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1. WO2007011139 - SUSTAINED-RELEASE TABLET CONTAINING PAROXETINE HYDROCHLORIDE AND MANUFACTURING METHOD THEREOF

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Description
SUSTAINED-RELEASE TABLET CONTAINING PAROXETINE HYDROCHLORIDE AND MANUFACTURING METHOD

THEREOF
Technical Field
[1] The present invention relates to a sustained-release tablet containing paroxetine hydrochloride and manufacturing method thereof.
Background Art
[2] Paroxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI) and is used to treat depression and/or anxiety disorder. Therapeutic agents of depression and/ or anxiety disorder, such as SSRI, usually have initial side effects including nausea, drowsiness and fatigue, so that administration of such drugs often discontinue.
Considering treating methods of depression that usually recommends enough administration periods until amelioration of symptom, this stop of administration is undesirable. Further, like most psychiatric drugs, the sudden interruption of SSRI intake may make adverse effects such as dizziness, dysesthesia, somnipathy, agitation
(anxiety), nausea, sweating and so on, so that a stopping method gradually decreasing the amount of the drug is preferred.
[3] Because of these problems, a sustained-release formulation or controlled-release formulation that can slowly release drug and have a long duration time is preferable for treating depression and/or anxiety disorder. As this formulation, Paxil CR™
(Paroxetine controlled-release tablet, Glaxo Smith Kline) is commercially available.
[4] However, Paxil CR™ is a bilayer tablet consisting of an active layer containing paroxetine hydrochloride and a support platform, and its manufacturing is difficult and complex, and needs a specific tabletting machine to make the bilayer tablet.
Disclosure of Invention
Technical Problem
[5] Accordingly, an object of the present invention is to provide a paroxetine hydrochloride -containing sustained-release tablet that has little burst effect and can
release the drug at near zero-order rate over about 12 hrs.
[6] Another object of the present invention is to provide a manufacturing method of a paroxetine hydrochloride-containing sustained-release tablet, wherein the method is simple and cost-effective, and does not need the specific machine for mass production. Technical Solution
[7] To achieve the above object, the present invention provides a paroxetine hy- drochloride-containing sustained-release tablet comprising a paroxetine hydrochloride, a highly viscous polymer, a low viscous hydroxypropylmethylcellulose and a pharmaceutically acceptable excipient.
[8] Preferably, the present invention provides said paroxetine hydrochloride-containing sustained-release tablet wherein the highly viscous polymer is at least one selected from the group consisting of a highly viscous hydroxypropylmethylcellulose; an
8:2(w/w) physical mixture of polyvinylacetate and povidone (hereinafter,
"polyvinylacetate/povidone"); and an ethylcellulose.
[9] More preferably, the present invention provides said paroxetine hydrochloride- containing sustained-release tablet wherein the viscosity of the highly viscous hydroxypropylmethylcellulose is between 3,000 and 5,600 cP (when estimated as 2 wt%
aqueous solution and at 2O0C).
[10] More preferably, the present invention provides said paroxetine hydrochloride- containing sustained-release tablet wherein the highly viscous polymer comprises the highly viscous hydroxypropylmethylcellulose and the polyvinylacetate/povidone.
[11] More preferably, the present invention provides said paroxetine hydrochloride- containing sustained-release tablet wherein the viscosity of the low viscous hydroxypropylmethylcellulose is between 80 and 120 cP (when estimated as 2 wt% aqueous solution and at 2O0C).
[12] More preferably, the present invention provides said paroxetine hydrochloride sustained-release tablet wherein the pharmaceutically acceptable excipient comprises mannitol and lactose.
[13] The present invention also provides a paroxetine hydrochloride-containing
sustained-release tablet comprising between 6 and 14% by weight of paroxetine hydrochloride; between 6 and 20% by weight of highly viscous polymer; between 20 and 40% by weight of low viscous hydroxypropylmethylcellulose; and between 30 and
60% by weight of pharmaceutically acceptable excipient based on the total weight of the tablet.
[14] Preferably, the present invention provides said paroxetine hydrochloride-containing sustained-release tablet wherein the highly viscous polymer is at least one selected from the group consisting of a highly viscous hydroxypropylmethylcellulose, a
polyvinylacetate/povidone and an ethylcellulose.
