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WO2005099672A1 - Formulation pharmaceutique a liberation modifiee contenant de l'amoxicilline et du clavulanate - Google Patents

Formulation pharmaceutique a liberation modifiee contenant de l'amoxicilline et du clavulanate Download PDF

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Publication number
WO2005099672A1
WO2005099672A1 PCT/IB2005/000975 IB2005000975W WO2005099672A1 WO 2005099672 A1 WO2005099672 A1 WO 2005099672A1 IB 2005000975 W IB2005000975 W IB 2005000975W WO 2005099672 A1 WO2005099672 A1 WO 2005099672A1
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WIPO (PCT)
Prior art keywords
amoxicillin
pharmaceutical formulation
release
modified release
phase
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
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PCT/IB2005/000975
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English (en)
Inventor
Anurag Sood
Paramjit Singh
Girish Kumar Jain
Ashok Rampal
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of WO2005099672A1 publication Critical patent/WO2005099672A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to a modified release formulation comprising amoxicillin and clavulanate and processes for the preparation thereof. Also provided is a method of treating bacterial infections using these formulations.
  • Background of the Invention The current pharmaceutical formulations approved for marketing in the U.S. which include amoxicillin and clavulanate are in the form of immediate release and modified release formulations. These formulations contain various weight ratios of amoxicillin and potassium clavulanate (“clavulanate”) ranging from 2: 1 to 16: 1.
  • conventional tablets include 250/125, 500/125, 500/62.5, and 875/125 mg of amoxycillin/clavulanic acid (in the form of potassium clavulanate).
  • Such tablets comprise amoxicillin and clavulanic acid in the ratio 2:1, 4:1, 8:1 and 7:1, respectively.
  • the 875/125 mg tablet was developed to provide a tablet formulation, which could be administered in a bid (twice daily) dosage regimen. It is also marketed for tid (three times daily) dosing in Italy and Spain.
  • the 500/62.5 mg tablet was developed to provide a tablet forrrmlation that could be administered in a bid dosage regimen, two such tablets being taken every 12 hours, which is preferable to a single 1000/125 mg tablet.
  • a 1000/125 mg single dosage is also available, in France, but as a single dosage sachet rather than a tablet.
  • the approved regimen provides for a single dosage of 125 mg of potassium clavulanate.
  • U.S. Patent No. 6,372,255 describes a multi-layer tablet for the instant and prolonged release of active substances.
  • the tablet includes at least two layers where the first outer layer comprises a mixture of excipients and an active substance, allowing for the immediate release of the active substance within the first layer.
  • a second layer is arranged in contact with the first layer.
  • the second layer includes a nonbiodegradable inert porous polymeric matrix in which an active substance is dispersed, allowing for the prolonged release of the active substance within the second layer.
  • U.S. Patent No. 6,294,200 discloses a pharmaceutical tablet capable of delivering the active substance or the active substances according to a predetexn ined release profile.
  • the tablet comprises a core with an external partial coating in which said core consists of 3 layers.
  • the upper layer contains an amount of the active substance with suitable excipients.
  • the intermediate layer consists of a polymeric material with a retarding barrier function and the lower layer contains the remaining amount of the active substance with suitable excipients.
  • the external coating consists of controlled permeability polymeric materials applied by compression to the lower surface and to the lateral surface of the core.
  • WO95/20946 discloses layered tablets comprising amoxicillin and, optionally, potassium clavulanate, having a first layer, which is an immediate release layer and a second layer, which is a slow release layer.
  • the ratio of amoxicillin to clavulanic acid disclosed therein ranges from 30: 1 to 1 : 1 , with a preferred range o 8 : 1 to 1 : 1.
  • the formulations disclosed therein have a pharmacokinetic profile such as there is no early burst of amoxicillin, but a much more protracted release over a period of time as reflected by a lower C max value, is obtained.
  • U.S. Patent No. 6,136,345 discloses a tablet formulation for oral administration comprising amoxicillin and clavulanate in aratio of 30:1 to 1:1 in which a portion of the amoxicillin is in a central core which is surrounded by a release-ret;arding coating layer.
  • U.S. Patent No. 5,910,322 discloses a pharmaceutical tablet formulation, comprising a matrix which includes a beta-lactam antibiotic and a beta-lactamase inhibitor.
