Oral sustained-release triple layer tablet

Abstract

The present invention relates to an oral sustained-release triple layer tablet, more particularly, a triple layer tablet consisting of an inner immediate-release layer containing a pharmaceutically active ingredient and two outer layers containing swellable polymers. Upon exposure to aqueous media, the two outer layers swell to form gelled layers surrounding the lateral side of the inner layer rapidly, thereby control effectively the release of the pharmaceutically active ingredient from the inner immediate-release layer.

Claims

1. An oral sustained-release triple-layer tablet comprising: an inner immediate-release layer comprising a pharmaceutically active ingredient and a binder, and two outer layers, each outer layer comprising a swellable polymer which is polyethylene oxide having a viscosity of 400 cps or greater in 2% aqueous solution, or hydroxypropyl methylcellulose having a viscosity of 4,000 cps or greater in 2% aqueous solution, or a mixture of the polyethylene oxide and the hydroxypropyl methylcellulose, wherein the inner immediate-release layer has an exposed lateral side which is not covered by the two outer layers, wherein only the two outer layers comprise the swellable polymer, and the two outer layers swell upon exposure to aqueous medium to form gelled layers that surround the exposed lateral side of the inner immediate-release layer, and wherein the two outer layers comprise 40 to 95% by weight of the swellable polymer, based on the total weight of the tablet.

2. The oral sustained-release triple layer tablet of claim 1, wherein the inner immediate-release layer is characterized during dissolution testing in an aqueous medium such that 80% or more of the pharmaceutically active ingredient is released from the inner immediate-release layer without the outer layers within one hour from exposure to the aqueous medium.

3. The oral sustained-release triple layer tablet of claim 1, wherein the inner immediate-release layer further comprises a pharmaceutically acceptable excipient.

4. The oral sustained-release triple layer tablet of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of doxazosin, terazosin, tamsulosin, simvastatin, lovastatin, fluvastatin, acetaminophen, zaltoprofen and tramadol.

5. The oral sustained-release triple layer tablet of claim 3, wherein the pharmaceutically active ingredient is terazosin or tamsulosin.

6. The oral sustained-release triple layer tablet of claim 1, wherein the two outer layers containing the swellable polymer include a pharmaceutically acceptable excipient, binder, disintegrant or lubricant.

7. The oral sustained-release triple layer tablet of claim 1, wherein each of the two outer layers containing the swellable polymer include a pharmaceutically active ingredient.

8. The oral sustained-release triple layer tablet of claim 1, wherein the inner immediate-release layer is included in an amount of 5 to 60% by weight, based on the total weight of the tablet.

9. The oral sustained-release triple layer tablet of claim 8, wherein the two outer layers comprise 60 to 90% by weight of the swellable polymer, based on the total weight of the tablet.

10. An oral sustained-release triple-layer tablet comprising: an inner immediate-release layer comprising a pharmaceutically active ingredient and a binder, wherein the pharmaceutical active ingredient is selected from the group consisting of doxazosin, terazosin, tamsulosin, simvastatin, lovastatin, fluvastatin, acetaminophen, zaltoprofen and tramadol, and two outer layers comprising polyethylene oxide having a viscosity of 400 cps or greater in 2% aqueous solution, wherein the inner immediate-release layer is characterized during dissolution testing in an aqueous medium such that 80% or more of the pharmaceutically active ingredient is released from the inner immediate-release layer without the outer layers within one hour from exposure to the aqueous medium, wherein the inner immediate-release layer has an exposed lateral side which is not covered by the two outer layers, wherein only the two outer layers comprise the polyethylene oxide, and the two outer layers swell upon exposure to aqueous medium to form gelled layers that surround the exposed lateral side of the inner immediate-release layer, and wherein the oral sustained-release triple-layer tablet comprises 5 to 60% by weight of the inner immediate-release layer and 40 to 95% by weight of the polyethylene oxide, based on the total weight of the tablet.

11. The oral sustained-release triple layer tablet of claim 1, wherein the swellable polymer of at least one of the two outer layers comprises the polyethylene oxide.

12. The oral sustained-release triple-layer tablet of claim 10, wherein the inner immediate-release layer further comprises a pharmaceutical acceptable excipient.

