RU2442570C1 - Tablet with the slowed down liberation, containing a alfuzosin hydrochloride - Google Patents

Abstract

FIELD: medicine. ^ SUBSTANCE: invention refers namely to pharmaceutical industry, and concerns tablets with the slowed down liberation, containing alfuzosin hydrochloride. The tablet includes: the top layer including 0,2 weight parts of alfuzosin HC1, 90 weight. parts of hypromellose, 29. 6 weight parts of polyethylene oxide, 1 weight part of stearyl alcohol, 0.4 weight parts of easy waterless silicon acid and 1 weight part of ethyl cellulose; and the bottom layer including 9.8 weight parts alfuzosin HC1, 36-62 weight parts of microcrystalline cellulose, 24-60 weight parts of polyethylene oxide, 20 weight parts low substituted hydroxypropyl cellulose, 1-6 weight parts of stearyl alcohol and 99 weights parts of hydroxypropyl cellulose. ^ EFFECT: received tablet is characterized by the liberation of the medicine with the curve of the zero order. ^ 3 cl, 2 tbl, 10 ex, 6 dwg

Description

BACKGROUND OF THE INVENTION

Technical field

The present invention relates to sustained-release tablets containing alfuzosin HCl, in particular to sustained-release tablets containing alfuzosin Hcl as an active ingredient, polyethylene oxide and hydroxypropyl methylcellulose as hydrophilic polymeric substances, stearyl alcohol as a fat-soluble resin, and also a structure consisting of an upper layer comprising 2 wt.% of the total mass of the active ingredient, as well as a lower layer comprising 98 wt.% of the total ma sy active substance.

State of the art

Alfuzosin Hcl is an effective blocker of alpha-adrenergic receptors and is widely used as an agent for the treatment of benign prostatic hyperplasia. However, alfuzosin Hcl has a very short half-life in vivo and a very high absorption rate in the duodenum and small intestine, therefore, formulations containing alfuzosin Hcl, developed at the initial stage, had the disadvantages of the need for administration twice or thrice a day.

So, to achieve the desired therapeutic goal, even with a single administration per day, controlled release formulations have been developed that are characterized by the controlled release of the active ingredient in proximal portions (i.e., the duodenum and small intestine). For example, Korean Patent Publication No. 2000-35929 describes sustained release alfuzosin HCl tablets comprising: a first layer that rapidly swells upon contact with aqueous body fluids; a second layer containing the active ingredient alfuzosin Hcl, and a third layer controlling the release of the active ingredient.

The controlled release tablets described in Korean Patent Publication No. 2000-35929 have an active ingredient retention effect since the active ingredient is contained only in the second layer coated with the first layer and the third layer located on the upper and lower surfaces, respectively. However, since the rates of expansion of the layers differ from each other, a capping phenomenon (the phenomenon of the formation of a “cap”) may occur, in which the first and third layers separate from the second during swelling. When this phenomenon occurs, the desired effect of a controlled release of the active ingredient cannot be expected.

In addition, Korean Patent Publication No. 2007-110068 discloses a controlled-release pharmaceutical composition in the form of tablets containing alfuzosin HCl, a hydrophilic copolymer, polyvinylpyrrolidone and lactose.

However, the disclosed compositions lack the property that allows the drug to remain in the gastrointestinal tract for a long time, and is also not characterized by reproducibility of drug release, since the initial drug release is controlled by an insoluble polymer. In addition, the composition is characterized by a release chart in which drug release occurs after a certain delay time.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide sustained release tablets containing alfuzosin HCl having a two-layer structure consisting of an upper layer and a lower layer and containing hydrophilic sustained release matrices together with a fat-soluble resin, thereby reducing the likelihood of excessive release of the active ingredient due to capping -phenomenon in vivo, obtained by a simple and convenient method, as well as having a better dissolution diagram in comparison with traditional sustained release tablets.

To achieve the above objectives, the present invention provides a sustained release tablet containing alfuzosin Hcl, which includes: an upper layer containing 0.2 wt. parts of alfuzosin Hcl, 90 wt. parts of hydroxypropyl methylcellulose, 29.6 wt. parts of polyethylene oxide, 1 wt. part of stearyl alcohol, 0.4 wt. parts of light anhydrous silicic acid and 1 wt. a portion of ethyl cellulose; and the lower layer containing 9.8 wt. parts of alfuzosin HCl, 36-62 wt. parts of microcrystalline cellulose, 24-60 wt. parts of polyethylene oxide, 20 wt. parts of low substituted hydroxypropyl cellulose, 1-6 wt. parts of stearyl alcohol and 99 wt. parts of hydroxypropyl cellulose.