  • the matrix includes granules in a delayed-release form which comprise a beta- lactam antibiotic and a beta-lactamase inhibitor.
  • EP1044680 discloses a modified release pharmaceutical formulation comprising amoxicillin and potassium clavulanate in a ratio from 14:1 to 20:1 in which all of the potassium clavulanate and a first part of amoxicillin are formulated with pharmaceutically acceptable excipients which allow for immediate release of the potassium clavulanate and the first part of amoxicillin. A second part of amoxicillin is formulated with pharmaceutically acceptable excipients which allow for the slow release of the secon-d part of amoxicillin.
  • the ratio of amoxicillin in the immediate and slow release phases is -from 3:1 to 1:3.
  • the patent discloses that it is very critical to select a ratio of amoxicillin in the immediate and slow release phase from 3:1 to 1:3 for achieving the desired pharmacokinetic profile.
  • the teachings of the patent suggest that the formulations containing a ratio of amoxicillin in the immediate and slow release phase lower than 1 :3 do not show the desired pharmacokinetic parameters, particularly the C max .
  • the modified release formulations of the present invention may comprise amoxicillin and clavulanate in a weight ratio of 14:1 to 20:1.
  • Summary of the Invention in one general aspect there is provided a modified release pharmaceutical formulation which includes an immediate release phase comprising amoxicillin, clavulanate and one or more disintegrants and a slow release phase comprising amoxicillin and one or more release retarding agents.
  • the pharmaceutical formulation has a ratio of amoxicillin in the immediate release phase and the slow release phase that is less than about 1:3.
  • Embodiments of the pharmaceutical formulation may include one or more of fhes following features.
  • the modified release pharmaceutical formulation may have a ratio of amoxicillin and clavulanate that is 14: 1 to 20: 1 or it may be 16: 1.
  • the one or more disintegrants may be one or more of croscarmellose sodium, so dium starch glycolate, crospovidone, sodium carboxymethyl cellulose and microcrystalliixe cellulose.
  • the one or more release retarding agents may be one or more of gums, hydrophobic polymers and hydrophihc polymers.
  • the gums may be one or more of xanthan gum, guar gum, agar, carrageenan, tragacanth and acacia.
  • the hydrophobic polymers may be one or more of cellulose derivatives, shellac and zein.
  • the hydrophihc polymers may be one or more of cellulose derivatives, polyvinylalcohol, polyvinylpyrrolidone, polyethylene oxide and alginic acid or salts thereof.
  • the hydrophihc polymers may be one or more cellulose derivatives.
  • the one or more cellulose derivatives may be one or more of carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and ethylcellulose.
  • the cellulose derivative may be ethylcellulose.
  • the immediate release layer and slow release layer may also include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may be one or more of diluents, binders, lubricants, glidants and coloring agents.
  • the diluents maybe one or more of microcrystalline cellulose, lactose, mannitol and calcium phosphate.
  • the binders may be one or more of polyvinylpyrrolidone, pregelatinised starch, gelatin and hydroxypropyl cellulose.
  • the lubricants may be one or more of talc, magnesium stearate and zinc stearate.
  • the immediate release phase may include two different sets of granules, wherein one set includes amoxicillin and the other set includes clavulanate.
  • the modified release pharmaceutical formulation may be in the form of bilayered tablet, trilayered tablet, capsule or sachet. In another general aspect there is provided a modified release pharmaceutical formulation which includes an immediate release phase and a slow release phase.
  • the immediate release phase includes clavulanate as the only active ingredient and one or more disintegrants.
  • the slow release phase includes amoxicillin as the only active ingredient and one or more release retarding agents.
  • Embodiments of the pharmaceutical formulation may include any one of the following features. For example, ratio of amoxicillin and clavulanate maybe 14:1 to 20:1 or it may be 16:1.
  • the modified release phannaceutical formulation may be in the form of a bilayered tablet, trilayered tablet, capsule or sachet.
  • the immediate release phase and slow release phase further include one or more pharmaceutically acceptable excipients.
  • a method of treating bacterial infections which includes administering to a patient in need thereof a modified release pharmaceutical formulation.
