WO2006129966A1

WO2006129966A1 - Manufacturing method of controlled-release tablet containing doxazocin mesylate

Info

Publication number: WO2006129966A1
Application number: PCT/KR2006/002094
Authority: WO
Inventors: Hong-Ryeol Jeon; Bong-Sang Lee; Se-Geun Yu; Hyun-Il Kim
Original assignee: Ctc Bio, Inc.
Priority date: 2005-05-31
Filing date: 2006-05-30
Publication date: 2006-12-07
Also published as: KR20080028365A; KR101366764B1

Abstract

The present invention relates to a manufacturing method of the controlled-release tablet comprising doxazocin mesylate. The manufacturing method of the present invention is simple and economical, and can provide the controlled-release tablet that releases doxazocin mesylate at zero-order rate for 12 hours and has reduced content variation and dissolution variation. Therefore, the manufacturing method of the present invention can provide a cost-effective controlled-release tablet comprising doxazocin mesylate that shows its efficacy for a long time, and has reduced in vivo absorption variation.

Description

MANUFACTURING METHOD OF CONTROLLED-RELEASE TABLET CONTAINING DOXAZOCIN MESYLATE

Technical Field

[1] The present invention relates to a manufacturing method of a controlled-release tablet comprising doxazocin mesylate. Background Art

[2] Doxazocin mesylate is mesylate salt of

4-amino-2-[4-(l-4-benzodioxan-2-carbonyl)piperazine-l-yl]-6,7-dimethoxyquinazolin e and widely used as angiotensin II antagonist, a kind of anti-hypertension drug.

[3] A sustained-release preparation which can release drug at constant rate for a relatively long time is usually used in treatment of hypertension to keep the effect of a drug constantly and reduce side-effects caused by the drug. From this point of view, low variation of dissolution rate (pattern) regardless of ambient condition as well as constant release rate of drug are desirable, and variation of dissolution rate between each preparation should be minimized. This dissolution variation is a very important factor in view of uniformity of specification of each preparation. Furthermore, because this dissolution variation is closely connected with in vivo absorption variation, reducing variation is very desirable when considering the purpose of continuance of efficacy and reduction of side-effect.

[4] Cardura XL™ (Pfizer Inc.) is a commercially available extended release tablet containing doxazocin mesylate, which releases doxazocin mesylate for over 12 hours at constant rate. However, Cardura XL™ is a preparation that releases the drug at constant rate using osmosis, so that a minute pore through which the drug is released on surface of the tablet and osmosis boundary membrane are needed, which makes the manufacturing of Cardura XL™ complex and needs a specific equipment that can make a pore on surface of tablet. Disclosure of Invention

Technical Problem

[5] Therefore, the object of the present invention is to provide a simple manufacturing method of a controlled-release tablet comprising doxazocin mesylate, wherein the method does not need the specific equipment and the tablet can release doxazocin mesylate at zero-order rate for pre-determined time and has reduced dissolution variation (i.e., reduced in vivo absorption variation). Technical Solution

[6] To achieve the object, the present invention is to provide a manufacturing method of a controlled-release tablet comprising doxazocin mesylate having reduced dissolution variation, i.e. reduced in vivo absorption variation, wherein the method comprises the steps of: (Sl) mixing doxazocin mesylate; low- viscosity hydroxypropyl- methylcellulose; at least one gum selected from the group consisting of xanthan gum, arabia gum, guar gum and locust bean gum; diluent; and lubricant to make a mixture; (S2) compacting the mixture to make dry granule; and (S3) mixing the dry granule with lubricant to make a final mixture and tabletting the final mixture.

[7] More preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the viscosity of the low-viscosity hydroxypropylmethylcellulose is between 80 and 120 cP when measured as 2 wt% aqueous solution at 20⁰C.

[8] Preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the diluent is at least one selected from the group consisting of lactose, mannitol, microcrystalline cellulose and corn starch, and more preferably, the diluent is lactose.

[9] More preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the gum is xanthan gum.

[10] More preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the tablet comprises 0.5 to 2 wt% of doxazocin mesylate; 40 to 50 wt% of low- viscosity hydroxypropylmethylcellulose; 4 to 10 wt% of xanthan gum; and 25 to 35 wt% of lactose based on the total weight of the controlled-release tablet.