[15] More preferably, the present invention provides said paroxetine hydrochloride- containing sustained-release tablet wherein the highly viscous polymer comprises between 4 and 10% by weight of polyvinylacetate/povidone and between 2 and 10% by weight of highly viscous hydroxypropylmethylcellulose based on the total weight of the tablet.
[16] More preferably, the present invention provides said paroxetine hydrochloride- containing sustained-release tablet wherein the pharmaceutically acceptable excipient comprises mannitol and lactose.
[17] Preferably, the present invention provides said paroxetine hydrochloride-containing sustained-release tablet wherein the tablet is coated by at least one release-controlling polymer, and more preferably, the release-controlling polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, ethyl- cellulose, ammonio methacrylate copolymer, methacrylic acid copolymer and
methacrylic acid-acrylic acid ethyl ester copolymer.
[18] The present invention also provides a method for preparing a paroxetine hydrochloride-containing sustained-release tablet, comprising the acts of:
[19] (Sl) mixing paroxetine hydrochloride and mannitol;
[20] (S2) dissolving polyvinylacetate/povidone or ethylcellulose in lower alcohol to
make a binding solution;
[21] (S3) making granules using the binding solution of the (S2) act and the mixture of the (Sl) act;
[22] (S4) mixing the granules of the (S3) act, highly viscous hydroxypropylmethylcellulose, low viscous hydroxypropylmethylcellulose and pharmaceutically acceptable excipient, and tabletting them; and
[23] (S5) enteric coating the tablet prepared in the (S4) act.
[24] Preferably, the present invention provides said method for preparing a paroxetine hydrochloride-containing sustained-release tablet wherein at least one ingredient
selected from the group consisting of a pharmaceutically acceptable excipient, a
polyvinylacetate/povidone and an ethylcellulose is added and mixed in the (Sl) act.
[25]
[26] Hereinafter, the paroxetine hydrochloride-containing sustained-release tablet and its manufacturing method according to the present invention will be described in more detail.
[27] The present invention provides a paroxetine hydrochloride-containing sustained- release tablet comprising a paroxetine hydrochloride, a highly viscous polymer, a low viscous hydroxypropylmethylcellulose and a pharmaceutically acceptable excipient.
Preferably, the present invention provides said paroxetine hydrochloride-containing sustained-release tablet characterized by the fact that the highly viscous polymer is at least one selected from the group consisting of a highly viscous hydroxypropylmethylcellulose, a polyvinylacetate/povidone, and an ethylcellulose. More preferably, the present invention provides said paroxetine hydrochloride-containing sustained-release tablet characterized by the fact that the highly viscous polymer comprises both a highly viscous hydroxypropylmethylcellulose and a polyvinylacetate/povidone.
[28] As used herein, the viscosity of polymer means a viscosity estimated as 2 wt% aqueous solution of the polymer at 2O0C, and an average of results measured three times. Preferably, the viscosity of the highly viscous hydroxypropylmethylcellulose is between 3,000 and 5,600 cP and the viscosity of the low viscous hydroxypropylmethylcellulose is between 80 and 120 cP.
[29] As usual, control of drug release may be carried out with a viscous or water- insoluble polymer, and an amount of the polymer is adjusted to achieve a desirable drug release rate. However, it is well known to a person skilled in the art that an
identical formulation can not be necessarily applied to every kind of drug and drug release pattern may be changed according to physical characteristics such as drug solubility, drug particle size, excipients included in the formulation such as binders, diluents and disintegrators, and its manufacturing method etc.
[30] The present invention is based on the surprising facts below happening when the drug is paroxetine hydrochloride.
[31] Firstly, paroxetine hydrochloride-containing sustained-release tablets made with only highly viscous polymer (for example, highly viscous hydroxypropylmethylcellulose) or water-insoluble polymer (for example, ethylcellulose) show a parabola type of drug release pattern that release rate decreases over time. Thus, it is difficult, even impossible, to lead to near zero-order release of paroxetine over about 12 hrs.
This release pattern is undesirable considering the therapy of depression emphasizing the fact that it is important to decrease initial side effects like nausea, drowsiness
fatigue and so on.