  • the pharmaceutical composition includes an immediate release phase which includes amoxicillin, clavulanate and one or more disintegrants.
  • the pharmaceutical formulation also includes a slow release phase which includes amoxicillin and one or more release retarding agents.
  • the phannaceutical formulation has a ratio of amoxicillin in the immediate release phase and the slow release phase that is less than about 1:3.
  • a method of treating bacterial infections which include administering to a patient in need thereof a modified release pharmaceutical formulation.
  • the pharmaceutical formulation includes an immediate release phase and a slow release phase.
  • the immediate release phase includes clavulanate as the only active ingredient and one or more disintegrants.
  • the slow release phase includes amoxicillin as the only active ingredient and one or more release retarding agents.
  • the modified release formulations of the present invention include amoxicillin and clavulanate in a weight ratio of about 14:1 to about 20:1, preferably about 16:1.
  • the amoxicillin in the immediate release phase and the slow release phase is present at a ratio of less than about 1:3.
  • amoxicillin refers to amoxicillin, its alkali, alkaline, or acid salts, hydrates, solvates and mixtures thereof.
  • amoxicillin trihydrate and sodium amoxicillin (crystallized) may be used without distinction unless otherwise indicated.
  • the amoxicillin may be crystalline or amorphous.
  • the weights of amoxicillin and potassium clavulanate refer to the equivalent weights of the corresponding free acids
  • the weights of amoxicillin and clavulanate to be incorporated into a formulation will be further adjusted in accordance with conventional practice to take account of the potency of the amoxicillin and clavulanate.
  • immediate release refers to the release of the majority of the active material content within a relatively short time. For example, the release is within 1 hour, preferably within 30 minutes, after oral ingestion. Examples of such immediate release formulations include conventional swallow tablets, dispersible tablets, chewable tablets, single dose sachets and capsules, and effervescent forms thereof.
  • modified release refers to the release of a drug substance from a pharmaceutical formulation, which is at a slower rate than from an immediate release formulation.
  • the modified release formulation includes both an immediate release phase and a slow release phase.
  • Modified release formulations are well known in the art. See Remington: The Science and Practice of Pharmacy, Nineteenth Edn, 1995, Mack Publishing Co, Pennsylvania, USA.
  • the modified release formulations may be in the form of tablets, capsules, granules, sachets and any other suitable oral dosage form.
  • the modified release formulation of the present invention can be a single dosage comprising a slow release phase and an immediate release phase or may be a combination of the slow release phase and the immediate release phase given separately.
  • the single dosage form may be a single tablet comprising 1000 mg amoxicillin and 62.5 mg of clavulanic acid.
  • the dosage for may be made up of a number of smaller tablets, for example, minitablets filled into capsules.
  • a dosage form which includes 1000 mg of amoxicillin and 62.5 mg of clavulanic acid may be provided by combining one tablet of 800 mg amoxicillin and another tablet of 200 mg amoxicillin and 62.5 mg clavulanic acid.
  • the tablet dosage form may be bilayered, trilayered or multilayered, preferably bilayered. These layered tablets may contain barrier layers with or without the active ingredient.
  • the modified release formulation may contain the immediate and slow release phase together in one tablet or in the form of different tablets containing the immediate and slow release phases.
  • the ratio of amoxicillin in the immediate release phase and slow release phase is less than about 1:3.
  • the modified release phannaceutical formulations disclosed herein comprise two phases, an immediate release phase and slow release phase.
  • the immediate release phase comprises amoxicillin and potassium clavulanate and the slow release phase comprises amoxicillin alone.
  • the slow release phase may contain sodium amoxicillin, amoxicillin trihydrate and mixtures thereof.
  • the immediate release phase and the slow release phases may be incorporated in one layer or different layers of the tablet.
  • the immediate release phase may include one or more pharmaceutically acceptable excipients.
  • the one or more pharmaceutically acceptable excipits may include one or more fillers, one or more disintegrants, one or more binders, one or more pH modifiers and one or more lubricant/glidants.
  • the immediate release phase may be in the form of granules, a powder and mixtures thereof. The granules, powder or mixtures thereof may be filled into capsules or compressed to one or more layers of the tablet.