[11] Preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein binder is further mixed with the mixture of (Sl) step, and more preferably, the binder is 5 to 15 wt% of linear copolymer of N-vinyl-2-pyrrolidone and vinylacetate based on the total weight of the controlled-release tablet.

[12] Preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the method further comprises the step of (S4) coating the controlled-release tablet with coating solution comprising release- sustaining polymer and pore-maker, and more preferably, the release-sustaining polymer is polyvinylacetate and the pore-maker is polyvinylpyrrolidone, vinylpyrrolidone- vinylacetate copolymer or their mixture.

[13] Hereinafter, the manufacturing method of the controlled-release tablet comprising doxazocin mesylate according to the present invention will be described in detail.

[14] The present invention is to provide a manufacturing method of a controlled-release tablet comprising doxazocin mesylate having reduced dissolution variation (ultimately, reduced in vivo absorption variation), wherein the method comprises the steps of: (Sl) mixing doxazocin mesylate; low-viscosity hydroxypropylmethylcellulose; at least one gum selected from the group consisting of xanthan gum, arabia gum, guar gum and locust bean gum; diluent; and lubricant to make a mixture; (S2) compacting the mixture to make dry granule; and (S3) mixing the dry granule with lubricant to make a final mixture and tabletting the final mixture.

[15] The manufacturing method of the present invention uses a mixture of low- viscosity hydroxypropylmethylcellulose and gum as release-controlling material to release doxazocin mesylate at zero-order rate for pre-determined time.

[16] The manufacturing method of the present invention uses low-viscosity hydroxypropylmethylcellulose to control the release of doxazocin mesylate unlike high- viscosity hydroxypropylmethylcellulose of conventional sustained-release preparations. In case of using high- viscosity hydroxypropylmethylcellulose to control the release of the drug, the content of the high- viscosity hydroxypropylmethylcellulose is relatively small, which may cause dissolution variation larger. Low-viscosity hydroxypropylmethylcellulose of the present invention means that the viscosity of that polymer is less than 200 cP when measured as 2 wt% aqueous solution at 2O⁰C, and more preferably, the viscosity is between 80 and 120 cP.

[17] Besides, a controlled-release tablet containing doxazocin mesylate made with only low- viscosity hydroxypropylmethylcellulose has larger dissolution variation than that of the present invention. The present invention is based on the surprising fact that this problem is overcome by mixing the tablet containing doxazocin mesylate and low- viscosity hydroxypropylmethylcellulose with gum. Surprisingly, the controlled-release tablet comprising doxazocin mesylate, low- viscosity hydroxypropylmethylcellulose and gum has reduced dissolution variation (i.e., in vivo absorption variation) as well as improved sustainability of the release. The physical property of gum is believed to play a unique role in reducing dissolution variation by keeping entire configuration against outside physical influence, but the scope of the present invention is not limited to this theory.

[18] The gum playing the role includes, but is not limited to, xanthan gum, arabia gum, guar gum and locust bean gum. Xanthan gum is more preferable when considering the efficiency of controlling the release of doxazocin mesylate in connection with low- viscosity hydroxypropylmethylcellulose.

[19] As the diluent of the present invention, at least one selected from the group consisting of lactose, mannitol, microcrystalline cellulose and corn starch can be used. Lactose is more preferable because microcrystalline cellulose and corn starch may work as disintegrator to increase in vivo absorption variation, and mannitol has relatively worse storage- stability than lactose. [20] Therefore, more preferred embodiment of the present invention comprises doxazocin mesylate, low-viscosity hydroxypropylmethylcellulose, xanthan gum and lactose, and optimally, 0.5 to 2 wt% of doxazocin mesylate; 40 to 50 wt% of low- viscosity hydroxypropylmethylcellulose; 4 to 10 wt% of xanthan gum; and 25 to 35 wt% of lactose based on the total weight of the controlled-release tablet. In case that the content of low- viscosity hydroxypropylmethylcellulose is more than that range, the release rate is too slow. In case that the content of low-viscosity hydroxypropylmethylcellulose is less than that range, the release rate is too fast to keep a desirable release rate. In case that the content of xanthan gum is outside that range, reducing dissolution variation as well as controlling release rate is difficult like hydroxypropylmethylcellulose. In case that the content of the diluent, lactose, is outside that range, controlling the release rate of doxazocin mesylate is difficult because the increase of the lactose content necessarily causes the decrease of the release-controlling polymer content or the gum content, and vice versa.

