KR100970665B1 - Sustained release tablet containing alfuzosin or its salt - Google Patents

Abstract

The present invention provides oral sustained release tablets and methods for preparing the same, comprising a therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof and carrageenan, in the form of a single phase matrix. Sustained release tablets according to the present invention can slow the dissolution of the active ingredient, ie Alfuzosin or its salts, by effectively increasing the residence time in the stomach due to swelling of carrageenan. In addition, since the sustained-release tablet according to the present invention is manufactured in the form of a matrix of a single phase, it can be manufactured using a conventional tablet maker without the use of an expensive multilayer tablet manufacturing equipment, which makes the production simple and greatly reduces the production cost. You can.

Alfuzosin, Carrageenan, Sustained Release Tablets

Description

Sustained release tablet containing alfuzosin or its salt

The present invention relates to a sustained release tablet containing alfuzosin or a salt thereof having α 1 -adrenergic receptor antagonistic activity and a method for preparing the same, and more particularly to alfuzosin or a salt thereof and carrageenan, An oral sustained release tablet having a single-phase matrix form and a method for preparing the same.

Alfuzosin or a pharmaceutically acceptable salt thereof (e.g. hydrochloride) is a compound having α1-adrenergic receptor antagonistic activity and has therapeutic activity in the treatment of hypertension and benign prostatic hyperplasia. In particular, alfuzosin or its salts are known to be useful in the treatment of prostatic hyperplasia by selectively acting on the urethra.

Conventional tablets containing alfuzosin or salts thereof have a problem that, due to their short half-life, they must be administered several times a day. In an attempt to solve this problem, WO 98/08515 (Korean Patent No. 10-0364638) discloses an oral controlled-release tablet having a multilayer structure. That is, the oral controlled-release tablet having the multi-layered structure includes (1) a first layer having the property of expanding rapidly and significantly upon contact with aqueous biological body fluids; (2) a second layer, adjacent to the first layer, to which the alfuzosin hydrochloride is transported, prepared with a hydrophilic polymer and other auxiliary materials; And (3) hydrophilic polymers, which are predominantly impermeable to the passage of the active substance, and which have a protective membrane function to control the release of alfuzosin hydrochloride from the second layer, which can generally gel or swell and then selectively disintegrate. Consisting of an optional third layer. However, since the controlled-release tablet according to WO98 / 08515 has a multilayer structure of a double layer or a triple layer, it is not only difficult to manufacture due to the multi-step manufacturing process, but also expensive to manufacture a multilayer structure tablet. This requires a multi-layered tablet manufacturing equipment, there is a problem that the production cost increases.

In addition, WO2006 / 21692 (Korean Patent Publication No. 10-2007-0046124) discloses (1) povidone and / or polyvinyl acetate, (2) crospovidone to increase the swelling degree of gastric matrix tablets. , And (3) use of a carbomer in combination. WO2006 / 21692 discloses the use of super-disintegrants such as low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, or sodium croscarmellose instead of or with crospovidone. have. However, when the matrix is composed of the polymers as described above to increase the swelling degree, the swelling property may be increased to some extent, but due to the strong disintegration force, the swollen matrix is destroyed, which makes it difficult to control drug release. In the case of using the bomber, the hygroscopicity is strong, so that the tablet properties easily break down when exposed to moisture. In addition, when a super disintegrant is used instead of or together with the crospovidone, the form of the tablet is destroyed by the strong disintegration force, thereby increasing the initial release of the active ingredient (alfuzosin or its salt), which makes it difficult to achieve the sustained release goal. Can be.

In addition, International Patent Publication No. WO 2001/51053 (Korean Patent Registration No. 10-0614361), International Patent Publication No. WO 2003/070281 (Korean Patent Publication No. 10-2004-0082431), International Patent Publication No. WO 2003 / 022310 (Korean Patent Publication No. 10-2004-0033024), International Patent Publication No. WO 2004/022064 (Korean Patent Publication No. 10-2005-0057245), and International Patent Publication No. WO 2004/084878 (Republic of Korea) Patent Publication No. 10-2005-0119135) discloses penetration enhancers such as alkyl-2- (N, N-disubstituted amino) -alkanoate esters, (N, N-disubstituted amino) -alkanol alkanoates, etc. A composition for topical administration is disclosed.