13. An oral sustained-release triple-layer tablet comprising: an inner immediate-release layer comprising a pharmaceutically active ingredient and a binder, wherein the pharmaceutical active ingredient is selected from the group consisting of doxazosin, terazosin, tamsulosin, simvastatin, lovastatin, fluvastatin, acetaminophen, zaltoprofen and tramadol, and two outer layers comprising polyethylene oxide having a viscosity of 400 cps or greater in 2% aqueous solution, wherein the inner immediate-release layer is characterized during dissolution testing in an aqueous medium such that 80% or more of the pharmaceutically active ingredient is released from the inner immediate-release layer without the outer layers within one hour from exposure to the aqueous medium, wherein the inner immediate-release layer has an exposed lateral side which is not covered by the two outer layers, wherein the two outer layers swell upon exposure to aqueous medium to form gelled layers that surround the exposed lateral side of the inner immediate-release layer, and wherein the oral sustained-release triple-layer tablet comprises 5 to 60% by weight of the inner immediate-release layer and 40 to 95% by weight of the polyethylene oxide, based on the total weight of the tablet.

14. The oral sustained-release triple-layer tablet of claim 13, wherein the inner immediate-release layer further comprises a pharmaceutical acceptable excipient.

15. An oral sustained-release triple-layer tablet comprising: an inner immediate-release layer comprising a pharmaceutically active ingredient, a pharmaceutical acceptable diluent and a binder, and two outer layers, each outer layer comprising a swellable polymer which is polyethylene oxide having a viscosity of 400 cps or greater in 2% aqueous solution, or hydroxypropyl methylcellulose having a viscosity of 4,000 cps or greater in 2% aqueous solution, or a mixture of the polyethylene oxide and the hydroxypropyl methylcellulose, wherein the inner immediate-release layer is characterized during dissolution testing in an aqueous medium such that 80% or more of the pharmaceutically active ingredient is released from the inner immediate-release layer without the outer layers within one hour from exposure to the aqueous medium, wherein the inner immediate-release layer has an exposed lateral side which is not covered by the two outer layers, wherein the two outer layers swell upon exposure to aqueous medium to form gelled layers that surround the exposed lateral side of the inner immediate-release layer, and wherein the two outer layers comprise 40 to 95% by weight of the swellable polymer, based on the total weight of the tablet.

16. The oral sustained-release triple-layer tablet of claim 15, wherein the inner immediate-release layer further comprises a pharmaceutical acceptable excipient.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows an oral sustained-release triple layer tablet, consisting of an inner immediate-release layer (102) containing a pharmaceutically active ingredient, an upper outer layer (101) and lower outer layer (103) containing swellable polymers;

(2) FIG. 2 shows the results of the stirring and gelling test of Example 1;

(3) FIG. 3 shows the results of the dissolution test of Comparative Examples 1 and 2; and

(4) FIG. 4 shows the results of the dissolution test of Examples 3 to 6.

BEST MODE

(5) The triple layer tablet of the present invention is characterized in that upon exposure to aqueous media, the two outer layers swell to form gelled layers surrounding an inner immediate-release layer, thereby controlling the release of pharmaceutically active ingredient from the inner layer.

(6) Hereinafter, the sustained-release triple layer tablet according to the present invention will be described in more detail.

(7) In the present invention, the inner immediate-release layer is contained in an amount of 5 to 60 w/w %, preferably 10 to 40 w/w %, based on the total weight of the tablet.

(8) Examples of the pharmaceutically active ingredient contained in the inner immediate-release layer may include antihypertensives (doxazosin mesylate, terazosin hydrochloride, etc.), anti-benign prostatic hyperplasia agents (tamsulosin hydrochloride, etc.), antihyperlipidemics (simvastatin, lovastatin, fluvastatin, etc.), nonsteroidal anti-inflammatory drugs (acetaminophen, zaltoprofen, etc.), analgesic drugs (tramadol hydrochloride, etc.), antidiabetes drugs, and hypnotics.

(9) It is preferable that, when the dissolution test is performed in aqueous media, 80% or more of the pharmaceutically active ingredient is released from the inner immediate-release layer without the outer layers within 1 hour.

(10) In addition to the pharmaceutically active ingredient, the inner immediate-release layer may further include pharmaceutically acceptable excipients (e.g., lactose, dextrose, sucrose, dextrate, mannitol, sorbitol, xylitol, sodium chloride, magnesium chloride, calcium phosphate dibasic, citric acid, microcrystalline cellulose, etc.), binders (e.g., copovidone, polyvinylpyrrolidone, hydroxypropylcellulose, etc.), disintegrants (e.g., sodium starch glycolate, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose), lubricants (e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, colloidal silicone dioxide, etc.), or the like.

(11) In the present invention, the dissolution media quickly permeates the sustained-release triple layer tablet through the inner immediate-release layer, and is rapidly supplied to the swellable polymers of the two outer layers in contact with the inner layer to facilitate the formation of gelled layers surrounding the inner layer.

(12) In the present invention, the two outer layers contain the swellable polymer in an amount of 40 to 95 w/w %, preferably 60 to 90 w/w %, based on the total weight of the tablet. The compositions and amounts of the two outer layers may be the same or different from each other, as required.