[21] Furthermore, direct compression method without the step of (S2) compacting the mixture of doxazocin mesylate, low- viscosity hydroxypropylmethylcellulose, xanthan gum, lactose etc. to make dry granule causes large weight variation, and even if the weight variation is small, the dissolution variation is large. This problem is believed to be caused by a drop of mixing uniformity made by vibration of tabletting and/or conveyance of granules for tabletting, but the scope of the present invention is not limited to this theory.

[22] The compacting of (S2) step of the present invention can be performed by conventional equipments, such as but not limited to, roller compactor, extruder for compacting or tabletting machine for making dry granule. Roller compactor is more preferable when considering mass-production ability.

[23] In addition, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein binder is further mixed with the mixture of (Sl) step. Binder is believed to play a role in increasing coherence of dry granule, which not only makes the following steps such as conveyance or tabletting easier, but also may control dissolution rate and reduce dissolution variation by keeping property of doxazocin mesylate and other excipients.

[24] Examples of the binder according to the present invention include, but are not limited to, polyvinylpyrrolidone, linear copolymer of vinylpyrrolidone and vinylacetate, hydroxypropylcellulose and low-substituted hydroxypropylcellulose. Preferably, the binder is linear copolymer of vinylpyrrolidone and vinylacetate (for example, Copovidone™, BASF, Germany) when considering the interaction with other excipients to control dissolution rate, and more preferably, the content of the linear copolymer of vinylpyrrolidone and vinylacetate is 5 to 15 wt% based on the total weight of the controlled-release tablet.

[25] Some embodiments of the controlled-release tablet comprising doxazocin mesylate made according to the present invention have relatively fast dissolution rate at early stage of dissolution, so that controlling the early stage of dissolution rate is necessary to get a desirable entire dissolution rate. Therefore, preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the method further comprises the step of (S4) coating the controlled-release tablet with coating solution comprising release-sustaining polymer and pore-maker. This coating process can be performed with conventional tablet coating machine by a variety of methods well known to one of ordinary skill in the art to which the present invention pertains.

[26] Preferable examples of the release- sustaining polymer include polyvinylacetate, hy- droxypropylmethylcellulose phthalate, methacrylic acid copolymer, hydroxypropyl- methylcellulose acetate succinate and their mixtures. Polyvinylacetate is more preferable when considering the efficiency of controlling the dissolution rate of early stage.

[27] The coating solution used in the present invention also comprises pore-maker. If the controlled-release tablet is coated with only the release-sustaining polymer, there may be a possibility that the dissolution rate is too slow. Thus, the pore-maker is needed. Preferable examples of the pore-maker include polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethyl- cellulose, low-viscosity hydroxypropylcellulose and their mixtures. Polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or their mixture is more preferable.

[28] The coating solution used in the present invention optionally further comprises surfactant for coating that can plasticize the release-sustaining polymer. Examples of the surfactant for coating include, but are not limited to, dibutylsebacate, triethylcitrate, propyleneglycol, poly ethylenegly col and their mixtures.

[29] The coating solution used in the present invention optionally further comprises lubricant (for example, talc), lightproof agent (for example, titanium dioxide).

[30] More preferably, the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the method further comprises the step of (S4) coating the controlled-release tablet with coating solution comprising 0.5 to 5 parts by weight of polyvinylacetate; 0.5 to 3 parts by weight of pore-maker selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethyl- cellulose, low-viscosity hydroxypropylcellulose and their mixtures; 0.5 to 3.5 parts by weight of talc, titanium dioxide or their mixture; 0.1 to 2 parts by weight of surfactant for coating, until the weight of the tablet increases by 3 to 9 wt% based on the total weight of the tablet.