The present invention also provides a sustained release tablet containing alfuzosin HCl, comprising: an upper layer containing 0.2 wt. parts of alfuzosin HCl, 90 wt. parts of hydroxypropyl methylcellulose, 29.6 wt. parts of polyethylene oxide, 1 wt. part of stearyl alcohol, 0.4 wt. parts of light anhydrous silicic acid and 1 wt. part of ethyl cellulose, 1 wt. part of magnesium stearate, 6.55 wt. parts of hydrogenated castor oil and 0.25 wt. parts of iron oxide; and the lower layer containing 9.8 wt. parts of alfuzosin HCl, 55.95 wt. parts of microcrystalline cellulose, 30 wt. parts of polyethylene oxide, 20 wt. parts of low substituted hydroxypropyl cellulose, 3 wt. parts of stearyl alcohol, 99 wt. parts of hydroxypropyl cellulose, 2 wt. parts of magnesium stearate and 0.25 wt. parts of iron oxide.

In the present invention, the lower layer may consist of a colored layer containing iron oxide as a dye, and a colorless layer not containing iron oxide.

Short Description of Shapes

The objects described above and other, features and advantages of the present invention will become more clear from the following detailed description, taken into account together with the Figures in which:

FIGURE 1 is a diagram illustrating the dissolution profile of alfuzosin HCl depending on the presence or absence of stearyl alcohol;

FIGURE 2 is a diagram illustrating the dissolution profile of alfuzosin Hcl at pH 1, 2;

FIGURE 3 is a diagram illustrating the dissolution profile of alfuzosin HCl at pH 4, 0;

FIG. 4 is a diagram illustrating the dissolution profile of alfuzosin HCl at pH 6, 8;

FIG. 5 is a diagram illustrating a dissolution curve of alfuzosin HCl in distilled water; FIG. and

FIG.6 is a series of photographs illustrating the swelling and erosion of the tablets of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention will be described in more detail.

Sustained-release tablets containing alfuzosin HCl according to the present invention include a top layer containing 2 wt.% Of the total weight of the active ingredient (i.e., alfuzosin HCl) and a bottom layer containing 98 wt.% Of the total weight of the active ingredient.

The upper layer includes 0.2 wt. parts of alfuzosin HCl, 90 wt. parts of hydroxypropyl methylcellulose, 29.6 wt. parts of polyethylene oxide, 1 wt. part of stearyl alcohol, 0.4 wt. parts of light anhydrous silicic acid and 1 wt. part of ethyl cellulose.

The lower layer includes 9.8 wt. parts of alfuzosin HCl, 36-62 wt. parts of microcrystalline cellulose, 24-60 wt. parts of polyethylene oxide, 20 wt. parts of low substituted hydroxypropyl cellulose, 1-6 wt. parts of stearyl alcohol and 99 wt. parts of hydroxypropyl cellulose.

In the present invention, hydroxypropylmethyl cellulose, polyethylene oxide and hydroxypropyl cellulose are sustained release hydrophilic matrices that substantially swell upon contact with aqueous biological fluids, which allows the drug to remain in the gastrointestinal tract for a long time, and which slowly erode with the release of a drug characterized by a zero-order curve .

Also, the low substituted hydroxypropyl cellulose serves as a binder or disintegrant, stearyl alcohol as a fat-soluble resin, which serves to control the initial release of the drug. In addition, light anhydrous silicic acid serves as an excipient, and ethyl cellulose and hydroxypropyl cellulose as binders.

Meanwhile, the sustained release tablets of the invention may include, in addition to the main components described above, conventional lubricants and colorants. The lubricant used in the present invention may be one or more, for example, magnesium stearate and hydrogenated castor oil, the dye used in the present invention may be iron oxide.

In a preferred embodiment, the sustained release tablets of the present invention include: 0.2 wt., Parts of alfuzosin Hcl, 90 wt. parts of hydroxypropyl methylcellulose, 29.6 wt. parts of polyethylene oxide, 1 wt. part of stearyl alcohol, 0.4 wt. parts of light anhydrous silicic acid and 1 wt. part of ethyl cellulose, 1 wt. part of magnesium stearate, 6.55 wt. parts of hydrogenated castor oil and 0.25 wt. parts of iron oxide; and the lower layer containing 9.8 wt. parts of alfuzosin HCl, 55.95 wt. parts of microcrystalline cellulose, 30 wt. parts of polyethylene oxide, 20 wt. parts of low substituted hydroxypropyl cellulose, 3 wt. parts of stearyl alcohol, 99 wt. parts of hydroxypropyl cellulose, 2 wt. parts of magnesium stearate and 0.25 wt. parts of iron oxide.

In the present invention, the compositions of the upper layer and the lower layer, each of which contains the above components in the above ratios, are prepared and then compressed into tablets in a conventional tablet machine.