(13) The polymers contained in the two outer layers are swellable upon exposure to aqueous media, and examples thereof may include polyethyleneoxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinylalcohol, carbomer and so on, preferably polyethyleneoxide having a viscosity of 400 cps or more (in 2% aqueous solution) and hydroxypropylmethylcellulose having a viscosity of 4000 cps or more (in 2% aqueous solution).

(14) For the purpose of obtaining various dissolution profiles, the two outer layers may optionally include a pharmaceutically active ingredient. In an embodiment, the pharmaceutical active ingredient in an outer layer may be the pharmaceutically active ingredient contained in the inner immediate-release layer.

(15) The two outer layers may additionally include pharmaceutically acceptable excipients (e.g., lactose, dextrose, sucrose, dextrate, mannitol, sorbitol, xylitol, sodium chloride, magnesium chloride, calcium phosphate dibasic, citric acid, microcrystalline cellulose), binders (e.g., copovidone, polyvinylpyrrolidone, hydroxypropylcellulose), lubricants (e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, colloidal silicone dioxide), or the like.

(16) In the present invention, when the sustained-release triple layer tablet is exposed to aqueous media, the two outer layers swell to form gelled layers surrounding the inner immediate-release layer. This effect can prevent an initial burst of pharmaceutically active ingredient from the inner immediate-release layer and ensures that the tablet strength is not separated into each layer by gastrointestinal motility. Further, the gelled layer becomes a release-controlling membrane, making the sustained release dosage form.

(17) In addition, the present invention provides a method for preparing the oral sustained-release triple layer tablet, comprising the steps of:

(18) mixing the drug and pharmaceutically acceptable additives and optional granulating to prepare mixtures for the inner immediate-release layer of sustained-triple layer tablets;

(19) mixing the swellable polymers, pharmaceutically acceptable additives, and optional drug and optionally granulating to prepare each mixture for the two outer layers; and tabletting the mixtures in turn.

(20) The above tablets are prepared by a conventional method. That is, ingredients of each layer are mixed using a mixer, and then directly compressed using a multilayer tabletting machine, or ingredients of each layer are mixed to prepare granules using a machine such as a vertical granulator and a roller compactor, and then compressed to prepare the oral sustained-release triple layer tablet.

MODE FOR INVENTION

(21) Hereinafter, the present invention will be described in more detail with examples. However, these examples are for the illustrative purpose only, and the invention is not intended to be limited by these examples.

Examples 1 and 2

(22) According to table 1, aqueous pigment (Yellow No. 5), copovidone, and dextrate passed through a 50 mesh sieve were blended for an inner layer, and a swellable polymer such as polyethyleneoxide (commercial name: Polyox WSR Coagulant, Dow Chemicals) or hydroxypropylmethylcellulose (commercial name: Methocel 100M CR, Dow Chemicals) and magnesium stearate passed through a 30 mesh sieve were blended for two outer layers. Each mixture was compressed in turn to be a triple layer tablet with a diameter of 9.0 mm at the final pressure of 6 MPas using a hydraulic press.

(23) TABLE-US-00001 TABLE 1 Compositions of Examples 1 and 2 (unit: mg) Layers Ingredients Example 1 Example 2 Upper layer Polyethyleneoxide 99.5 (Polyox WSR Coagulant) Hydroxypropylmethylcellulose 99.5 (Methocel K100M CR) Magnesium stearate 0.5 0.5 Intermediate Yellow No. 5 1.0 1.0 layer Dextrate 46.5 46.5 Copovidone 2.5 2.5 Lower layer Polyethylene oxide 99.5 (Polyox WSR Coagulant) Hydroxypropyl methylcellulose 99.5 (Methocel K100M CR) Magnesium stearate 0.5 0.5 Total 250.0 250.0

Examples 3 to 6

(24) According to table 2, terazosin hydrochloride dihydrate, copovidone, and dextrate or lactose passed through a 50 mesh sieve were blended for an inner layer, and polyethyleneoxide (commercial name: Polyox WSR Coagulant, Dow Chemicals) and magnesium stearate passed through a 30 mesh sieve were blended for two outer layers. Each mixture was compressed in turn to be a triple layer tablet with a diameter of 9.0 mm at the final pressure of 6 MPas using a hydraulic press.