[31] In case that the coated weight is less than 3 wt% based on the total weight of the controlled-release tablet, the dissolution rate of the early stage may be too fast. In case that the coated weight is more than 9 wt% based on the total weight of the controlled- release tablet, the dissolution rate of the early stage may be too slow. Brief Description of the Drawings

[32] Figure 1 is a graph showing mean blood plasma concentrations of doxazocin over time after the administration of Cardura XL™ (Pfizer Inc.) or one embodiment of the present invention. Mode for the Invention

[33] Hereinafter, preferred embodiments of the present invention will be described in detail. Prior to the description, it should be understood that various modifications are possible to the embodiments of the present invention, and it should be understood that the scope of the invention is not limited to the following embodiments. Embodiments of the present invention are disclosed to provide more complete explanation to one of ordinary skill in the art.

[34] <Manufacturing of examples 1~4 and comparative examples 1~2>

[35] Controlled-release tablets comprising doxazocin mesylate were manufactured with ingredients and contents shown in the below table 1. 1,000 times amount of weight of No. 1 to No. 6 ingredients, respectively, were measured and mixed well to a mixture, and then the mixture was compacted with Roller compactor (TF- Mini, Freund Corp., Japan) and sieved with 16 mesh sieve to make adequate size of dry granules. The dry granules were mixed with pre-determined amounts of No. 7 and 8 ingredients according to the ratio of table 1, respectively. After that, the mixture was tabletted by a tabletting machine (KI- 1300, Kisan, South Korea) to make tablets having about 292 mg of weight per a tablet and 10 1 Kp of hardness.

[36] Table 1

[37] <Dissolution tests of examples 1-4 and comparative examples 1~2>

[38] Dissolution tests were performed with the above manufactured examples 1-4 and comparative examples 1-2 according to the paddle method (75 rpm, 900 ml) of the dissolution test method of South Korea Pharmacopoeia. pH 1.2 buffered solution (2.0 of NaCl was mixed with 7.0 ml of hydrochloric acid, and then distilled water was added to make the volume 1 liter) was used as dissolution medium. Cardura XL™ (Pfizer Inc.) was used as control. Total 18 samples (6 samples x 3 times) of each example were tested, and the mean and standard deviation were shown in table 2. [39] Table 2

[40] As shown in table 2, the controlled-release tablets of the present invention released doxazocin mesylate at zero-order rate for 12 hours and showed small dissolution variation. Comparative examples 1 and 2, which did not comprise xanthan gum, did not showed desirable dissolution pattern and had large dissolution variation. In addition, the controlled-release tablets of the present invention showed similar rate ratio (slope) in dissolution pattern to commercially available preparation, Cardura XL™ and less dissolution variation than Cardura XL™. Therefore, the manufacturing method according to the present invention is very useful when considering the method of the present invention is simple and cost-effective.

[41] <Manufacturing of comparative example 3 using direct compression method>

[42] Comparative example 3 having the very same ingredients and contents as example

1 was manufactured by direct compression method without making dry granules. All ingredients of example 1 in table 1 were mixed, and the mixture was tabletted with the tabletting machine used in example 1.

[43] <Dissolution test of comparative examples 3>

[44] Dissolution test on comparative example 3 was performed according to the same method as used in dissolution test on example 1. Results were shown in table 3.

[45] Table 3

[46] As shown in table 3, comparative example showed similar dissolution pattern to example 1, but showed larger dissolution variation.

[47] <Manufacturing of example 5>

[48] The controlled-release tablet comprising doxazocin mesylate made in example 1 was coated with coating solution comprising a release-sustaining polymer and pore- maker to slow the dissolution rate of the early stage because the tablet of example 1 showed too fast dissolution rate at early stage. The tablet of example 1 was coated with a coating solution consisting of 10 parts by weight of Kollicoat SR30D™ (aqueous suspension comprising 27% of polyvinylacetate, 2.7% of povidone and 0.3% of sodium lauryl sulfate, B ASF), 1.2 parts by weight of polyvinylpyrrolidone K30, 0.9 parts by weight of talc, 0.8 parts by weight of titanium dioxide, 0.3 parts by weight of propyleneglycol and 11. 5 parts by weight of water, until the weight of each tablet of example 1 increased to 106 wt% based on the weight of the tablet of example 1.

