WO2006129966A1 - Procede de fabrication de comprime a liberation controlee contenant du mesylate de doxazocine - Google Patents

Procede de fabrication de comprime a liberation controlee contenant du mesylate de doxazocine Download PDF

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Publication number
WO2006129966A1
WO2006129966A1 PCT/KR2006/002094 KR2006002094W WO2006129966A1 WO 2006129966 A1 WO2006129966 A1 WO 2006129966A1 KR 2006002094 W KR2006002094 W KR 2006002094W WO 2006129966 A1 WO2006129966 A1 WO 2006129966A1
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WO
WIPO (PCT)
Prior art keywords
manufacturing
controlled
release
release tablet
gum
Prior art date
Application number
PCT/KR2006/002094
Other languages
English (en)
Inventor
Hong-Ryeol Jeon
Bong-Sang Lee
Se-Geun Yu
Hyun-Il Kim
Original Assignee
Ctc Bio, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ctc Bio, Inc. filed Critical Ctc Bio, Inc.
Priority to KR1020077028790A priority Critical patent/KR101366764B1/ko
Publication of WO2006129966A1 publication Critical patent/WO2006129966A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin

Definitions

  • the present invention relates to a manufacturing method of a controlled-release tablet comprising doxazocin mesylate.
  • Doxazocin mesylate is mesylate salt of
  • 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.
  • Cardura XLTM (Pfizer Inc.) is a commercially available extended release tablet containing doxazocin mesylate, which releases doxazocin mesylate for over 12 hours at constant rate.
  • Cardura XLTM 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 XLTM complex and needs a specific equipment that can make a pore on surface of tablet. Disclosure of Invention
  • 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).
  • 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.
  • 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 20 0 C.
  • 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.
  • the present invention is to provide the manufacturing method of the controlled-release tablet comprising doxazocin mesylate, wherein the gum is xanthan gum.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 2O 0 C, and more preferably, the viscosity is between 80 and 120 cP.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the release rate is too slow.
  • the release rate is too fast to keep a desirable release rate.
  • the content of xanthan gum is outside that range, reducing dissolution variation as well as controlling release rate is difficult like hydroxypropylmethylcellulose.
  • 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.
  • 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.
  • 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.
  • binder examples include, but are not limited to, polyvinylpyrrolidone, linear copolymer of vinylpyrrolidone and vinylacetate, hydroxypropylcellulose and low-substituted hydroxypropylcellulose.
  • the binder is linear copolymer of vinylpyrrolidone and vinylacetate (for example, CopovidoneTM, 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.
  • 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.
  • release- sustaining polymer examples 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.
  • 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.
  • 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.
  • the coating solution used in the present invention optionally further comprises surfactant for coating that can plasticize the release-sustaining polymer.
  • surfactant for coating include, but are not limited to, dibutylsebacate, triethylcitrate, propyleneglycol, poly ethylenegly col and their mixtures.
  • the coating solution used in the present invention optionally further comprises lubricant (for example, talc), lightproof agent (for example, titanium dioxide).
  • lubricant for example, talc
  • lightproof agent for example, titanium dioxide
  • 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.
  • 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, vinylpyrrolidon
  • 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.
  • Figure 1 is a graph showing mean blood plasma concentrations of doxazocin over time after the administration of Cardura XLTM (Pfizer Inc.) or one embodiment of the present invention. Mode for the Invention
  • 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.
  • a tabletting machine KI- 1300, Kisan, South Korea
  • 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.
  • the controlled-release tablets of the present invention showed similar rate ratio (slope) in dissolution pattern to commercially available preparation, Cardura XLTM and less dissolution variation than Cardura XLTM. 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.
  • 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.
  • 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 SR30DTM (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.
  • Kollicoat SR30DTM aqueous suspension comprising 27% of polyvinylacetate, 2.7% of povidone and
  • 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.
  • the present invention can manufacture simply and cost-effectively the controlled-release tablet showing similar in vivo absorption pattern to the commercially available OROSTM preparation using osmosis technology.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé de fabrication de comprimé à libération contrôlée contenant du mésylate de doxazocine. Le procédé de fabrication de cette invention est simple et économique, et peut fournir des comprimés à libération contrôlée qui libèrent du mésylate de doxazocine à un taux de libération d'ordre zéro pour douze heures et présente une variation de contenu et de dissolution réduite. C'est pourquoi, le procédé de fabrication de l'invention peut fournir des comprimés à libération contrôlée économiques contenant du mésylate de doxazocine qui présente son efficacité depuis longtemps, et qui présente une variation d'absorption in vivo réduite.
PCT/KR2006/002094 2005-05-31 2006-05-30 Procede de fabrication de comprime a liberation controlee contenant du mesylate de doxazocine WO2006129966A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020077028790A KR101366764B1 (ko) 2005-05-31 2006-05-30 메실산독사조신 서방정의 제조방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20050046003 2005-05-31
KR10-2005-0046003 2005-05-31

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WO2006129966A1 true WO2006129966A1 (fr) 2006-12-07

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5128143A (en) * 1988-09-19 1992-07-07 Edward Mendell Co., Inc. Sustained release excipient and tablet formulation
US6416786B1 (en) * 1998-12-11 2002-07-09 Nostrum Pharmaceuticals, Inc. Sustained release tablet containing hydrocolloid and cellulose ether
US20030059467A1 (en) * 2001-09-14 2003-03-27 Pawan Seth Pharmaceutical composition comprising doxasozin
WO2004037290A1 (fr) * 2002-10-23 2004-05-06 Hanmi Pharm. Co., Ltd. Composition a liberation prolongee destinee a une administration orale de medicaments

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5128143A (en) * 1988-09-19 1992-07-07 Edward Mendell Co., Inc. Sustained release excipient and tablet formulation
US6416786B1 (en) * 1998-12-11 2002-07-09 Nostrum Pharmaceuticals, Inc. Sustained release tablet containing hydrocolloid and cellulose ether
US20030059467A1 (en) * 2001-09-14 2003-03-27 Pawan Seth Pharmaceutical composition comprising doxasozin
WO2004037290A1 (fr) * 2002-10-23 2004-05-06 Hanmi Pharm. Co., Ltd. Composition a liberation prolongee destinee a une administration orale de medicaments

Also Published As

Publication number Publication date
KR20080028365A (ko) 2008-03-31
KR101366764B1 (ko) 2014-02-25

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