  • the slow release phase may include one or more may include one or more pharmaceutically acceptable excipients.
  • the one or more pharmaceutically acceptable excipients may include one or more release retarding agents, one or more fillers, one or more disintegrants, one or more binders, one or more pH modifiers and one or more lubricant/glidants.
  • the slow release phase may be in the form of granules, powders and mixtures thereof.
  • the granules, powders and mixtures thereof may be filled into capsules or compressed to one or more layers of the tablet.
  • Suitable release retarding agents include one or more of gums, hydrophobic polymers and hydrophihc polymers.
  • the gum may be xanthan gum, guar gum, agar, carrageenan, tragacanth, acacia and mixtures thereof.
  • the hydrophobic polymers may be cellulose derivatives, such as ethylcellulose, shellac, zein and mixtures thereof.
  • the hydrophihc polymer may be cellulose derivatives, polyvinylalcohol, polyvinylpyrrolidone- polyethylene oxide (PEO-WSR-301), alginic acid and salts thereof (Keltone LNCR).
  • the cellulose derivatives may be hydrophihc polymers, such as carboxymethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose (Methocel K4MCR, Methocel E5).
  • the release retarding agent may be present at a concentration range from about 0.2% to about 50% w/w based on the weight of the slow release phase.
  • Suitable disintegrants include one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, pregelatinised starch, microcrystalline cellulose, and any other suitable disintegrant.
  • the disintegrant may be present at a concentration range of from about 0.5% to about 10% w/w based on the weight of the immediate release phase.
  • Suitable diluents include one or more of microcrystalline cellulose, lactose, mannitol and calcium phosphate.
  • Suitable binders may include one or more of polyvinylpyrrolidone, pregelatinised starch, methacrylic acid polymers (Eudragit E 100), gelatin, hydroxypropyl cellulose and mixtures thereof.
  • Suitable pH modifiers include one or more of citric acid, succinic acid and any other suitable buffers.
  • Suitable lubricants/glidants include one or more of talc, colloidal silicon dioxide, magnesium stearate, zinc stearate and mixtures thereof.
  • the modified release formulation may be prepared by one or more of wet granulation, dry granulation and direct compression process.
  • the preparation of layered tablets may involve preparing immediate release and slow release granules. Such slow and immediate release granules may then be formulated into immediate or slow release phases. In case ofa trilayer tablet there may be two immediate release phases and third slow release phase, which includes the same and/or a different active ingredient.
  • the slow release phase includes slow release granules of amoxicillin and the immediate release phase includes immediate release granule of amoxicillin and/or potassium clavulanate.
  • the immediate release phase includes immediate release granule of amoxicillin and/or potassium clavulanate.
  • a non-functional coating layer may cover the modified release formulation.
  • the coating layer may include one or more polymers, such as hydroxypropyl cellulose, hydroxy ethylcellulose and hydroxypropyl methylcellulose; one or more plasticizers such as polyethylene glycol, triacetin, dibutyl sebecate and diethyl tartrate; one or more opacifying agents such as titanium dioxide and talc; and one or more coloring agents.
  • the modified release formulation may be in the fonn of a bilayer tablet which includes 1000 mg ⁇ 5% of amoxicillin and 62.5 mg ⁇ 5% of clavulanic acid in a weight ratio of 16:1.
  • the tablets includes a slow release phase and an immediate release phase wherein the ratio of amoxicillin in the immediate release phase and slow release phase is less than about 1:3.
  • the bilayer tablet may include the following: a) a first layer which includes the immediate release phase comprising amoxicillin, potassium clavulanate and one or more disintegrants present at a concentration of about 0.5% to about 10% w/w based on the weight of the immediate release phase; and, b) a second layer which includes the slow release phase comprising amoxicillin and oen or more release retarding agents present at a concentration of about 0.2%) to about 50% w/w based on the weight of the slow release phase.
  • the modified release formulation may be in the form of trilayered tablet which includes 1000 mg ⁇ 5% of amoxicillin and 62.5 mg ⁇ 5% of clavulanic acid in a weight ratio of 16: 1.
  • the trilayered tablet includes a slow release phase and an immediate release phase, wherein the ratio of amoxicillin in the immediate release phase and the slow release phase is less than about 1 :3.