The inventors have conducted various studies to ameliorate the problems of conventional oral controlled release formulations containing alfuzosin or salts thereof. As a result, it was found that when alfuzosin or its salt is formulated in the form of a single phase matrix with carrageenan, one of the gums, it not only shows excellent sustained release property but also is simple to manufacture, thus reducing production costs. .

Accordingly, an object of the present invention is to provide an oral sustained release tablet containing alfuzosin or a salt thereof and carrageenan.

Another object of the present invention is to provide a method for producing the sustained release tablet.

According to one aspect of the present invention there is provided an oral sustained release tablet comprising a therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof and carrageenan and in the form of a single phase matrix.

Carrageenan content may be 1 to 30% by weight based on the total weight of the tablet, kappa (κ)-carrageenan, iota (ι)-carrageenan, lambda (λ)-carrageenan, mu (μ)-carrageenan, and ita ( η) -carrageenan can be selected from one or more. In addition, the sustained-release tablet of the present invention may further comprise potassium or calcium-containing salts, wherein the potassium or calcium-containing salts are calcium sulfate, calcium phosphate, calcium carbonate, calcium stearate, potassium phosphate, potassium sulfate and hydrochloric acid. It may be selected from one or more of the group consisting of potassium, the content may be 5 to 50% by weight relative to the total weight of the tablet.

According to another aspect of the invention, (a) adding a binder solution to a mixture comprising a therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof and carrageenan to form granules; And (b) mixing the granules with a lubricant and tableting the same to provide a method for preparing oral sustained-release tablets having a single-phase matrix form.

According to another aspect of the present invention, an oral having a single-phase matrix form comprising tableting a therapeutically effective amount of alfuzosin or a mixture with a pharmaceutically acceptable salt, carrageenan, and glidant thereof. Provided is a method of preparing a controlled release tablet.

In the preparation method, the amount of carrageenan may be 1 to 30% by weight based on the total weight of the tablet, kappa (κ) -carrageenan, iota (ι) -carrageenan, lambda (λ) -carrageenan, mu (μ) One or more selected from the group consisting of -carrageenan, and ita (η) -carrageenan. In the preparation method, the mixture may further include potassium or calcium-containing salts, wherein the potassium or calcium-containing salts are calcium sulfate, calcium phosphate, calcium carbonate, calcium stearate, potassium phosphate, potassium sulfate and hydrochloric acid. It may be selected from one or more of the group consisting of potassium, the content may be 5 to 50% by weight relative to the total weight of the tablet.

According to the present invention, when alfuzosin or a salt thereof is formulated together with a carrageenan in the form of a single phase matrix, the dissolution of the active ingredient ie alfuzosin or a salt thereof by effectively increasing the residence time in the stomach due to the swelling of the carrageenan Can be sustained. Moreover, it is surprising that effective swelling can be achieved without the use of complex compositions of polymers or super disintegrants (eg WO2006 / 21692). In addition, since the sustained-release tablet according to the present invention is manufactured in the form of a matrix of a single phase, since it can be produced using a conventional tablet maker without the use of special equipment, the production is simple and the production cost can be greatly reduced.

The present invention provides oral sustained release tablets comprising a therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof and carrageenan and having a single-phase matrix form.

The term "therapeutically effective amount" refers to an amount that provides the desired therapeutic response when the active ingredient (eg, alfuzosin or a pharmaceutically acceptable salt thereof) is orally administered, which is understood by those skilled in the art. Can be easily determined. For example, a therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof may range from 0.1 to 200 mg / day. The therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof contained in the unit dosage form is 1-50% by weight, preferably 3-30% by weight, based on the total weight of the sustained-release tablet. It may be included in the range of. The therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof may be contained in one unit dosage form or divided into two or more unit dosage forms.