[32] Secondly, paroxetine hydrochloride-containing sustained-release tablets made with only low viscous polymer show a very fast release of paroxetine so that it is difficult to appropriately sustain drug release over about 12 hrs, and reveal a large dissolution variation. On the other hand, when the early dissolution rate of the tablet is controlled by increasing an amount of the polymer, paroxetine hydrochloride-containing
sustained-release tablets using only low viscous polymer show decreased dissolution amount at the later dissolution stage. Moreover, the amount of the low viscous polymer included to control drug release increases the total weight and size of one tablet, which degrades the value of the tablet and patient compliance.
[33] Thirdly, it is easy to enable near zero-order release of paroxetine over about 12 hrs when using both a highly viscous polymer and a low viscous hydroxypropylmethylcellulose, more preferably, using a highly viscous hydroxypropylmethylcellulose, a polyvinylacetate/povidone and a low viscous hydroxypropylmethylcellulose. More specifically, when using three polymers of a highly viscous hydroxypropylmethylcellulose, a polyvinylacetate/povidone and a low viscous hydroxypropylmethylcellulose, the dissolution variation can be much decreased.
[34] The present invention, preferably, provides said paroxetine hydrochloride- containing sustained-release tablet wherein the highly viscous polymer is at least one selected from the group consisting of a highly viscous hydroxypropylmethylcellulose, a polyvinylacetate/povidone (for example, Kollidon SR , commercially available from BASF, Germany) and an ethylcellulose, more preferably, the highly viscous polymer comprises a highly viscous hydroxypropylmethylcellulose and a polyvinylacetate/ povidone. As said above, controlling release of paroxetine hydrochloride is easier and dissolution variation is much decreased when using both a highly viscous hydroxypropylmethylcellulose and a polyvinylacetate/povidone as the highly viscous
polymer.
[35] More preferably, the present invention provides said paroxetine hydrochloride- containing sustained-release tablet wherein the pharmaceutical excipient comprises mannitol and lactose. A stability of a paroxetine hydrochloride-containing sustained- release tablet is attained by using mannitol as filler that has little water content and is not hygroscopic because paroxetine hydrochloride is unstable to water. However, the formulation using only mannitol as filler often causes tabletting problems like sticking, which can be solved by using a mixture of mannitol and lactose as filler. As used
herein, lactose includes lactose hydrous, lactose anhydrous or their mixture. However, considering the water-stability of paroxetine hydrochloride, lactose anhydrous is
preferred than lactose hydrous.
[36] The present invention also provides a paroxetine hydrochloride-containing
sustained-release tablet comprising by weight between 6 and 14% of paroxetine hydrochloride; between 6 and 20% of highly viscous polymer; between 20 and 40% of low viscous hydroxypropylmethylcellulose; and between 30 and 60% of pharmaceutically acceptable excipient based on the total weight of the tablet.
[37] Preferably, the present invention provides said paroxetine hydrochloride-containing sustained-release tablet wherein the highly viscous polymer is at least one selected from the group consisting of a highly viscous hydroxypropylmethylcellulose, a
polyvinylacetate/povidone and an ethylcellulose. More preferably, the present
invention provides said paroxetine hydrochloride-containing sustained-release tablet wherein the highly viscous polymer comprises by weight between 4 and 10% of
polyvinylacetate/povidone and between 2 and 10% of highly viscous hydroxypropylmethylcellulose based on the total weight of the tablet.
[38] Release rates of formulations having the same kind of ingredients may differ
according to the content ratio of the ingredients described above, and especially,
release rate of a sustained-release tablet may be severely changed by an adjustment of a content ratio because an alteration of a total formulation construct caused by a
change of the content ratio may change a release rate.
[39] A desirable release pattern depends on a therapeutic method of depression and/or anxiety disorder and the spirit of the present invention is not limited to the content ratio of the ingredients described above. However, when the sustained-release tablet of the present invention has the above content ratio, the tablet of the present invention can release the drug at near zero-order rate over about 12 times and has little burst effect and dissolution variation, and is most preferable in accordance with a current
therapeutic method of depression.
[40] The present invention also provides said paroxetine hydrochloride-containing
sustained-release tablet wherein the tablet is coated with release-controlling polymer. As said above, because there are many cases that the administration discontinues in mental disorder therapy such as depression, anxiety disorder and so on due to side effects of the initial stage of therapy, it is preferable to decrease amounts of paroxetine hydrochloride released in the early stage. This release of the early stage can be
controlled by coating the sustained-release tablet with release-controlling polymer without change of the total release pattern.