  • the trilayered tablet may include the following: a) a first layer comprises the immediate release phase comprising amoxicillin and one or more disintegrants present at a concentration of about 0.5% to about 10 % w/w based on the weight of the immediate release phase; b) a second layer which includes the immediate release phase comprising potassium clavulanate and one or more disintegrants present at a concentration of about 0.5%) to about 10 % w/w based on the weight of the immediate release phase; and, c) a third layer which includes the slow release phase comprising amoxicillin and one or more release retarding agents present at a concentration of about 0.2% to about 50 % w/w based on the weight of the slow release phase.
  • the modified release formulation may be in the form of a trilayered tablet which includes 1000 mg ⁇ 5% of amoxicillin and 62.5 mg ⁇ 5% of clavulanic acid in a weight ratio of 16: 1.
  • the trilayered tablet includes a slow release phase and an immediate release phase, wherein the ratio of amoxicillin in immediate release phase and slow release phase is less than about 1:3.
  • the trilayered tablet may include the following: a) a first layer which includes the immediate release phase comprising amoxicillin, potassium clavulanate and one or more disintegrants present at a concentration of about 0.5% to about 10 % w/w based on the weight of the immediate release phase; b) a second layer which includes the slow release phase comprising amoxicillin trihydrate and one or more release retarding agents present at a concentration of about 0.2% to about 50 % w/w based on the weight of the slow release phase; and, c) a third layer which includes the slow release phase comprising sodium amoxicillin and one or more release retarding agents present at a concentration of about 0.2% to about 50 % w/w based on the weight of the slow release phase.
  • the modified release formulations thus prepared according to this invention may be used to treat bacterial infections caused by S. pneumoniae (including drug resistant S. pneumoniae (DRSP), for example, penicillin resistant S. pneumoniae (PRSP). Also included are the beta.-lactamase producing respiratory pathogens, for example, H. influenzae and M. catarrhalis, respiratory tract infections, for example, community acquired pneumoniae (CAP), acute exacerbations of chronic bronchitis (AECB) and acute bacterial sinusitis (ABS), where the higher break points achievable through the improved pharmacokinetic profile will be especially advantageous when compared to existing antibacterial agents. Most outpatient respiratory infections are caused by either S.
  • DRSP drug resistant S. pneumoniae
  • PRSP penicillin resistant S. pneumoniae
  • beta.-lactamase producing respiratory pathogens for example, H. influenzae and M. catarrhalis
  • respiratory tract infections for example, community acquired pneumoniae (CAP), acute exacerbations of chronic bronchitis (AECB) and acute bacterial sinus
  • Example 1 Bilayered tablets
  • Amoxicillin sodium (immediate release portion B) was mixed with microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide to obtain a powder mix. 4.
  • the powder mix of step 3 was granulated using solution of polyvinylpyrrolidone in isopropyl alcohol, followed by drying and sieving to obtain granules. 5.
  • the granules of step 2 and the granules of step 4 were mixed to obtain granule mix.
  • the granule mix of step 5 was mixed with microcrystalline cellulose and magnesium stearate (ingredients 9&10) to obtain blend 1.
  • sustained release phase 7.
  • Amoxicillin trihydrate sustained release portion A was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, mannitol, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • the powder mix of step 7 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • Amoxicillin trihydrate (sustained release portion B) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, sodium alginate, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix. 10.
  • the powder mix of step 9 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules. 11.
  • Amoxicillin sodium (sustained release portion C) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, mannitol, sodium alginate, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • the powder mix of step 11 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • the granules of steps 8, 10 & 12 were mixed together to obtain blend 2.
  • Bilayered tablets were then prepared by compressing blend 1 and blend 2 in either order.
  • Example 2 Bilayered tablet
  • step 1 Potassium Clavulanate (immediate release portion A) was mixed with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate to obtain a powder mix. 2. The powder mix of step 1 was dry granulated (by compaction followed by sieving) to obtain granules. 3. Amoxicillin trihydrate (immediate release portion B) was mixed with microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide to obtain a powder mix. 4. The powder mix of step 3 was granulated using solution of polyvinylpyrrolidone and eudragit El 00 in isopropyl alcohol, followed by drying and sieving to obtain granules. 5.