In this case, the total content of sustained release tablets is 350 mg, and the content of the active ingredient in the tablet is 10 mg.

If necessary, the lower layer may consist of a colored layer containing iron oxide as a dye; and a colorless layer not containing iron oxide. In this case, the colored and colorless layers do not differ in structure or effect, with the exception of the presence or absence of dye.

In addition, on the surface of each upper and lower layers, you can

apply a coating layer.

The present invention will now be described in detail with reference to examples.

Examples 1-5

[Table 1] Classification Example 1 Example 2 Example 3 Example 4 Example 5 Upper layer Alfuzosin HCl 0.2 As in Example 1 GPMC 2208 90.0 Polyethylene oxide 29.6 Stearyl alcohol 1,0 Light anhydrous silicic acid 0.4 Ethyl cellulose 1,0 Magnesium stearate 1,0 Hydrogenated Castor Oil 6.55 Iron oxide 0.25 Total (mg) 130 bottom layer Alfuzosin HCl 9.8 9.8 9.8 9.8 9.8 Microcrystalline cellulose 55.95 57.95 52.95 61.95 35.95 Polyethylene oxide 30,0 30,0 30,0 24.0 50,0 Low Substitute GPC 20,0 20,0 20,0 20,0 20,0 Stearyl alcohol 3.0 1,0 6.0 3.0 3.0 GPTs-N 99.0 99.0 99.0 99.0 99.0 Magnesium stearate 2.0 2.0 2.0 2.0 2.0 Iron oxide 0.25 0.25 0.25 0.25 0.25 Total (mg) 220 220 220 220 220

In accordance with the ratios of the composition of the upper layer shown in Table 1 above, alfuzosin HCl, hydroxypropyl methylcellulose 2208 (HPMC 2208; Methocel K100M CR Premium), hydrogenated castor oil (Lubri-wax) and iron oxide were mixed together, a binder solution consisting of from stearyl alcohol and ethyl cellulose (Ethocel 100cp STD. PREM.). The mixture was granulated wet. The granules obtained were dried, sieved, then polyethylene oxide, magnesium stearate and light anhydrous silicic acid were added to them, thereby obtaining a top layer,

At this time, in accordance with the ratios of the composition of the lower layer shown in Table 1, alfuzosin HCl, microcrystalline cellulose, hydroxypropyl cellulose-H (N-HPC) and iron oxide were mixed and then stearyl alcohol was added to the mixture. The mixture was granulated wet. The granules obtained were dried, sieved, and polyethylene oxide, low substituted hydroxypropyl cellulose (HPC) and magnesium stearate were added to obtain a lower layer composition.

Finally, the compositions of the upper layer and the lower layer were compressed into tablets in a conventional tablet machine, and then coated with conventional film material, thereby obtaining sustained release tablets containing 10 mg alfuzosin HCl and a weight of 350 mg.

Comparative Example 1

Tablets containing alfuzosin HCl in an amount of 10 mg and a mass of 350 mg were obtained by the method described in Example 1, however, without the addition of stearyl alcohol in the upper layer, and the content of hydrogenated castor oil was increased to 5.81 g.

Examples 6-10

In accordance with the ratios of the composition of the upper layer shown in Table 2 above, alfuzosin HCI, hydroxypropyl methylcellulose 2208 (HPMC-2208; Methocel K100M CR Premium), hydrogenated castor oil (Lubri-wax) and iron oxide were mixed together, a binder solution was added to the mixture, consisting of stearyl alcohol and ethyl cellulose (Ethocel 100cp STD. PREM.). The mixture was granulated wet. The obtained granules were dried, sieved, then polyethylene oxide, magnesium stearate and light anhydrous silicic acid were added to them, thereby obtaining an upper layer.

At this time, in accordance with the ratios of the composition of the lower layer shown in Table 2, alfuzosin Hcl, microcrystalline cellulose, hydroxypropyl cellulose-N (N-HPC) were mixed, and then stearyl alcohol was added to the mixture. The mixture was granulated wet. The granules obtained were dried, sieved, and polyethylene oxide, low substituted hydroxypropyl cellulose (HPC) and magnesium stearate were added to obtain a colorless lower layer composition.

Also, in accordance with the ratios of the composition of the lower layer shown in Table 2, alfuzosin Hcl, microcrystalline cellulose, hydroxypropyl cellulose-H (N-HPC) and iron oxide were mixed and then stearyl alcohol was added to the mixture. The mixture was granulated wet. The granules obtained were dried, sieved, and polyethylene oxide, low substituted hydroxypropyl cellulose (GOC) and magnesium stearate were added to obtain a colored lower layer composition.

