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WO2007058397A1 - Comprime dispersible comportant le melange d'amoxicilline et d'acide clavulanique ou ses sels et son procede de preparation - Google Patents

Comprime dispersible comportant le melange d'amoxicilline et d'acide clavulanique ou ses sels et son procede de preparation Download PDF

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Publication number
WO2007058397A1
WO2007058397A1 PCT/KR2005/003891 KR2005003891W WO2007058397A1 WO 2007058397 A1 WO2007058397 A1 WO 2007058397A1 KR 2005003891 W KR2005003891 W KR 2005003891W WO 2007058397 A1 WO2007058397 A1 WO 2007058397A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
granulate
amoxicillin
clavulanic acid
total
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2005/003891
Other languages
English (en)
Inventor
Woo Heon Song
Jun Sang Park
Hun Sik Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GL Pharmtech Corp
Original Assignee
GL Pharmtech Corp
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 GL Pharmtech Corp filed Critical GL Pharmtech Corp
Priority to PCT/KR2005/003891 priority Critical patent/WO2007058397A1/fr
Publication of WO2007058397A1 publication Critical patent/WO2007058397A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems

Definitions

  • This invention relates to an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts, and processes for preparing the same.
  • Amoxicillin is a typical beta-lactam antibiotic with a broad spectrum of antibacterial activity.
  • Clavulanic acid is a beta- lactamase inhibitor to counter a beta- lactamase mediated resistance mechanism.
  • the combination of amoxicillin and clavulanic acid is an effective treatment for bacterial infections and may be administered by oral dosage forms, for instance, film-coated tablets and a dry syrup for especially pediatric patients.
  • a dispersible tablet may overcome these drawbacks.
  • the dispersible tablet is designed to be disintegrated and dispersed rapidly when immersed in a small amount of water for reconstitution into such suspensions.
  • one tablet contains one-time dose of active ingredients, patients are allowed to take an accurate amount of drug and are also easy to swallow due to easier dispersion in water.
  • the use of dispersible tablet is quite useful to prevent reduced contents of clavulanic acid and its discoloration during long-term storage, as one-time dosage is dispersed in a small of water prior to administration.
  • dispersible tablets should be disintegrated within 3 minutes when immersed in water of 15-25 0 C, and dispersed particle sizes should be in the range of less than 710 D.
  • the Korean Patent Publication No. 1996-9182 describes an amphoteric beta-lactam antibiotic as a dispersible tablet which has been prepared by wet granulation process, using an amorphous or fine cellulose as an intragranular disintegrant and low- substituted hydroxypropyl cellulose as an extragranular disintegrant.
  • hydrophobic lubricants should be essentially contained in the granulate but these excipients appear to slow down the disintegration of granulate and/or tablet.
  • Diluents or binders should be necessary to compact the powder mixture for granulate and a certain amount of hydrophobic lubricants should be contain to prevent adherence of the granulated powder to metal machinery parts in a roller compactor.
  • the disintegration time of the dispersible tablet may significantly vary depending on the types and amounts of diluents, binders and lubricants.
  • the Korean Patent No. 228450 discloses a dispersible tablet formulation containing a beta-lactam antibiotic and clavulanic acid or its salts.
  • the tablet formulation comprise granulate which is prepared by roller compaction and contain intragranular disintegrants such as N-vinyl-2-pyrrolidone, corn starch, rice starch, croscarmellose sodium, formaldehyde casein or mixture thereof.
  • the object of this invention is to provide an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts and its manufacturing method that may solve the adherence of the granulated ingredients to metal machinery parts during the dry granulation process.
  • Another object of this invention is to provide an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts, wherein the dispersible tablet prepared by the dry granulation process using roller compaction is rapidly disintegrated, when immersed in water.
  • This invention is to provide an oral dispersible tablet using formulations comprising amoxicillin and clavulanic acid or its salts thereof with intragranular and extragranular ingredients whose preparation is available by a dry granulation process using roller compaction and tabletting, characterized in that:
  • intragranular ingredients include a lubricant and a microcrystalline cellulose in the amounts of 0.5-1.5 weight% and 5-15 weight%, respectively, based on the total granulate weight, and
  • extragranular ingredients include 20-40 weight% of microcrystalline cellulose based on the total tablet weight.
  • composition of dispersible tablet of this invention containing amoxicillin and clavulanic acid comprise following two steps; a dry granulation and tabletting.
  • the granulate of this invention is produced by roller compaction.
  • the dispersible tablet of this invention using microcrystalline cellulose as a diluent does not slow down the disintegration, unlike other pharmaceutical acceptable diluents such as D-mannitol or lactose.
  • the physical properties of dry granulate and disintegration of the dispersible tablet may significantly vary depending on the Intragranular and extragranular ratio of microcrystalline cellulose.
  • the use of the intragranular micro- crystalline cellulose in the amount of more than 5 weight% based on the total granulate weight may lead to favorable compaction of granulated powder during the dry granulation process without adherence of the granulated powder to metal machinery parts in a roller compactor.