  • step 2 The granules of step 2 and the granules of step 4 were mixed to obtain granule mix. 6.
  • the granule mix of step 5 was mixed with microcrystalline cellulose and magnesium stearate (ingredients 10&11) to obtain blend 1.
  • sustained release phase 7.
  • Amoxicillin trihydrate sustained release portion A was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • the powder mix of step 7 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • Amoxicillin trihydrate (sustained release portion B) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, sodium alginate, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix. 10.
  • the powder mix of step 9 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • the granules of step 8 and step 10 were mixed together to obtain blend 2. 12.
  • Bilayered tablets were then prepared by compressing blend 1 and blend 2 in either order.
  • step 1 The powder mix of step 1 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain blend 2.
  • step 2 3. Amoxicillin trihydrate (sustained release portion B) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, sodium alginate, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix. 4.
  • the powder mix of step 3 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain blend 3. 5.
  • Trilayered tablets were then prepared by compressing blend 1, blend 2 and blend 3 in either order.
  • Example 4 Bilayered tablet
  • Amoxicillin trihydrate (sustained release portion B) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, sodium alginate, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • step 3 The powder mix of step 3 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • Amoxicillin sodium sustained release portion C was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), hydroxypropyl methylcellulose (Methocel-E5), hydroxypropyl cellulose, mannitol, polyethylene oxide, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • step 6 The powder mix of step 5 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • step 3 The powder mix of step 3 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules. 5. The granules of step 2 & 4 were mixed together to obtain blend 2. 6. Bilayered tablets were then prepared by compressing blend 1 and blend 2 in either order.
  • step 1 Potassium Clavulanate (immediate release portion A) was mixed with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate to obtain a powder mix. 2. The powder mix of step 1 was dry granulated (by compaction followed by sieving) to obtain granules. 3. Amoxicillin trihydrate (immediate release portion B) was mixed with microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide to obtain a powder mix. 4. The powder mix of step 3 was granulated using solution of polyvinylpyrrolidone and eudragit El 00 in isopropyl alcohol, followed by drying and sieving to obtain granules. 5.
  • step 2 The granules of step 2 and the granules of step 4 were mixed to obtain granule mix. 6.
  • the granule mix of step 5 was mixed with microcrystalline cellulose and magnesium stearate (ingredients 10&11) to obtain blend 1.
  • sustained release phase 7.
  • Amoxicillin trihydrate sustained release portion A
  • microcrystalline cellulose polyethylene oxide, mannitol, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • the powder mix of step 7 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • Amoxicillin sodium was mixed with microcrystalline cellulose, polyethylene oxide, mannitol, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix. 10.
  • step 9 The powder mix of step 9 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules. 11. The granules of step 8 and step 10 were mixed together to obtain blend 2. 12. Bilayered tablets were then prepared by compressing blend 1 and blend 2 in either order.
  • Example 7 Bilayered tablet
  • step 3 The powder mix of step 3 was granulated using solution of polyvinylpyrrolidone and eudragit El 00 in isopropyl alcohol, followed by drying and sieving to obtain granules. 5. The granules of step 2 and the granules of step 4 were mixed to obtain granule mix. 6. The granule mix of step 5 was mixed with microcrystalline cellulose and magnesium stearate (ingredients 10&11) to obtain blend 1. B. Preparation of sustained release phase: 7.
  • Amoxicillin trihydrate (sustained release portion A) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), polyethylene oxide, mannitol, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • the powder mix of step 7 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules.
  • Amoxicillin sodium (sustained release portion B) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), mannitol, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix. 10.
  • step 9 The powder mix of step 9 was dry granulated (by compaction followed by sieving) and then lubricated with extragranular magnesium stearate to obtain granules. 11. The granules of step 8 and step 10 were mixed together to obtain blend 2. 12. Bilayered tablets were then prepared by compressing blend 1 and blend 2 in either order.