[41] The release -controlling polymer includes, but is not limited to, hydroxypropyl- methylcellulose acetate succinate, ethylcellulose, ammonio methacrylate copolymer
(for example, Eudragit RL™ or Eudragit RS™, Degussa, Germany), methacrylic acid copolymer (for example, Eudragit L™ or Eudragit S™, Degussa, Germany), and
methacrylic acid-acrylic acid ethyl ester copolymer (for example, Eudragit L
100-55™, Degussa, Germany).
[42] The present invention also provides a method for preparing a paroxetine hydrochloride-containing sustained-release tablet, comprising the acts of:
[43] (Sl) mixing paroxetine hydrochloride and mannitol;
[44] (S2) dissolving polyvinylacetate/povidone or ethylcellulose in lower alcohol to make a binding solution;
[45] (S3) making granules using the binding solution of the (S2) act and the mixture of the (Sl) act;
[46] (S4) mixing the granules of the (S3) act, highly viscous hydroxypropylmethyl- cellulose, low viscous hydroxypropylmethylcellulose and pharmaceutically acceptable excipient, and tabletting them; and
[47] (S5) enteric coating the tablet prepared in the (S4) act.
[48] Preferably, the present invention provides said method for preparing a paroxetine hydrochloride-containing sustained-release tablet wherein at least one ingredient selected from the group consisting of a pharmaceutically acceptable excipient, a
polyvinylacetate/povidone and an ethylcellulose is further added and mixed in the (Sl) act.
[49] It is important and difficult to control a content variation of paroxetine hydrochloride-containing tablet during manufacturing process because paroxetine hy- drochloride itself is easy to fly away and only small amount of paroxetine hydrochloride is included in one tablet. This content variation can be much decreased by granulating paroxetine hydrochloride with mannitol. In addition, some amount of pharmaceutically acceptable excipient like lactose and/or the polymers of the present
invention may be added into the granulating process for easiness of granulating. This polymer for controlling drug release will act as a binder when making granules, which increases the lasting quality of the granules during conveyance, mixing and tabletting and also sustains mixture ratio in granules for tabletting so as to keep good variation of dissolution and content of paroxetine.
[50] Also, lower alcohol is preferred for wet granulation process according to the present invention because paroxetine hydrochloride is unstable to water. Lower alcohol
includes, but is not limited to, ethanol, isopropylalcohol or their mixture.
Brief Description of the Drawings
[51] These and other features, aspects, and advantages of preferred embodiments of the present invention will be more fully described in the above and following detailed description, taken an accompanying drawing. In the drawing:
[52] Fig. 1 is a graph showing dissolution rates (%) of paroxetine hydrochloride- containing sustained-release tablets over time.
Mode for the Invention
[53] Hereinafter, the present invention is described in considerable detail to help those skilled in the art understand the present invention. However, the following examples are offered by way of illustration and are not intended to limit the scope of the
invention. It is apparent that various changes may be made without departing from the spirit and scope of the present invention or sacrificing all of its material advantages.
[54]
[55] <Preparation of examples 1~3 and comparative examples 1~7>
[56] Sustained-release tablets containing paroxetine hydrochloride were prepared using ingredients and amounts shown in table 1.
[57] Example 1, example 2 and comparative example 1 were prepared as follows: No. 1 ingredient, No. 6 ingredient, No. 7 ingredient and 2.2 g of No. 2 ingredient were
mixed. A binding solution was made by dissolving the rest of No. 2 ingredient in 7.5 ml of ethanol. Granules were made with the binding solution and the mixture, and then dried at 4O0C until loss on drying (hereinafter, "LOD") became about 2.5%. The dried granules were passed through a sieve (30 mesh). After that, the passed granules and the rest of the ingredients shown in table 1 were mixed and tabletted with a tabletting
machine (KI- 1300, Kisan machinery, South Korea) to make about 150 mg of tablet.