Sustained release tablets of the present invention comprise alfuzosin or a pharmaceutically acceptable salt thereof as the active ingredient. The "pharmaceutically acceptable salts of alfuzosin" include all known salt forms, for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, Citrate, gluconate and the like. Among these, the hydrochloride form may be preferably used.

In addition, the sustained-release tablet of the present invention may further contain other active ingredients having prostatic hypertrophy activity in addition to the alfuzosin or a pharmaceutically acceptable salt thereof as the active ingredient, for example doxazosin , Tetrazosin, tamsulosin, finasteride, dutasteride, and the like, including pharmaceutically acceptable salts thereof. In the case of including the other active ingredients described above in addition to alfuzosin or its pharmaceutically acceptable salts, the respective doses, or therapeutically effective amounts, may be appropriately selected by one skilled in the art to maximize the therapeutic effect of prostate hyperplasia. .

Carrageenan included in the sustained-release tablet of the present invention slows the release of alfuzosin, thereby allowing the drug to be sustained for a long time. The carrageenan is a polysaccharide obtained by extracting the red sea gills, Gigartinaceae Gigartina, Chongdrus, and Solieriaceae Eucheuma, with galactose and 3,6-anhydrogalactose. It is a polysaccharide which has a main component. Carrageenan has a hemister moiety sulfate group in the unit structure and, depending on its content, kappa (κ) -carrageenan, iota (ι) -carrageenan, lambda (λ) -carrageenan, mu (μ) -carrageenan and ita (η) -carrageenan and the like. The sustained-release tablet according to the present invention may be used alone of each type of carrageenan or may be used by mixing two or more types of carrageenan. Of these, lambda-carrageenan can be preferably used. When using two or more types of carrageenan mixtures, the ratio is not particularly limited and may be appropriately selected depending on the purpose. The molecular weight of the carrageenan is not particularly limited, but preferably has a molecular weight of 100,000 to 500,000.

Carrageenan content in the sustained-release tablet according to the present invention may be 1 to 30% by weight, preferably 5 to 25% by weight based on the total weight of the tablet. If the content of carrageenan is less than 1% by weight, there is difficulty in increasing swelling and sustained release, and when it is greater than 30% by weight q, the swelling property may be decreased.

The sustained-release tablet of the present invention further comprises potassium or calcium-containing salts, thereby generating potassium or calcium ions in vivo, thereby allowing carrageenan to easily promote gel formation in the microenvironment inside the tablet to control swelling and drug release. have. The potassium or calcium-containing salts may be selected from one or more selected from the group consisting of calcium sulfate, calcium phosphate, calcium carbonate, calcium stearate, potassium phosphate, potassium sulfate and potassium hydrochloride, the content of which is 5 based on the total weight of the tablet It may range from-50% by weight. In this case, when the calcium-containing salt is 5 wt% or less, gel formation may be difficult, and when 50 wt% or more, carrageenan may lose its ability to control drug release.

Sustained release tablets of the present invention may include diluents, binders, glidants, and the like conventionally used in the pharmaceutical art. The diluent includes white sugar, lactose, glucose, fructose, sucrose, mannitol, sorbitol, arabinose, xylitol, dextrose, hydroxypropylmethylcellulose, microcrystalline cellulose (e.g., Avicel RC 581, etc.), carboxymethylcellulose Sodium, xanthan gum, and the like, and the binder may include methyl cellulose, polyethylene glycol, polyvinylpyrrolidone or a copolymer thereof (eg, povidone, copovidone (V64)), and the like. Examples of the lubricant include magnesium stearate, light silicic anhydride, talc, sodium lauryl sulfate, and the like. Also, if necessary, a coloring agent such as iron sulfate may be contained. The amount of the diluent, binder, lubricant, colorant and the like may be appropriately selected depending on the intended purpose.