  • step 3 The powder mix of step 3 was granulated using solution of polyvinylpyrrolidone and eudragit El 00 in isopropyl alcohol, followed by drying and sieving to obtain granules. 5. The granules of step 2 and the granules of step 4 were mixed to obtain grannie mix. 6. The granule mix of step 5 was mixed with microcrystalline cellulose and magnesium stearate (ingredients 10&11) to obtain blend 1. B. Preparation of sustained release phase: 7.
  • Amoxicillin trihydrate (sustained release portion A) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4M ), polyethylene oxide, mannitol, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix.
  • the powder mix of step 7 was dry granulated (by compaction followed by sieving) to obtain granules.
  • Amoxicillin sodium (sustained release portion B) was mixed with microcrystalline cellulose, hydroxypropyl methylcellulose (Methocel K4MCR), mannitol, colloidal silicon dioxide and intragranular magnesium stearate to obtain a powder mix. 10.
  • step 9 The powder mix of step 9 was dry granulated (by compaction followed by sieving) to obtain granules. 11. The granules of step 8 and step 10 were mixed together and then lubricated with extragranular magnesium stearate to obtain blend 2. 12. Bilayered tablets were then prepared by compressing blend 1 and blend 2 in. either order.
  • Example 9 Bilayered tablet
  • step 6 The powder mix of step 6 was dry granulated (by compaction followed by sieving) and then lubricated with magnesium stearate and talc to obtain blend 2. 5.
  • Bilayered tablets were then prepared by compressing blend 1 and blend 2 in either order. Note: 1. Process was carried out in area with relative humidity less than 20%. 2. All excipients were dried to equilibrium relative humidity less than 10% before use.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne une formulation à libération modifiée contenant de l'amoxicilline et du clavulanate, des procédés de préparation associés, ainsi qu'une méthode pour traiter des infections bactériennes au moyen de ces formulations.
PCT/IB2005/000975 2004-04-13 2005-04-13 Formulation pharmaceutique a liberation modifiee contenant de l'amoxicilline et du clavulanate Ceased WO2005099672A1 (fr)

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IN707/DEL/2004 2004-04-13

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008029351A3 (fr) * 2006-09-04 2008-07-10 Ranbaxy Lab Ltd Formulation à libération modifiée comprenant de l'amoxicilline et un clavulanate
JP2010511607A (ja) * 2006-12-04 2010-04-15 ミドルブルック ファーマスーティカルス，インコーポレイテッド 変性放出アモキシシリン製剤
WO2014033077A1 (fr) 2012-08-28 2014-03-06 Dsm Sinochem Pharmaceuticals Netherlands B.V. Composition comprenant un antibiotique et un inhibiteur de la bêta-lactamase, au moins l'un d'entre eux se trouvant sous la forme de mini-comprimés
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US9254261B2 (en) * 2014-03-03 2016-02-09 Sandoz Ag Stable quick dissolving dosage form comprising amoxicillin and clavulanic acid
EP2827845B1 (fr) 2012-03-22 2018-12-26 Novo Nordisk A/S Compositions comprenant un agent d'administration et préparation associée
US10933120B2 (en) 2012-03-22 2021-03-02 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US10960052B2 (en) 2010-12-16 2021-03-30 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl) amino) caprylic acid
US11033499B2 (en) 2012-06-20 2021-06-15 Novo Nordisk A/S Tablet formulation comprising a GLP-1 peptide and a delivery agent
US11034746B2 (en) 2011-04-12 2021-06-15 Novo Nordisk A/S Double-acylated GLP-1 derivatives
US11123296B2 (en) 2012-03-22 2021-09-21 Novo Nordisk A/S Compositions comprising a delivery agent and preparation thereof
WO2021234724A1 (fr) * 2020-05-16 2021-11-25 Twenty First Century Pharmaceuticals Pvt. Ltd. Formulation pharmaceutique contenant des granules stables d'acide clavulanique
CN115554273A (zh) * 2022-09-07 2023-01-03 新发药业有限公司 一种儿童用阿莫西林克拉维酸钾双相释放颗粒及其制备方法