  • the use of the intragranular microcrystalline cellulose in the amount of less than 15 weight% based on the total weight of the granulate and of the extragranular microcrystalline cellulose in the amount of more than 20 weight% based on the total tablet weight may lead to obtainment of a suitable dispersible tablet, thus ensuring the optimal disintegration and proper hardness to prevent the physical damage of tablet during storage.
  • the dispersible tablet of this invention may minimize the amount of the extragranular disintegrant which accelerate the discomposition of clavulanic acid due to its severe hygroscopicity.
  • the intragranular disintegrant of this invention is selected from a group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, polacrilin potassium and mixture thereof; such disintegrant is present in the amount of 2-5 weight% based on the total granulate weight.
  • the intragranular lubricant of this invention is selected from a group consisting of stearic acid or its salts, talc, colloidal silicon dioxide, magnesium silicate, glyceryl behenate, sodium stearyl fumarate and mixture thereof; such lubricant is present in the amount of 0.5-2 weight% based on the total granulate weight.
  • the granular composition may also include a pharmaceutically acceptable, a moisture scavenger (e.g. silicon dioxide), a sweetener (e.g. acesulfam potassium) and a pigment (e.g. iron oxide).
  • a moisture scavenger e.g. silicon dioxide
  • a sweetener e.g. acesulfam potassium
  • a pigment e.g. iron oxide
  • the particle size of the granulate of this invention is preferably in the range of 75D to
  • the granulate has a particle size of 710D or less, when immersed in water and is present in the amount of 60-80 weight% base on the total tablet weight.
  • an oral dispersible tablet is prepared using the granulate, a microcrystalline cellulose as a extragranular dilent in the amount of 20-40 weight% based on the total tablet weight, a disintegrant and a lubricant.
  • the amount of extragranular microcrystalline cellulose should not exceed 40 weight% based on the total table weight, since the total granulate weight is in the amount of 60-80 weight% based on the total tablet weight.
  • the appropriate extragranular disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, sodium lauryl sulfate and mixture thereof; such disintegrant is present in the amount 3-10 weight% based on the total tablet weight.
  • the appropriate extragranular lubricant is selected from the group consisting of stearic acid or its salts, talc, colloidal silicon dioxide, magnesium silicate, glyceryl behenate, sodium stearyl fumarate, poloxamer and mixture thereof; such lubricant is present in the amount of 0.5-1.5 weight% based on the total tablet weight.
  • the oral dispersible tablet of this invention may encompass a pharmaceutically acceptable flavor and pigment.
  • the oral dispersible tablet of this invention has hardness of more than 3 kp with friability of less than 0.5%.
  • the dispersible tablet of this invention is completely disintegrated within 1 minute, when immersed in water of 15-25 0 C and easily dispersed to form suspensions.
  • Another embodiment of this invention is to provide a method for preparing an oral dispersible tablet comprising the following steps of:
  • the dry granulation process is conducted by roller compaction (e.g. roller compactor, Freund Co.).
  • roller compaction e.g. roller compactor, Freund Co.
  • the granulated powder is compressed to mold sheets under the following conditions: roller speed (2-10 rpm), screw speed (5-20 rpm) and pressure (5-10 MPa).
  • the sheets are passed through #14 to #20 sieves to obtain an appropriate size of granulate.
  • the granulate, so obtained, is further mixed with a disintegrant, a lubricant and microcrystalline cellulose in the amount of more than 20 weight% based on the total tablet weight and tabletted using a tabletting machine (e.g. rotary tableting machine, ERWEKA Co.) that is widely used in the pharmaceutical industry.
  • a tabletting machine e.g. rotary tableting machine, ERWEKA Co.
  • the oral dispersible tablet of this invention containing amoxicillin and clavulanic acid is advantageous in that (1) the large-scale production is possible as the dispersible tablet is endowed with more compressibility without adherence of the granulated powder to metal machinery parts in a roller compactor, and (2) the dispersible tablet of this invention is rapidly disintegrated and easily dispersed, when immersed in water, to form suspensions.
  • Fig. 1 shows the results of disintegration test according to different contents of in- tragranular microcrystalline cellulose.
  • Fig. 2 shows the results of disintegration test according to different contents of ex- tragranular microcrystalline cellulose.
  • a dispersible tablet were prepared using amoxicillin and clavulanate potassium (4:1), intragranular micro- crystalline cellulose in the amount of 5-15 weight% based on the total granulate weight and extragranular microcrystalline cellulose in the amount of 20-40 weight% based on the total tablet weight.
  • Microcrystalline cellulose and crospovidone was added to the granulate, followed by the addition of mixture of powdered flavor and iron oxide (passed through #100 sieve) and then the mixture was mixed with colloidal silicon dioxide and magnesium stearate (passed through #30 sieve) and tabletted using an automatic tabletting machine (Erweka Co.) to prepare a dispersible tablet.
  • a dispersible tablet was prepared using the in- tragranular microcrystalline cellulose in the amount of 5-15 weight% based on the total granulate weight and extragranular microcrystalline cellulose in the amount of 20-40 weight% based on the total tablet weight.
  • Comparative examples 1-4 In the same manner as Examples 1-3, a dispersible tablet containing amoxicillin and clavulanate potassium (4:1) was prepared under the following contents as shown in Table 3, except that Comparative examples 1-2 employed D-mannitol or lactose instead of microcrystalline cellulose as a diluent, while Comparative examples 3-4 employed copovidone or hydroxypropylmethyl cellulose 2910 as a binder instead of intragranular microcrystalline cellulose,