(25) TABLE-US-00002 TABLE 2 Compositions of Examples 3 to 6 (unit: mg) Exam- Exam- Exam- Exam- Layers Ingredients ple 3 ple 4 ple 5 ple 6 Upper layer Polyethyleneoxide 99.500 99.500 99.500 99.500 (Polyox WSR Coagulant) Magnesium stearate 0.500 0.500 0.500 0.500 Intermediate Terazosin 3.561 3.561 3.561 3.561 layer hydrochloride dihydrate Lactose 62.939 24.939 Dextrate 62.939 24.939 Copovidone 3.500 1.500 3.500 1.500 Lower layer Polyethyleneoxide 99.500 99.500 99.500 99.500 (Polyox WSR Coagulant) Magnesium stearate 0.500 0.500 0.500 0.500 Total 270.00 230.00 270.00 230.00

Examples 7 and 8

(26) According to table 3, a solution of tamsulosin hydrochloride and povidone K30 dissolved in 4 mg of purified water per tablet was added to lactose, kneaded, dried and granulated. Then, copovidone and dextrate passed through a 50 mesh sieve were blended for an inner layer, and polyethyleneoxide (commercial name: Polyox WSR Coagulant, Dow Chemicals) and magnesium stearate passed through a 30 mesh sieve were blended for two outer layers. Each mixture was compressed in turn to be a triple layer tablet with a diameter of 9.0 mm at the final pressure of 6 MPas using a hydraulic press.

(27) TABLE-US-00003 TABLE 3 Compositions of Examples 7 and 8 (unit: mg) Layers Ingredients Example 7 Example 8 Upper layer Polyethyleneoxide 99.50 99.50 (Polyox WSR Coagulant) Magnesium stearate 0.50 0.50 Intermediate Tamsulosin hydrochloride 0.40 0.40 layer Povidone K30 1.80 1.80 Lactose 53.60 53.60 Copovidone 4.20 7.00 Dextrate 37.20 Lower layer Polyethyleneoxide 99.50 99.50 (Polyox WSR Coagulant) Magnesium stearate 0.50 0.50 Total 260.00 300.00

Comparative Examples 1 and 2

(28) According to table 4, terazosin hydrochloride dihydrate, copovidone, and dextrate or lactose passed through a 50 mesh sieve were blended to prepare a tabletting composition. The mixture was compressed into a tablet with a diameter of 9.0 mm, at the pressure of 6 MPas using a hydraulic press.

(29) TABLE-US-00004 TABLE 4 Compositions of Comparative Examples 1 and 2 (unit: mg) Ingredients Comparative Example 1 Comparative Example 2 Terazosin 3.561 3.561 hydrochloride dihydrate Lactose 62.939 Dextrate 62.939 Copovidone 3.500 3.500 Total 70.000 70.000

Comparative Example 3

(30) According to table 5, a solution of tamsulosin hydrochloride and povidone K30 dissolved in 4 mg of purified water per tablet was added to lactose, kneaded, dried and granulated. After being mixed with copovidone, the mixture was compressed into a tablet with a diameter of 9.0 mm at the pressure of 6 MPas using a hydraulic press

(31) TABLE-US-00005 TABLE 5 Composition of Comparative Example 3 (Unit: mg) Ingredients Comparative Example 3 Tamsulosin hydrochloride 0.40 Povidone K30 1.80 Lactose 53.60 Copovidone 4.20 Total 60.00

(32) Test 1: Stirring and gelling test

(33) A stirring and gelling test for Example 1 was performed to confirm whether, upon exposure to aqueous media, the triple layer tablet formed gelled layers surrounding the inner layer and whether the layers separated or not. Stirring was performed in 900 mL of pH 6.8 phosphate buffer (Korean Pharmacopoeia, disintegration test 2.sup.nd solution) using a magnetic stirrer. The results are shown in FIG. 2.

(34) FIG. 2 shows that the triple layer tablet of Example 1 formed gelled layers, upon exposure to aqueous media, surrounding the inner layer as the two outer layers swell. Further, that no layer separation occurred after stirring for 3 hours provided that the triple layer tablet was strong enough to endure gastrointestinal motility and to control the release of drug from the inner layer. The swollen triple layer tablet after 3 hours of testing was completely dried in a drier. As shown in the cross-sectional view, the inner immediate-release layer at initial exposure was surrounded by the two swollen outer layers, and completely isolated from the dissolution media by a gelled layer.

(35) Test 2: Dissolution test

(36) Dissolution tests for Comparative Examples 1 and 2 and Examples 4 to 7 were performed in 900 mL of pH 6.8 phosphate buffer (Korean Pharmacopoeia, disintegration test 2 solution) at 100 rpm using the paddle method. The results are shown in FIGS. 3 and 4.

(37) Comparative Examples 1 and 2 show tablets composed of the inner immediate-release layer of a triple layer tablet only wherein 90% or more of active ingredients were released within 30 min. In contrast, it was found that since the triple layer tablets of Examples 4 to 7 had outer layers containing a swellable polymer to control the release on the upper and lower sides of the inner immediate-release layer, the two outer layers surrounded the lateral side of the inner immediate-release layer to effectively control the release of pharmaceutically active ingredient from the inner layer for about 24 hrs.

(38) The present invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.