WO1998005306A1 - Composition de comprime a liberation controlee d'isosorbide-5-mononitrate - Google Patents

Composition de comprime a liberation controlee d'isosorbide-5-mononitrate Download PDF

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Publication number
WO1998005306A1
WO1998005306A1 PCT/IE1997/000055 IE9700055W WO9805306A1 WO 1998005306 A1 WO1998005306 A1 WO 1998005306A1 IE 9700055 W IE9700055 W IE 9700055W WO 9805306 A1 WO9805306 A1 WO 9805306A1
Authority
WO
WIPO (PCT)
Prior art keywords
controlled release
capsule
isosorbide mononitrate
weight ratio
granules
Prior art date
Application number
PCT/IE1997/000055
Other languages
English (en)
Inventor
Dermot Mccafferty
Original Assignee
Cal International Limited
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 Cal International Limited filed Critical Cal International Limited
Priority to AU38613/97A priority Critical patent/AU3861397A/en
Publication of WO1998005306A1 publication Critical patent/WO1998005306A1/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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • nitrates have been available, for some considerable time, to treat angina pectoris. These nitrates have been formulated in many different ways to provide clinical relief of angina. for example, glyceryl trinitrate has been formulated as a sublingual tablet, spray and as a transdermal patch. Modified-release oral preparation (tablets and capsules) have also been made using the longer-acting nitrates, isosorbide dinitrate and isosorbide mononitrate.
  • Isosorbide-5-mononitrate has been formulated in a number of different ways to allow either immediate release or controlled release of the drug.
  • the use of controlled release has various advantages over immediate release dosage forms. For example, a controlled release system will provide a more uniform plasma concentration of a drug and will tend to avoid the peak and trough effects associated with immediate release dosage forms. The number of daily administrations is reduced with a concomitant increase in patient compliance. Gastrointestinal side-effects also tend to be reduced when taking a controlled release dosage form.
  • the purpose of the present invention is to formulate a controlled release tablet of ISMN, the diameter of which is less than 6 mm. This, in turn, will allow the tablet to be swallowed more easily and also allow the tablet to fit into a No. 1 capsule.. It is another objective of the invention to develop a controlled release formulation containing ISMN. However, due to the comparatively large amount of drug required for this -purpose, typically 60 mg , it is difficult to obtain such a tablet with a suitable controlled release profile due to the die fill required. Clearly, with die diameters less than 6 mm the volume available to receive the final formulation, before compression, is reduced. In practice, this can mean that not more than 140 mg of the final formulation can be filled into the die. However, it has been discovered, with the present invention, that, unusually, suitable controlled release profiles can be achieved using a total formulation weight less than 140 mg .
  • a controlled release tablet formulation of an isosorbide mononitrate comprising granules of isosorbide mononitrate and a controlled release agent wherein the weight ratio of isosorbide mononitrate to controlled release agent is from 30:70 to 80:20.
  • the weight ratio of isosorbide mononitrate to controlled release agent is from 1:2 to 7:3. Ideally, the weight ratio of isosorbide mononitrate to controlled release agent is approximately 3:2.
  • the controlled release agent is a cellulose-based controlled release agent, most preferably a MethocelTM release agent.
  • the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a solution of a granulating aid, the weight ratio of isosorbide mononitrate to water in the solution of granulating aid being in the range of from 6:1 to 1:1.
  • the weight ratio of isosorbide mononitrate to water in the solution of granulating aid is in the range of from 2.4:1 to 1.5:1, ideally approximately 2:1.
  • the granulating aid is a polyvinylpyrollidone granulating aid, especially KollidonTM 30.
  • the formulation includes a lubricant in a weight ratio of lubricant to active and controlled release agent of less than 1:20.
  • the formulation includes a lubricant in a weight ratio of lubricant to active and controlled release agent of less than 1:100.
  • the weight of the tablet is less than 140 mg, most preferably approximately 100 mg. Most preferably, the size of the tablet corresponds approximately to a 5.5 mm punch.
  • the invention also provides a capsule incorporating a tablet of the invention. Most preferred is a No. l capsule.
  • the capsule may contain a second active ingredient, especially Aspirin which may be in the form of granules, coated granules and especially a tablet, preferably a coated tablet.