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

Abstract

La présente invention a trait à un comprimé dispersible oral comportant de l'amoxicilline et de l'acide clavulanique ou ses sels et son procédé de préparation, caractérisé par les deux étapes suivantes: (A) la préparation d'un granulé sec par un procédé de compactage par rouleau, dans lequel des ingrédients intragranulaires comportent un mélange d'amoxicilline et d'acide clavulanique ou ses sels en tant que principes actifs, un délitant et un lubrifiant en une quantité comprise entre 0,5 et 1,5 % en poids par rapport au poids total du granulé et de la cellulose microcristalline en une quantité comprise entre 5 et 15 % en poids par rapport au poids total du granulé, et (B) la transformation en comprimés du granulé sec, ainsi obtenu de l'étape (A), avec les ingrédients extra-granulaires comprenant un délitant, un lubrifiant et de la cellulose microcristalline en une quantité comprise entre 20 et 40 % en poids par rapport au poids total de comprimé.
PCT/KR2005/003891 2005-11-17 2005-11-17 Comprime dispersible comportant le melange d'amoxicilline et d'acide clavulanique ou ses sels et son procede de preparation Ceased WO2007058397A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2005/003891 WO2007058397A1 (fr) 2005-11-17 2005-11-17 Comprime dispersible comportant le melange d'amoxicilline et d'acide clavulanique ou ses sels et son procede de preparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2005/003891 WO2007058397A1 (fr) 2005-11-17 2005-11-17 Comprime dispersible comportant le melange d'amoxicilline et d'acide clavulanique ou ses sels et son procede de preparation