[58] Example 3 was prepared as follows: No. 1 ingredient, No. 6 ingredient and No. 7 ingredient were mixed. A binding solution was made by dissolving No. 2 ingredient in 13 ml of ethanol. Granules were made with the binding solution and the mixture, and then dried at 4O0C until LOD became about 2.5%. The dried granules were passed through a sieve (30 mesh). After that, the passed granules and the rest of the ingredients written in table 1 were mixed and tabletted with a tabletting machine to make about 150 mg of tablet.
[59] Comparative example 2 was prepared as follows: No. 1 ingredient, No. 6 ingredient and No. 7 ingredient were mixed. A binding solution was made by dissolving No. 2 ingredient in 7.5 ml of ethanol. Granules were made with the binding solution and the mixture, and then dried at 4O0C until LOD became about 2.5%. The dried granules were passed through a sieve (30 mesh). After that, the passed granules and the rest of the ingredients written in table 1 were mixed and tabletted with a tabletting machine to make about 150 mg of tablet.
[60] Comparative examples 3 and 5 were prepared as follows: No. 1 ingredient, No. 6 ingredient and No. 7 ingredient were mixed. A binding solution was made by
dissolving 0.9 g of No. 3 ingredient in 8 ml of ethanol. Granules were made with the binding solution and the mixture, and then dried at 4O0C until LOD became about
2.5%. The dried granules were passed through a sieve (30 mesh). After that, the passed granules and the rest of the ingredients written in table 1 were mixed and tabletted with a tabletting machine to make about 150 mg of tablet.
[61] Comparative examples 4, 6 and 7 were prepared as follows: No. 1 ingredient, No. 6 ingredient and No. 7 ingredient were mixed. A binding solution was made by
dissolving 0.7 g of No. 2 ingredient in 7.5 ml of ethanol. Granules were made with the binding solution and the mixture, and then dried at 4O0C until LOD became about
2.5%. The dried granules were passed through a sieve (30 mesh). After that, the passed granules and the rest of the ingredients written in table 1 were mixed and tabletted with a tabletting machine to make about 150 mg of tablet.
[62] Table 1




[63]
[64] <Dissolution test of examples 1~3 and comparative examples 1~7>
[65] Dissolution rates of tablets prepared in examples 1~3 and comparative examples
1-7 were evaluated according to USP dissolution test method (with paddle, 100 rpm, 900 ml). pH 6.8 buffer solution and Paxel CR™ (Glaxo Smith Kline, South Korea) were used as dissolution medium and control, respectively. Dissolution rate of a tablet prepared in each example was determined six times, and the average of results was shown in table 2 and Fig. 1. The results were expressed as a percent (%) of dissolved paroxetine in medium compared to the total amount of paroxetine included in each tested tablet.
[66] Table 2




[67] As shown in table 2, control and the sustained-release tablets of the present
invention released paroxetine hydrochloride at near zero-order rate over about 12 hrs. As shown in the dissolution results of comparative examples 4, 6 and 7, the dissolution rates of the sustained-release tablets having only highly viscous polymer decreased rapidly over time and the total dissolution amounts of the tablets were very low
compared to control. Especially, as shown in the result of comparative example 7 using only highly viscous polymer, the later dissolution rate was very slow even if the early dissolution rate was fast. As shown in the dissolution results of comparative examples 1, 2 and 3, it was difficult to appropriately sustain paroxetine release when using only low viscous hydroxypropylmethylcellulose. Even if a large increase of the low viscous hydroxypropylmethylcellulose content can sustain the release to some extent, it causes a large increase of the size and weight of the tablet, which is believed to have bad effects on manufacturing cost and patient compliance. Comparative example 5 using low viscous hydroxypropylmethylcellulose and another water-insoluble material
(stearic acid) showed bad dissolution pattern, which proves indirectly that it is difficult to make a desirable sustained-release tablet of paroxetine hydrochloride.
[68] Considering these results and the fact that the manufacturing method according to the present invention is simple and cost-effective, a paroxetine hydrochloride- containing sustained-release tablet according to the present invention is very valuable.

[69]
Industrial Applicability
[70] The present invention provides a paroxetine hydrochloride-containing sustained- release tablet that releases paroxetine following near zero-order kinetics over about 12 hrs and has little burst effect and dissolution variation. The present invention also provides a simple and cost-effective manufacturing method of a paroxetine hydrochloride sustained-release tablet.