  • a second active ingredient especially Aspirin which may be in the form of granules, coated granules and especially a tablet, preferably a coated tablet.
  • the weight ratio of isosorbide mononitrate to Aspirin is from 1:5 to 3:2, preferably approximately 4:5.
  • a method for formulating a controlled release tablet formulation of an active ingredient comprising the steps of :-
  • the weight ratio of isosorbide mononitrate to controlled release agent is from 1:2 to 7:3. Ideally, the weight ratio of isosorbide mononitrate to controlled release agent is approximately 3:2.
  • the controlled release agent is a cellulose based controlled release agent, preferably a MethocelTM release agent.
  • the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a granulating aid and drying the granules thus formed.
  • the granules of isosorbide mononitrate are formed by granulating isosorbide mononitrate with a solution of a granulating aid, the weight ratio of isosorbide mononitrate to water in the solution of granulating aid being in the range of from 6:1 to 1:1, most preferably in the range of from 2.4:1 to 1.5:1, ideally approximately 2:1.
  • the active ingredient is preferably granulated with a solution of a granulating aid, typically a 10% aqueous solution of the granulating aid.
  • the active ingredient is granulated with from 15 to 50% w/w, most preferably 30 to 40% w/w of a granulating aid based on the weight of active ingredient.
  • the granulating aid is a polyvinylpyrollidone granulating aid, preferably KollidonTM 30.
  • the method includes the step of sieving the granules to obtain granules of a desired size.
  • the granules are sieved by passing the granules through a lOOO ⁇ m mesh screen.
  • the dry granules are dry blended with the controlled release agent, preferably for at least ten minutes and usually for approximately fifteen minutes.
  • the method comprises the step, after blending, of adding a lubricant to the mixture prior to tabletting. Preferably, after addition of the lubricant the mixture is further blended prior to tabletting.
  • the lubricant is magnesium stearate.
  • the weight ratio of the lubricant to active and controlled release agent is less that 1:10, typically 1:100 active and excipients.
  • the tablets have a tablet weight of less than 140 mg, ideally approximately 100 mg or less.
  • the tablets are formed usirfg a 5.5. mm punch.
  • the active ingredient is isosorbide mononitrate.
  • the invention also provides a controlled release tablet whenever formed by the method of the invention.
  • the invention further provides a capsule incorporating a tablet of the invention.
  • the capsule is a number 1 size capsule.
  • the capsule may contain a second active ingredient which may be formed into a plug for placing into the capsule.
  • the plug may be formed by mixing the second active with a plug forming agent, such as a cellulose based agent, preferably Avicel PH 101.
  • the second active ingredient may comprise or include Aspirin which may be in the form of granules, especially coated granules, or preferably a tablet, most preferably a coated tablet.
  • Aspirin which may be in the form of granules, especially coated granules, or preferably a tablet, most preferably a coated tablet.
  • the weight ratio of the ISMN to coated Aspirin is from 1:5 to 3:2, most preferably approximately 4:5.
  • Isosorbide Mononitrate 600 g was granulated with a 10% aqueous solution of Kollidon 30 and passed through a 1000 ⁇ m mesh. After drying the granules were passed through a 1000 ⁇ m mesh.
  • Methocel K100 Premium 400 g was dry blended with the ISMN granule-s for 15 minutes using a Y-cone blender. Thereafter, magnesium -stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg. Samples of tablets were assessed in vi tro using the rotating paddle standard dissolution apparatus (100 rpm) at a temperature of 37°C using HPLC grade water. A typical dissolution profile is shown in Fig. 1.
  • Kollidon 30 is a polyvinylpyrollidone granulating aid available from BASF.
  • Methocel K100 Premium is a cellulose-based coating agent available from COLORCON LIMITED.
  • ISMN 600 g was granulated with a 10% aqueous solution of Kollidon 30 and passed through a 1000 ⁇ m mesh. After drying the granules were then passed through a 1000 ⁇ m mesh. Methocel E10 Premium (400 g) was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg . Samples of tablets were assessed in vi tro using the rotating paddle standard dissolution apparatus (.100 rpm) at a temperature of 37"C using HPLC grade water. A typical dissolution profile is shown in Fig. 2. The three samples plotted indicate the reproducibility of these results.