Finally, the upper layer compositions, the colorless lower layer composition, and the colored lower layer composition were pressed into tablets using a conventional tablet machine, and then a conventional film coating was applied to the tablets, thereby obtaining sustained release tablets containing 10 mg of alfuzosin HCl and a weight of 350 mg .

Dissolution test

A. Test for the presence and absence of stearyl alcohol

First, the tablets obtained in Example 1 and Comparative Example 1 were examined in a test for dissolution in distilled water, the test results are graphically presented in Figure 1. As can be seen from Figure 1, the sustained release tablets obtained according to Example 1 of the present invention are characterized by a significant decrease in the dissolution rate at the initial stage (i.e., between 1 hour and 10 hours) compared to the tablets of Comparative Example 1, not containing stearyl alcohol.

B. Comparison with a commercial product

The currently available commercially available sustained release product of HCI alfuzosin (Xatral XL ^™ , Sanofi-Aventis) and the sustained release tablets of Example 1 were investigated in a dissolution test at pH 1.2; 4.0; 6.8 and in distilled water, test results are graphically presented in FIGS. 2-5.

As can be seen from FIG. 2-5, the tablets of the present invention are characterized by a dissolution chart substantially identical or slightly better than a commercial product.

C. Comparison of the processes of swelling and erosion

6 is a series of photographs illustrating a comparison of swelling and erosion between the sustained release tablets of the present invention and a commercial product (Xatral XL ^™ , Sanofi-Aventis). 6, “A” corresponds to the commercial product, “B” represents the tablet of Example 1, “C” corresponds to the tablets of Example 6. FIG. 6 shows the top to bottom appearance of these tablets photographed before and after 1, 6, 12 and 20 hours after the addition of distilled water.

As can be seen from FIG. 6, in the case of commercial product (A), the first layer was swollen within 6 hours after the addition of distilled water, however, the second and third layers were quickly eroded. On the one hand, in the case of tablets (B and C) of the present invention, the upper and lower layers were in a swollen state, essentially the same shape, even 20 hours after the addition of distilled water. This prolonged swollen state allows the drug to remain in the gastrointestinal tract for a long time. Accordingly, the sustained release tablets of the present invention have a very stable dissolution chart over time.

As described above, in sustained release tablets containing alfuzosin HCl of the present invention, the top layer and the bottom layer contain delayed release hydrophilic matrices and a fat-soluble resin. So, the swelling ability is the same between the layers, the adhesion between the layers is good, which eliminates the likelihood of a capping phenomenon during dissolution. In addition, since the sustained-release tablets of the present invention have a two-layer structure, they are obtained in a simple and convenient manner and have a good dissolution chart compared to conventional sustained-release tablets.

Although a preferred embodiment of the present invention is described for illustrative purposes, it will be apparent to those skilled in the art that various modifications, additives and substitutions are possible without changing the scope and purpose of the invention described by the appended claims.

Claims (3)

1. Sustained release tablet containing alfuzosin HC1, including:
the upper layer containing 0.2 wt. parts of alfuzosin Hcl, 90 wt. parts of hydroxypropyl methylcellulose, 29.6 wt. parts of polyethylene oxide, 1 wt. part of stearyl alcohol, 0.4 wt. parts of light anhydrous silicic acid and 1 wt. a portion of ethyl cellulose; and the lower layer containing 9.8 wt. parts of alfuzosin Hcl, 36-62 wt. parts of microcrystalline cellulose, 24-60 wt. parts of polyethylene oxide, 20 wt. parts of low substituted hydroxypropyl cellulose, 1-6 wt. parts of stearyl alcohol and 99 wt. parts of hydroxypropyl cellulose. 2. A sustained release tablet containing alfuzosin HC1, including:
the upper layer containing 0.2 wt. parts of alfuzosin Hcl, 90 wt. parts of hydroxypropyl methylcellulose, 29.6 wt. parts of polyethylene oxide, 1 wt. part of stearyl alcohol, 0.4 wt. parts of light anhydrous silicic acid and 1 wt. part of ethyl cellulose, 1 wt. part of magnesium stearate, 6.55 wt. parts of hydrogenated castor oil and 0.25 wt. parts of iron oxide; and the lower layer containing 9.8 wt. parts of alfuzosin Hcl, 55.95 wt. parts of microcrystalline cellulose, 30 wt. parts of polyethylene oxide, 20 wt. parts of low substituted hydroxypropyl cellulose, 3 wt. parts of stearyl alcohol, 99 wt. parts of hydroxypropyl cellulose, 2 wt. parts of magnesium stearate and 0.25 wt. parts of iron oxide. 3. The sustained release tablet of claim 2, wherein the lower layer consists of: a color layer containing iron oxide as a dye and a colorless layer not containing iron oxide.

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