CN114668736A - Perindopril amlodipine bilayer tablet and preparation method thereof - Google Patents

Abstract

The invention provides a perindopril amlodipine bilayer tablet and a preparation method thereof, the perindopril amlodipine bilayer tablet comprises a perindopril tablet layer and an amlodipine tablet layer, wherein the perindopril tablet layer contains arginine perindopril, microcrystalline cellulose, lactose, magnesium stearate and colloidal silicon dioxide; the amlodipine tablet layer contains amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, magnesium stearate and colloidal silicon dioxide. The preparation method of the perindopril amlodipine bilayer tablet provided by the invention not only ensures the high stability of arginine perindopril and amlodipine besylate, but also ensures the quality and curative effect of the perindopril amlodipine bilayer tablet. The preparation method is simple, low in production cost and suitable for industrial production.

Description

Perindopril amlodipine bilayer tablet and preparation method thereof

Technical Field

The invention relates to a perindopril amlodipine bilayer tablet and a preparation method thereof, belonging to the technical field of medicine preparation.

Background

L-arginine (2S, 3aS, 7aS) -1-N- [ (S) -1 ethoxycarbonylbutyl ] -L-alanyl) perhydroindole-2-carboxylate.

The chemical structural formula is as follows:

Amlodipine is a calcium channel blocker (calcium ion antagonist) that blocks calcium ions from entering myocardial and vascular smooth muscle cells across membranes. Chemical name: 3-Ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate. The chemical structural formula is as follows:

because the single drug treatment of hypertension is easy to generate drug resistance, the probability of toxic and side effects is higher when the dosage is larger, the single drug treatment of hypertension is difficult to reach the standard in a short period, and most patients need to take more than two antihypertensive drugs to achieve the aim of reducing blood pressure. A new treatment mode is gradually applied to clinic, and the adoption of a compound antihypertensive preparation is an internationally recognized treatment direction. The prescription of the compound antihypertensive drug generally follows the principle of proportioning drugs with different action mechanisms, so that the compound antihypertensive drug has the advantages of increasing the curative effect or reducing the side effect and obtains better blood pressure control effect. Perindopril and amlodipine are combined to be used for treating hypertension, so that a good blood pressure reducing effect can be achieved.

The dolapril amlodipine tablet is a monolithic compound preparation consisting of an Angiotensin Converting Enzyme Inhibitor (ACEI) and a CCB (calcium channel blocker), and the internal components of the tablet have a clear complementary synergistic antihypertensive effect on the action mechanism. Therefore, the combined application of the two can improve the blood pressure lowering curative effect and generate the blood pressure lowering effect of 1+1> 2.

Arginine perindopril has certain hygroscopicity, amlodipine is unstable after moisture absorption, the drugs have interaction, and unstable factors exist when amlodipine besylate is directly mixed into arginine perindopril granules. In addition, the direct mixing of lactose and amlodipine into tablets can cause condensation reaction, which affects stability, so that it is necessary to prepare a bilayer tablet containing perindopril tablets and amlodipine tablets.

The double-layer tablet takes a place in the application of the tablet in a new preparation form, and is receiving more and more attention from scholars at home and abroad. The bi-layer tablet is a tablet having a two-layer structure, each layer containing a different drug or excipient. The double-layer tablet is actually prepared by respectively blanking at two sides of a tablet machine, firstly blanking at one side, forming one layer of the tablet by certain tabletting pressure, then blanking at the other side, and then pressing and forming the other layer of the tablet to obtain the double-layer tablet.

Disclosure of Invention

The invention aims to overcome the defects of the existing preparation process of the varenicline tartrate and provides a preparation method of varenicline tartrate tablets and direct tabletting of powder of the varenicline tartrate tablets.

The technical solution of the invention is as follows: the perindopril amlodipine bilayer tablet is characterized by comprising the following components in percentage by weight:

(1) Perindopril tablet

Components	Particles (%, w/w)
		Arginine perindopril	9％-11％
Microcrystalline cellulose	10％-30％
		Lactose	50％-75％
Magnesium stearate	0.2％-1.0％
		Colloidal silica	0.2％-1.0％

(2) Amlodipine layer

The invention also discloses a method for preparing the perindopril amlodipine bilayer tablet, which comprises the following steps:

(1) arginine perindopril, microcrystalline cellulose, lactose, magnesium stearate and colloidal silicon dioxide are uniformly mixed to be used as perindopril tablet particles.

(2) Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, magnesium stearate and colloidal silicon dioxide are uniformly mixed to be used as amlodipine lamellar granules.

(3) And (3) filling the perindopril tablet layer particles obtained in the step (1) and the amlodipine tablet layer particles obtained in the step (2) into a double-layer tablet machine, and pressing into a double-layer tablet.

Lactose and amlodipine are directly mixed and pressed into tablets to generate condensation reaction, so that the stability is influenced, and therefore, lactose in an amlodipine tablet layer is replaced by anhydrous calcium phosphate.

Compared with the prior art, the perindopril amlodipine bilayer tablet prepared by the invention has good formability, high drug stability and high drug absorption and bioavailability in the bilayer tablet. The preparation method of the perindopril amlodipine bilayer tablet has the advantages of simple preparation process and low production cost, avoids unstable factors of all components, and ensures the stability of the product.