[49] <E valuation of in vivo absorption pattern using example 5>

[50] Two tablets of the controlled-release tablet made in example 5 and commercially available Cardura XL™, respectively, were administered to 26 healthy men, and then blood were collected at 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 48, 72 and 96 hours after the administration and doxazocin concentration in blood sample was measured. 26 subjects were randomly grouped into 2 groups having 13 subjects. At the first test, the commercially available product was administered to one group and the example 5 was administered to the other group at the same day, and vice versa at the second test. Subjects were fasted from 12 hours before the test to 4 hours of administration to remove the influence of food. Ethylacetate was used to extract doxazocin in blood and the concentration of doxazocin was analyzed with HPLC. Results were shown in figure 1.

[51] As shown figure 1, the controlled-release tablet comprising doxazocin mesylate of the present invention showed very small in vivo absorption variation regardless of the fact that the tablet of the present invention is a matrix-type of tablet using polymer. In addition, the present invention can manufacture simply and cost-effectively the controlled-release tablet showing similar in vivo absorption pattern to the commercially available OROS™ preparation using osmosis technology. Industrial Applicability

[52] The manufacturing method of the controlled-release tablet comprising doxazocin mesylate according to the present invention is simple and economical, and can provide the tablet that releases doxazocin mesylate at zero-order rate for 12 hours and has reduced dissolution variation. Therefore, the controlled-release tablet made by the method of the present invention has reduced in vivo absorption variation, which is advantageous because of reduced efficacy variation and side-effect.

Claims

[I] A manufacturing method of a controlled-release tablet comprising doxazocin mesylate, wherein the method comprises the steps of:

(51) mixing doxazocin mesylate; low- viscosity hydroxypropylmethylcellulose; at least one gum selected from the group consisting of xanthan gum, arabia gum, guar gum and locust bean gum; diluent; and lubricant to make a mixture;

(52) compacting the mixture to make dry granule; and

(53) mixing the dry granule with lubricant to make a final mixture and tabletting the final mixture.

[2] The manufacturing method of claim 1, wherein the viscosity of the low- viscosity hydroxypropylmethylcellulose is between 80 and 120 cP when measured as 2 wt% aqueous solution at 2O⁰C.

[3] The manufacturing method of claim 1, wherein the diluent is at least one selected from the group consisting of lactose, mannitol, microcrystalline cellulose and corn starch.

[4] The manufacturing method of claim 3, wherein the diluent is lactose.

[5] The manufacturing method of claim 1, wherein the gum is xanthan gum.

[6] The manufacturing method of claim 1, wherein the controlled-release tablet comprises 0.5 to 2 wt% of doxazocin mesylate; 40 to 50 wt% of low- viscosity hydroxypropylmethylcellulose; 4 to 10 wt% of xanthan gum; and 25 to 35 wt% of lactose based on the total weight of the controlled-release tablet.

[7] The manufacturing method of claim 1, wherein binder is further mixed with the mixture of (Sl) step.

[8] The manufacturing method of claim 7, wherein the binder is linear copolymer of vinylpyrrolidone and vinylacetate.

[9] The manufacturing method of claim 8, wherein the binder is present at a level of from 5 to 15 wt% based on the total weight of the controlled-release tablet.

[10] The manufacturing method of any one of claims 1-9, wherein the method further comprises the step of (S4) coating the controlled-release tablet with coating solution comprising release-sustaining polymer and pore -maker.

[I I] The manufacturing method of claim 10, wherein the release-sustaining polymer is polyvinylacetate.

[12] The manufacturing method of claim 10, wherein the pore-maker is polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or their mixture.

[13] The manufacturing method of claim 10, wherein the step of (S4) is performed with the coating solution comprising comprising 0.5 to 5 parts by weight of polyvinylacetate; 0.5 to 3 parts by weight of pore-maker selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, low-viscosity hydroxypropylmethylcellulose, low- viscosity hydroxypropyl- cellulose and their mixtures; 0.5 to 3.5 parts by weight of talc, titanium dioxide or their mixture; 0.1 to 2 parts by weight of surfactant for coating, until the weight of the tablet increases by 3 to 9 wt% based on the total weight of the tablet.