  • ISMN 600 g was granulated with a 10% aqueous solution of Kollidon 30 and passed through- a 1000 ⁇ m mesh. After drying the granules were passed through a 1000 ⁇ m mesh.
  • Methocel K15 Premium 400 g was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg . Samples of tablets were assessed in vi tro using the rotating paddle standard dissolution apparatus ( 100 rpm) at a temperature of 37°C using HPLC grade water. A typical dissolution profile is shown in Fig. 1.
  • ISMN 600 g was granulated with a 10% aqueous solution of Kollidon 30 and passed through a 1000 ⁇ m mesh. After drying the granules were then passed through a 1000 ⁇ m mesh.
  • Methocel K100 Premium 400 g was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg . The formed tablet cores were placed into a No.
  • Avicel PHlOl is a pharmaceutical excipient available from FMC Corporation.
  • ISMN 600 g was granulated with a 10% aqueous solution of Kollidon 30 (210 ml). The resultant mixture was dried directly in a fluidised bed dryer. Thereafter, the granules were then passed through a 1000 ⁇ m mesh. Methocel K100 M Premium (400 g) was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium stearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to an average tablet weight of 103 mg .
  • ISMN 600 g was granulated with a 10% aqueous solution of Kollidon 30. After drying the granules were then passed through a 1000 ⁇ m mesh and. left overnight before further processing.
  • Methocel K100 Premium 400 g was dry blended with the ISMN granules for 15 minutes using a Y-cone blender. Thereafter, magnesium -s-tearate (5 g) was added to the mixture which was further blended for 1 minute. The resulting mix was tabletted using 5.5 mm punches to a tablet weight of 100.5 mg. The formed tablet cores were placed into a No . 1 capsule to which was added 75 mg of aspirin granules which were coated with ethylcellulose .
  • Granular aspirin 750 g was blended with Sta-Rx 1500 (50g) and stearic acid (15 g) and tabletted using 5.5 mm punches.
  • the resultant tablets (average weight 81.5 mg ) contained 75 mg of aspirin. Tablets conformed to the B.P. specifications for uncoated tablets. Sta-Rx is available from Colorcon.
  • Aspirin tablets made according to Example 7 were film coated, 3% w/w of the tablet weight, using a cellulose based agent (Opadry) .
  • the film coated tablets conformed to the B.P. specifications for coated tablets. Opadry is available from Colorcon.
  • Aspirin tablets made according to Example 7 were enteric coated using methacrylic acid based polymers (Eudragit L) at a concentration of 5 mg cm "* surface area of tablets.
  • the coated tablets conformed to the B.P. specifications for enteric coated tablets.
  • Eudragit * is available from Rohm.
  • the Aspirin tablets -formulated as described in Examples 7 to 9 may be placed in a number 1 size capsule with the isosorbide mononitrate tablets described in Examples 1 to 6 as an alternative to a plug of coated Aspirin.
  • Example 5 As for Example 5 except Eudragit NE30D was used for granulation instead of Kollidon 30. A typical in vitro dissolution profile (using the same conditions as in other Examples) is shown in Fig. 7.
  • the particular advantage of Eudragit NE30D is that it also functions partially as a control release agent.
  • the slow release agent is preferably cellulose-based and the weight ratio of ISMN to the agent is from 30:70 to 80:20, preferably 1:2 to 7:3 and, ideally, approximately 3:2. This opens up the possibility of an ISMN tablet with a much smaller relative size than has heretofore been possible.
  • the tablet is much easier to take, and most importantly, can be fitted into a number 1 size capsule either alone, or, preferably in combination with a second active, especially aspirin, to provide a combined therapy in a single dose.
  • a single dose is not only easier for a patient to take but has cons-iderable advantages for patient compliance.
  • ISMN had to be granulated to obtain suitable flow properties; the crystal structure of the compound prevented uniform and consistent flow, for example, into a die of a tablet press. Unusually, for satisfactory granulation to occur, large proportions of granulating liquid were required. Typically these were 15-50% w/w based upon the weight of ISMN used; 30-40% w/w granulating liquid was particularly preferred. These amounts correspond to a weight ratio of ISMN to water in the solution of granulating aid in the range of 6:1 to 1:1, preferably 2.4:1 to 1.5:1. Particle size analyses (sieve method) indicated that the amount of liquid, used for granulation, had a critical effect on particle size distribution.
  • controlled release tablet of the invention may be used alone. It is not essential that it is placed in a capsule either alone or with another active ingredient. Any suitable active ingredient or ingredients with or without Aspirin may be used in the capsule.