Detailed Description

The technical scheme of the invention is further illustrated by the following examples. The technical solutions and resulting parameters given in the following examples are only exemplary and are intended to be used for explaining the present invention, and should not be construed as limiting the present invention. The tablet press used in the examples of the present invention was a Rochi rotary tablet press.

Example 1

(1) Perindopril tablet

(2) Amlodipine layer

Components	Each tablet (mg)	Particles (%, w/w)
			Amlodipine besylate	6.94	69
Microcrystalline cellulose	64	64
			Anhydrous calcium phosphate	21	21
Magnesium stearate	4	4
			Colloidal silica	4	4

The preparation method comprises the following steps:

(1) preparation of Perindopril lamellar granules

Arginine perindopril, microcrystalline cellulose, lactose, magnesium stearate and silicon dioxide in the formula are uniformly mixed to be used as perindopril tablet granules.

(2) Preparation of amlodipine-layered granules

The amlodipine besylate, the microcrystalline cellulose, the anhydrous calcium phosphate, the magnesium stearate and the silicon dioxide in the formula are uniformly mixed to be used as amlodipine lamellar granules.

(3) And (3) filling the perindopril tablet layer particles obtained in the step (1) and the amlodipine tablet layer particles obtained in the step (2) into a double-layer tablet machine, and pressing into a double-layer tablet.

Example 2

(1) Perindopril tablet

Components	Each tablet (mg)	Particles (%, w/w)
			Arginine perindopril	10	10
Microcrystalline cellulose	20	20
			Lactose	62	62
Magnesium stearate	4	4
			Colloidal silica	4	4

(2) Amlodipine layer

Components	Each tablet (mg)	Particles (%, w/w)
			Amlodipine besylate	6.94	6.7
Microcrystalline cellulose	66	64
			Anhydrous calcium phosphate	22	21
Magnesium stearate	4	4
			Colloidal silica	4	4

The preparation method is the same as example 1.

Example 3

(1) Perindopril tablet

Components	Each tablet (mg)	Particles (%, w/w)
			Arginine perindopril	10	10
Microcrystalline cellulose	21	21
			Lactose	62	61
Magnesium stearate	4	4
			Colloidal silica	4	4

(2) Amlodipine layer

Components	Each tablet (mg)	Particles (%, w/w)
			Amlodipine besylate	6.94	7
Microcrystalline cellulose	63	64
			Anhydrous calcium phosphate	20	20
Magnesium stearate	4	4
			Colloidal silica	4	4

The preparation method is the same as example 1.

Samples of perindopril amlodipine bilayer tablets obtained in examples 1-3 were continuously placed for 6 months under the conditions of 40 ℃ +/-2 ℃ and relative humidity of 75% +/-5%, and samples of samples at 1 st, 2 th, 3 th and 6 th months were taken for determination of related substances, and the results are shown in the following table:

from the stability data of 0 month to 6 months, the indexes of the related substances of the perindopril amlodipine bilayer tablet have no obvious change, and the quality of the sample is stable.

Dissolution rate measurements were performed using perindopril amlodipine bilayer tablets samples obtained in examples 1-3.

Perindopril dissolution test: according to the dissolution and release determination method (second method of 0931 general rules of the four parts of the 2015 year edition of Chinese pharmacopoeia), 900ml of 0.05mol/L sodium phosphate solution (pH value is adjusted to 6.8 by phosphoric acid) containing 0.05% sodium dodecyl sulfate is used as dissolution medium, and the rotating speed is 75 revolutions per minute.

Determination of dissolution rate of amlodipine besylate: according to the determination method of dissolution rate and release rate (second method of 0931 in the four general rules of the pharmacopoeia 2015 edition), 900ml of 0.01mol/L hydrochloric acid solution is used as a dissolution medium, and the rotating speed is 50 revolutions per minute.

The results are given in the following table:

the dissolution tests are all carried out in the same amount of release medium, and the dissolution data show that the perindopril amlodipine bilayer tablet has good in-vitro dissolution behavior.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (2)

1. A perindopril amlodipine bilayer tablet is characterized in that: the perindopril amlodipine double-layer tablet comprises a perindopril tablet layer and an amlodipine tablet layer, and the perindopril amlodipine double-layer tablet comprises the following specific components in percentage by mass:

(1) Perindopril tablet

Components Particles (%, w/w) Arginine perindopril 9％-11％ Microcrystalline cellulose 10％-30％ Lactose 50％-75％ Magnesium stearate 0.2％-1.0％ Colloidal silica 0.2％-1.0％

(2) Amlodipine layer

Components Particles (%, w/w) Amlodipine besylate 6％-8％ Microcrystalline cellulose 50％-75％ Anhydrous calcium phosphate 10％-30％ Magnesium stearate 0.2％-1.0％ Colloidal silica 0.2％-1.0％

。

2. A perindopril amlodipine bilayer tablet according to claim 1, characterized in that: the preparation method of the perindopril amlodipine bilayer tablet specifically comprises the following steps:

(1) arginine perindopril, microcrystalline cellulose, lactose, magnesium stearate and colloidal silicon dioxide are uniformly mixed to be used as perindopril tablet particles.

(2) Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, magnesium stearate and colloidal silicon dioxide are uniformly mixed to be used as amlodipine lamellar granules.

(3) And (3) filling the perindopril tablet layer particles obtained in the step (1) and the amlodipine tablet layer particles obtained in the step (2) into a double-layer tablet machine, and pressing into a double-layer tablet.