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WO2007058397A1 true WO2007058397A1 (fr) 2007-05-24

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PCT/KR2005/003891 Ceased WO2007058397A1 (fr) 2005-11-17 2005-11-17 Comprime dispersible comportant le melange d'amoxicilline et d'acide clavulanique ou ses sels et son procede de preparation

Country Status (1)

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WO (1) WO2007058397A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012060785A1 (fr) * 2010-11-05 2012-05-10 Mahmut Bilgic Procédé de production de formulations comprenant de la céphalosporine
WO2012060793A3 (fr) * 2010-11-05 2012-06-28 Mahmut Bilgic Procédé de préparation de formulations de cefdinir
CN103768056A (zh) * 2014-01-21 2014-05-07 东药集团沈阳施德药业有限公司 一种阿莫西林克拉维酸钾分散片
CN104188963A (zh) * 2014-07-30 2014-12-10 上海新亚药业闵行有限公司 阿莫西林克拉维酸钾片剂及其制备方法
WO2015132252A1 (fr) * 2014-03-03 2015-09-11 Sandoz Ag Forme galénique à dissolution rapide stable comprenant de l'amoxicilline et de l'acide clavulanique
US9549941B2 (en) 2011-11-29 2017-01-24 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
CN113304112A (zh) * 2021-05-26 2021-08-27 浙江耐司康药业有限公司 阿莫西林可溶性粉及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019227A2 (fr) * 1991-05-08 1992-11-12 Laboratorios Beecham Sa Preparations pharmaceutiques
WO2004000281A1 (fr) * 2002-06-21 2003-12-31 Lek Pharmaceuticals D.D. Comprimes a desagregation rapide
WO2004006917A1 (fr) * 2002-07-16 2004-01-22 Ranbaxy Laboratories Limited Comprimes dispersibles pour administration par voie orale
KR20050002738A (ko) * 2004-05-31 2005-01-10 삼아약품 주식회사 β-락탐계 항생제 현탁정 및 그의 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992019227A2 (fr) * 1991-05-08 1992-11-12 Laboratorios Beecham Sa Preparations pharmaceutiques
WO2004000281A1 (fr) * 2002-06-21 2003-12-31 Lek Pharmaceuticals D.D. Comprimes a desagregation rapide
WO2004006917A1 (fr) * 2002-07-16 2004-01-22 Ranbaxy Laboratories Limited Comprimes dispersibles pour administration par voie orale
KR20050002738A (ko) * 2004-05-31 2005-01-10 삼아약품 주식회사 β-락탐계 항생제 현탁정 및 그의 제조방법

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012060785A1 (fr) * 2010-11-05 2012-05-10 Mahmut Bilgic Procédé de production de formulations comprenant de la céphalosporine
WO2012060793A3 (fr) * 2010-11-05 2012-06-28 Mahmut Bilgic Procédé de préparation de formulations de cefdinir
WO2012060789A3 (fr) * 2010-11-05 2012-06-28 Mahmut Bilgic Procédé de production de formulations de cefdinir
US9549941B2 (en) 2011-11-29 2017-01-24 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
CN103768056A (zh) * 2014-01-21 2014-05-07 东药集团沈阳施德药业有限公司 一种阿莫西林克拉维酸钾分散片
CN103768056B (zh) * 2014-01-21 2015-01-07 东药集团沈阳施德药业有限公司 一种阿莫西林克拉维酸钾分散片
WO2015132252A1 (fr) * 2014-03-03 2015-09-11 Sandoz Ag Forme galénique à dissolution rapide stable comprenant de l'amoxicilline et de l'acide clavulanique
CN104188963A (zh) * 2014-07-30 2014-12-10 上海新亚药业闵行有限公司 阿莫西林克拉维酸钾片剂及其制备方法
CN113304112A (zh) * 2021-05-26 2021-08-27 浙江耐司康药业有限公司 阿莫西林可溶性粉及其制备方法
CN113304112B (zh) * 2021-05-26 2022-09-30 浙江耐司康药业有限公司 阿莫西林可溶性粉及其制备方法

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