US11833248B2 (en) 2018-02-02 2023-12-05 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US12239739B2 (en) 2013-05-02 2025-03-04 Novo Nordisk A/S Oral dosing of GLP-1 compounds

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WO1995020946A1 (fr) * 1994-02-04 1995-08-10 Smithkline Beecham Plc Comprimes de type bi-couche a base d'amoxycilline
WO1996004908A1 (fr) * 1994-08-17 1996-02-22 Smithkline Beecham Plc Composition pharmaceutique contenant de l'amoxycilline et du clavulanate de potassium
WO1999033448A1 (fr) * 1997-12-23 1999-07-08 Merck Patent Gmbh Comprime a liberation instantanee et prolongee d'un ou de plusieurs principes actifs
WO2000061116A2 (fr) * 1999-04-13 2000-10-19 Beecham Pharmaceuticals (Pte) Limited Nouveau procede de traitement
US20030224049A1 (en) * 2000-10-12 2003-12-04 Beecham Pharmaceuticals (Pte) Limited Novel formulation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995020946A1 (fr) * 1994-02-04 1995-08-10 Smithkline Beecham Plc Comprimes de type bi-couche a base d'amoxycilline
WO1996004908A1 (fr) * 1994-08-17 1996-02-22 Smithkline Beecham Plc Composition pharmaceutique contenant de l'amoxycilline et du clavulanate de potassium
WO1999033448A1 (fr) * 1997-12-23 1999-07-08 Merck Patent Gmbh Comprime a liberation instantanee et prolongee d'un ou de plusieurs principes actifs
WO2000061116A2 (fr) * 1999-04-13 2000-10-19 Beecham Pharmaceuticals (Pte) Limited Nouveau procede de traitement
US20030224049A1 (en) * 2000-10-12 2003-12-04 Beecham Pharmaceuticals (Pte) Limited Novel formulation

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008029351A3 (fr) * 2006-09-04 2008-07-10 Ranbaxy Lab Ltd Formulation à libération modifiée comprenant de l'amoxicilline et un clavulanate
JP2010511607A (ja) * 2006-12-04 2010-04-15 ミドルブルック ファーマスーティカルス，インコーポレイテッド 変性放出アモキシシリン製剤
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US10960052B2 (en) 2010-12-16 2021-03-30 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl) amino) caprylic acid
US11382957B2 (en) 2010-12-16 2022-07-12 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US11117947B2 (en) 2011-04-12 2021-09-14 Novo Nordisk A/S Double-acylated GLP-1 derivatives
US11034746B2 (en) 2011-04-12 2021-06-15 Novo Nordisk A/S Double-acylated GLP-1 derivatives
EP2827845B1 (fr) 2012-03-22 2018-12-26 Novo Nordisk A/S Compositions comprenant un agent d'administration et préparation associée
US11759503B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US10933120B2 (en) 2012-03-22 2021-03-02 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11759502B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11123296B2 (en) 2012-03-22 2021-09-21 Novo Nordisk A/S Compositions comprising a delivery agent and preparation thereof
US11759501B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11033499B2 (en) 2012-06-20 2021-06-15 Novo Nordisk A/S Tablet formulation comprising a GLP-1 peptide and a delivery agent
WO2014033077A1 (fr) 2012-08-28 2014-03-06 Dsm Sinochem Pharmaceuticals Netherlands B.V. Composition comprenant un antibiotique et un inhibiteur de la bêta-lactamase, au moins l'un d'entre eux se trouvant sous la forme de mini-comprimés
US12239739B2 (en) 2013-05-02 2025-03-04 Novo Nordisk A/S Oral dosing of GLP-1 compounds
US9254261B2 (en) * 2014-03-03 2016-02-09 Sandoz Ag Stable quick dissolving dosage form comprising amoxicillin and clavulanic acid
US11833248B2 (en) 2018-02-02 2023-12-05 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US12396953B2 (en) 2018-02-02 2025-08-26 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
WO2021234724A1 (fr) * 2020-05-16 2021-11-25 Twenty First Century Pharmaceuticals Pvt. Ltd. Formulation pharmaceutique contenant des granules stables d'acide clavulanique
CN115554273A (zh) * 2022-09-07 2023-01-03 新发药业有限公司 一种儿童用阿莫西林克拉维酸钾双相释放颗粒及其制备方法
CN115554273B (zh) * 2022-09-07 2024-03-15 新发药业有限公司 一种儿童用阿莫西林克拉维酸钾双相释放颗粒及其制备方法

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