The present invention includes a method for producing the sustained release tablet. The sustained release tablet of the present invention can be prepared by a conventional method for producing tablets, for example, by granulation compression or direct tableting.

That is, in one embodiment of the present invention, (a) adding a binder solution to a mixture comprising a therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof and carrageenan to form granules; And (b) mixing the granules with a lubricant and tableting the same to provide a method for preparing oral sustained-release tablets having a single-phase matrix form. The binder solution may be prepared by dissolving the binder commonly used in the pharmaceutical field in a conventional solvent such as purified water, ethanol, 1-propanol, 2-propanol, and the like.

In another embodiment of the present invention, oral use in the form of a single phase matrix comprising tableting a therapeutically effective amount of alfuzosin or a mixture with a pharmaceutically acceptable salt, carrageenan, and glidant thereof. A method for producing a sustained release tablet is provided.

In the preparation method, the amount of carrageenan may be 1 to 30% by weight based on the total weight of the tablet, kappa (κ) -carrageenan, iota (ι) -carrageenan, lambda (λ) -carrageenan, mu (μ) One or more selected from the group consisting of -carrageenan, and ita (η) -carrageenan. In the preparation method, the mixture may further include potassium or calcium-containing salts, wherein the potassium or calcium-containing salts are calcium sulfate, calcium phosphate, calcium carbonate, calcium stearate, potassium phosphate, potassium sulfate and hydrochloric acid. One or more may be selected from the group consisting of potassium, and the content thereof may be in the range of 5 to 50% by weight based on the total weight of the tablet.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example 1 Preparation of Tablet by Granulation Tableting

Alfuzosin hydrochloride 1500 mg, calcium sulfate 12,079 mg, lambda carrageenan 561 mg and iron sulfate 19 mg, Avicel RC 581 9,000 mg, hydroxypropylmethylcellulose 4800 mg, and xanthan gum 1800 mg were placed in a V-type mixer and about 30 Mixing for minutes gave a mixture. A binding solution was prepared by dissolving 2870 mg of copovidone (VA 64) in anhydrous ethanol. The mixture obtained above was placed in an associator (50 L ribbon mixer), fed together by the binding solution, passed through a Fitz mill (18 mesh), and dried at about 50 ° C. for about 13 hours to prepare granules. The granules obtained were passed through an oscillator equipped with an 18 mesh screen, and the tablets were prepared by mixing the granulated granules with 180 mg of magnesium stearate and then tableting on a tableting basis of 220 mg / Tablet.

Example 2-10

To the ingredients and contents of Tables 1 to 3 below, a tablet was prepared in the same manner as in Example 1. The contents of Tables 1 to 3 represent the weight percentages based on the total weight.

Example 2 Example 3 Example 4 Example 5 Alfuzosin hydrochloride (wt%) 4.5 5 15 20 Lambda carrageenan (wt%) One 10 5 15 Calcium sulfate (wt%) 37 30 35 25 Avicel RC 581 (wt%) 27 25 14 10 Copovidone (wt%) 8.5 7 7.5 6 Xanthan Gum (wt%) 5.5 5 6.5 6.5 Hypromellose (wt%) 15 14 13 14 Iron sulfate (wt%) 0.5 1.5 1.5 1.5 Magnesium Stearate (wt%) One 2.5 2.5 2

Example 6 Example 7 Example 8 Example 9 Alfuzosin hydrochloride (wt%) 5.5 5 20 30 Lambda carrageenan (wt%) 2 9 6 14 Calcium Phosphate (wt%) 35 31 34 26 Mannitol (wt%) 27 25 14 10 Povidone (wt%) 8.5 7 7.5 6 Polyethylene glycol (wt%) 5.5 5 6.5 6.5 Methyl Cellulose (wt%) 14 14 8 4 Talc (wt%) 2.5 4 4 3.5