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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)
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Abstract

La présente invention concerne une composition de comprimé à libération contrôlée de mononitrate d'isosorbide (ISMN) obtenue par granulation de l'ISMN avec une solution de polyvinylpyrollidone. Le rapport massique ISMN/eau dans la solution d'agent de granulation varie entre 6/1 et 1/1, et se situe de préférence autour de 2/1. Les granules secs sont mélangés à un agent de libération contrôlée à base de cellulose, le rapport massique ISMN / agent de libération contrôlée variant entre 30/70 et 20/80, et se situant de préférence autour de 3/2. Le comprimé est découpé à l'emporte-pièce de 5 mm de façon entrer dans une capsule numéro un qui peut également contenir un second élément actif tel qu'un comprimé d'aspirine enrobée.
PCT/IE1997/000055 1996-08-02 1997-07-31 Composition de comprime a liberation controlee d'isosorbide-5-mononitrate WO1998005306A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38613/97A AU3861397A (en) 1996-08-02 1997-07-31 Controlled release tablet formulation of isosorbide-5-mononitrate

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IE960559 1996-08-02
IE960559 1996-08-02
IE960621 1996-09-04
IE960621 1996-09-04
IE970053 1997-01-28
IE970053 1997-01-28

Publications (1)

Publication Number Publication Date
WO1998005306A1 true WO1998005306A1 (fr) 1998-02-12

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1088554A1 (fr) * 1999-09-30 2001-04-04 Libbs Farmaceutica LTDA Association à libération prolongée contenant du mononitrate d'isosorbide et de l'acide acétylsalicylique
JP2001354560A (ja) * 2000-06-07 2001-12-25 Toa Eiyo Ltd イソソルビド‐５‐モノニトレートを有効成分とする徐放性錠剤及びその製造方法
CN100366247C (zh) * 2004-04-07 2008-02-06 鲁南制药集团股份有限公司 单硝酸异山梨酯缓释片
CN103285017A (zh) * 2013-05-22 2013-09-11 刘光权 复方单硝酸异山梨酯阿司匹林缓释胶囊制剂及制备方法
CN104644589A (zh) * 2015-03-12 2015-05-27 王菊明 一种单硝酸异山梨酯缓释片及其制备工艺
CN105902509A (zh) * 2015-09-28 2016-08-31 天方药业有限公司 一种复方单硝酸异山梨酯缓释片及其制备方法
CN109316467A (zh) * 2018-01-31 2019-02-12 合肥合源药业有限公司 单硝酸异山梨酯缓释胶囊及其制备方法
WO2020258472A1 (fr) * 2019-06-24 2020-12-30 深圳翰宇药业股份有限公司 Comprimé à libération prolongée de mononitrate d'isosorbide et son procédé de préparation
CN115487162A (zh) * 2022-10-13 2022-12-20 山东力诺制药有限公司 一种单硝酸异山梨酯缓释片的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219161A2 (fr) * 1985-10-15 1987-04-22 EURAND ITALIA S.p.A. Procédé de préparation de comprimés d'isosorbide-5-mononitrate à effet retardé et leurs formulations ainsi obtenues
WO1994003421A2 (fr) * 1992-07-30 1994-02-17 Cal International Limited Esters et combinaisons d'un nitrate organique et d'un salicylate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219161A2 (fr) * 1985-10-15 1987-04-22 EURAND ITALIA S.p.A. Procédé de préparation de comprimés d'isosorbide-5-mononitrate à effet retardé et leurs formulations ainsi obtenues
WO1994003421A2 (fr) * 1992-07-30 1994-02-17 Cal International Limited Esters et combinaisons d'un nitrate organique et d'un salicylate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
STN International, File CAPLUS, CAPLUS accession no. 1986:75031, Toa Eiyo Co., Ltd. "Stable isosor- bide nitrate pharmacutical for treatment of angina pectoris"; & JP,A2,60181052, 850914 *
STN International, File CAPLUS, CAPLUS accession no. 1994:173223, Yang, Penghui et al: "Isosorbide 5-mononitrate controlled-release tablets"; & Zhongguo Yaoke Daxue Xuebao (1993), 24(6), 327-30 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1088554A1 (fr) * 1999-09-30 2001-04-04 Libbs Farmaceutica LTDA Association à libération prolongée contenant du mononitrate d'isosorbide et de l'acide acétylsalicylique
JP2001354560A (ja) * 2000-06-07 2001-12-25 Toa Eiyo Ltd イソソルビド‐５‐モノニトレートを有効成分とする徐放性錠剤及びその製造方法
JP4696210B2 (ja) * 2000-06-07 2011-06-08 トーアエイヨー株式会社 イソソルビド‐５‐モノニトレートを有効成分とする徐放性錠剤及びその製造方法
CN100366247C (zh) * 2004-04-07 2008-02-06 鲁南制药集团股份有限公司 单硝酸异山梨酯缓释片
CN103285017A (zh) * 2013-05-22 2013-09-11 刘光权 复方单硝酸异山梨酯阿司匹林缓释胶囊制剂及制备方法
CN104644589A (zh) * 2015-03-12 2015-05-27 王菊明 一种单硝酸异山梨酯缓释片及其制备工艺
CN105902509A (zh) * 2015-09-28 2016-08-31 天方药业有限公司 一种复方单硝酸异山梨酯缓释片及其制备方法
CN109316467A (zh) * 2018-01-31 2019-02-12 合肥合源药业有限公司 单硝酸异山梨酯缓释胶囊及其制备方法
WO2020258472A1 (fr) * 2019-06-24 2020-12-30 深圳翰宇药业股份有限公司 Comprimé à libération prolongée de mononitrate d'isosorbide et son procédé de préparation
CN115487162A (zh) * 2022-10-13 2022-12-20 山东力诺制药有限公司 一种单硝酸异山梨酯缓释片的制备方法
CN115487162B (zh) * 2022-10-13 2023-10-13 山东力诺制药有限公司 一种单硝酸异山梨酯缓释片的制备方法

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