hyprolose, hydroxypropyl potassium cellulose, the starch one or more.

5. stabilizing agent according to claim 2 is characterized in that comprising in sodium bicarbonate, the disodiumedetate one or more.

6. solubilizing agent according to claim 2 is characterized in that comprising in sodium lauryl sulphate, the Polyethylene Glycol one or more.

7. disintegrating agent according to claim 2 is characterized in that comprising one or more of carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch.

8. the hypertensive method for compositions of treatment according to claim 1, its feature comprises:

1) Lercanidipine hydrochloride and enalapril maleate are dissolved in the binding agent;

2) with filler, stabilizing agent, solubilizing agent and/or part disintegrating agent mix homogeneously;

3) with the binding agent that obtains among the A with the soft material of the mixture system among the B, 18 mesh sieves are granulated;

4) this particle drying to moisture less than 2%;

5) 24 mesh sieve granulate;

6) add lubricant and residue disintegrating agent mix homogeneously;

7) this granule compress tablet coating, or be packed in capsule or the pouch.

9. the hypertensive method for compositions of treatment according to claim 1, its feature comprises:

1) with the Lercanidipine hydrochloride micronization;

2) enalapril maleate and stabilizing agent are dissolved in the binding agent;

3) with micronization Lercanidipine hydrochloride and filler, solubilizing agent and/or part disintegrating agent mix homogeneously;

4) with the binding agent that obtains among the A with the soft material of the mixture system among the C, 18 mesh sieves are granulated;

5) this particle drying to moisture less than 2%;

6) 24 mesh sieve granulate;

7) add lubricant and residue disintegrating agent mixing;

8) this granule compress tablet coating, or be packed in capsule or the pouch.

10. the hypertensive method for compositions of treatment according to claim 1, its feature comprises:

1) with the Lercanidipine hydrochloride micronization;

2) with filler and part disintegrating agent mix homogeneously;

3) with binding agent with the soft material of the mixture system among the B, 18 mesh sieves are granulated;

4) this particle drying to moisture less than 2%;

5) 24 mesh sieve granulate;

6) add micronization Lercanidipine hydrochloride, enalapril maleate, stabilizing agent, solubilizing agent, lubricant and/or residue disintegrating agent mixing;

7) this granule compress tablet coating, or be packed in capsule or the pouch.