Example 10 Alfuzosin hydrochloride (wt%) 5 Doxazosin (wt%) 5 Lambda carrageenan (wt%) 8 Potassium Phosphate (wt%) 25 Sorbitol (wt%) 15 Polyvinylpyrrolidone (wt%) 8.5 Methyl Cellulose (wt%) 15 Silicic anhydride (wt%) 15 Sodium Lauryl Sulfate (wt%) 3.5

Example 11 Preparation of Tablets by Direct Tableting

Alfuzosin hydrochloride 1500 mg, calcium sulfate 12,079 mg, lambda carrageenan 561 mg, iron sulfate 19 mg, Avicel RC 581 9,000 mg, hydroxypropylmethylcellulose 4980 mg, xanthan gum 1800 mg, and 2870 mg copovidone (VA 64) Mixed. The mixture was mixed with 180 mg of magnesium stearate and then compressed on a tablet basis of 220 mg / T to prepare a tablet.

Example 12-20

Tablets were prepared in the same manner as in Example 11, with the ingredients and contents shown in Tables 1 to 3.

Comparative Example 1

Tablets were prepared in the same manner as in Example 1, except that lactose was used instead of lambda carrageenan.

Test example. Dissolution test

Elution tests of the tablets prepared according to Examples 1-20 and the tablets prepared according to Comparative Examples 1 and 2 were carried out. That is, the dissolution test was carried out at 100 rpm in a basket method in a 0.01M HCl solution at 37 ℃ (elutor model: Varian VK7025). The elution amount of alfuzosin hydrochloride was measured by 330 nm UV spectrophotometer. The elution amounts of doxazosin in Examples 10 and 20 were measured by HPLC, and the cumulative elution amount was calculated in combination with the elution amount of alfuzosin hydrochloride. The dissolution test results are shown in Table 4 below.

Dissolution rate (%) 1hr 4hr 6hr 12hr 20hr Example 1 13.16 34.29 45.93 72.82 96.17 Example 2 10.44 29.52 36.60 60.50 96.03 Example 3 15.60 36.06 47.27 75.87 99.86 Example 4 8.29 17.53 25.90 57.65 94.72 Example 5 14.38 33.53 44.58 73.57 98.82 Example 6 5.73 34.93 46.55 76.30 103.64 Example 7 15.10 37.18 49.22 78.82 97.68 Example 8 13.76 34.30 45.71 76.52 98.86 Example 9 5.02 27.75 49.46 78.87 99.03 Example 10 9.89 25.06 32.95 69.48 103.81 Example 11 14.33 34.54 45.37 73.56 97.37 Example 12 16.04 37.47 51.80 82.24 101.20 Example 13 14.57 34.52 46.29 75.04 98.58 Example 14 14.70 35.55 47.04 76.20 98.55 Example 15 13.18 34.30 45.90 72.87 99.85 Example 16 7.30 26.87 42.52 63.05 98.72 Example 17 13.68 34.18 47.20 73.82 99.01 Example 18 18.12 34.24 49.10 79.52 99.65 Example 19 16.09 36.25 48.25 82.55 101.66 Example 20 15.11 37.27 39 76.08 100.62 Comparative Example 1 42.40 57.22 92.50 99.03 101.22

As shown in Table 4, Examples 1 to 20 according to the present invention exhibited controlled release of the active ingredient at a constant rate for 20 hours, and thus showed excellent sustained release, but did not add lambda carrageenan. The case did not show sustained release.

Claims (6)

Therapeutically effective amount of alfuzosin or a pharmaceutically acceptable salt thereof; Lambda (λ) -carrageenan; Potassium or calcium-containing salts selected from the group consisting of calcium sulfate, calcium phosphate, and potassium phosphate; And a binder selected from the group consisting of methyl cellulose, polyethylene glycol, and polyvinylpyrrolidone or copolymers thereof, and having a single phase matrix form. The sustained-release tablet according to claim 1, wherein the content of carrageenan is 1 to 30% by weight based on the total weight of the tablet. delete delete delete The sustained-release tablet according to claim 1, wherein the potassium or calcium-containing salt is 5 to 50% by weight based on the total weight of the tablet.