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WO2021234724A1 - Formulation pharmaceutique contenant des granules stables d'acide clavulanique - Google Patents

Formulation pharmaceutique contenant des granules stables d'acide clavulanique Download PDF

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Publication number
WO2021234724A1
WO2021234724A1 PCT/IN2021/050415 IN2021050415W WO2021234724A1 WO 2021234724 A1 WO2021234724 A1 WO 2021234724A1 IN 2021050415 W IN2021050415 W IN 2021050415W WO 2021234724 A1 WO2021234724 A1 WO 2021234724A1
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WO
WIPO (PCT)
Prior art keywords
clavulanic acid
pharmaceutical formulation
formulation
granules
tablet
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/IN2021/050415
Other languages
English (en)
Inventor
Vengandur Srikumar RAGHUNATHAN
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.)
Twenty First Century Pharmaceuticals Pvt Ltd
Original Assignee
Twenty First Century Pharmaceuticals Pvt Ltd
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 Twenty First Century Pharmaceuticals Pvt Ltd filed Critical Twenty First Century Pharmaceuticals Pvt Ltd
Publication of WO2021234724A1 publication Critical patent/WO2021234724A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/41—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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • 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
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50

Definitions

  • the present invention generally relates to the field of pharmaceutical preparations, and more particularly to method for improving dissolution and stability of clavulanic acid formulation using pH independent hydrophobic polymer and hydrophilic plasticizer.
  • the invention also relates to pharmaceutical formulations of clavulanic acid with b-lactam antibiotic.
  • Amoxicillin and cephalosporins belongs to the group of broad spectrum b-lactam antibiotics whereas clavulanic acid is well-know b-lactamase inhibitor, and their combination is well-known for treating bacterial infections.
  • Amoxicillin is crystalline in nature, often lacking satisfactory flowability and density. Consequently, direct compressible grade materials are used to overcome flowability and density. Oral administration of cephalosporins tends to show bioavailability problems and slow dissolution.
  • Clavulanic acid stability is a key concern in developing pharmaceutical formulation.
  • the situation is very complex due to its hygroscopic nature.
  • Clavulanic acid readily decomposes in presence of water during wet granulation.
  • amoxicillin trihydrate With dry granulation process, amoxicillin trihydrate exhibit intimate contact with clavulanic acid, which results into degradation of clavulanic acid due to high water content in amoxicillin trihydrate.
  • the inventors of the present invention have found that when a pH independent hydrophobic polymer is granulated with clavulanic acid in a non-aqueous solvent, the deterioration in the stability of clavulanic acid can be surprisingly prevented. Furthermore, a hydrophilic plasticizer is added to improve dissolution of clavulanic acid granules.
  • a coating system and granulation technique to protect clavulanic acid from moisture absorption and thereby improving stability of clavulanic acid in the formulation.
  • the present invention provides granules prepared by granulating clavulanic acid with a pH independent hydrophobic polymer and a hydrophilic plasticizer in a non- aqueous solvent.
  • the granulation is performed in a rapid mixer granulator using spray technique with help of peristaltic pump for controlled spray to avoid local wetting of clavulanic acid.
  • the clavulanate granules preferably contains potassium clavulanate diluted with low moisture grade microcrystalline cellulose.
  • the percentage of hydrophilic plasticizer and pH independent hydrophobic polymer used in a pharmaceutical formulation determines the rate of dissolution and stability for clavulanic acid.
  • the granulated clavulanic acid is blended with amoxicillin trihydrate to prepare pharmaceutical formulations.
  • the granulated clavulanic acid is blended with a cephalosporin antibiotic to prepare pharmaceutical formulations.
  • Figure 1 Open exposure study for potency evaluation of clavulanic acid in tablet
  • Figure 2 Dissolution profile of plain clavulanic acid and granulated clavulanic acid in tablet
  • Figure 3 Open exposure study for potency evaluation of clavulanic acid in dry powder suspension
  • Figure 4 Dissolution profile of plain clavulanic acid and granulated clavulanic acid in dry powder suspension
  • the inventors of the present invention have found that when pH independent hydrophobic polymer and hydrophilic plasticizer is granulated with clavulanic acid in a non-aqueous solvent, the deterioration in the stability of clavulanic acid can be surprisingly prevented and also the dissolution is improved. As it is shown in the examples below, the percentage of hydrophilic plasticizer and pH independent hydrophobic polymer used, significantly prevents degradation and improves dissolution of clavulanic acid in a pharmaceutical formulation of the present invention.
  • the pharmaceutical formulation according to the present invention provides a granule containing clavulanic acid, pH independent hydrophobic polymer and hydrophilic plasticizer in a non-aqueous solvent.
  • the present invention provides a granule containing clavulanic acid, a pH independent hydrophobic polymer, and a hydrophilic plasticizer in a non- aqueous solvent.
  • Suitable pH independent hydrophobic polymer includes ethyl cellulose and polyvinyl ethyl acetate.
  • Ethyl cellulose is the preferred pH independent hydrophobic polymer.
  • Suitable hydrophilic plasticizer includes, but not limited to, polyethylene glycol, glycerin, propylene glycol, and sorbitol. Polyethylene glycol is the preferred hydrophilic plasticizer.
  • the formulation of the present invention may optionally comprise at least one excipient, such as a filler, a sweetener, a disintegrant, a viscosity enhancer, a glidant, a flavor, and a pH modifier.
  • the present invention provides a pharmaceutical formulation containing granules of clavulanic acid and amoxicillin trihydrate along with other pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical formulation containing granules of clavulanic acid and crystals of amoxicillin trihydrate.
  • the pharmaceutical formulations of the present invention can be prepared to provide immediate or modified release of the formulation.
  • immediate release refers to a formulation showing a release of active substance(s) which is not deliberately modified by a special formulation design and/or manufacturing method.
  • the dissolution profile of the active substance depends essentially on its intrinsic properties. This is further understood to be traditional or conventional release profile where no slow, delayed or extended-release effect is incorporated.
  • a percentage equal to or greater than 65% of the active ingredient is dissolved within 60 minutes, preferably within 30 minutes and more preferably within 15 minutes in a US Pharmacopeia type 1 apparatus in 0.05M acetate buffer, at pH 4.5, 100 rpm in a volume of 900 ml. More preferably the percentage of active ingredient dissolved is greater than 75%, more preferably greater than 80%.
  • modified release includes all types of modified release profiles such as controlled release, sustained release, delayed release, and the like.
  • the formulations of the present invention can be prepared by combining one or more dosage units in an oral formulation.
  • These dosage units can be tablets, granules, pellets, capsules, or particles or combinations thereof.
  • the term "granulation” refers to the act or process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Thus, it is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation is extensively used in the manufacturing of tablets and pellets (or spheroids).
  • tablette includes tablets, mini tablets or micro tablets.
  • capsule also can refer to micro capsules. Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, gelatin capsules being preferred. Two-piece hard gelatin capsules are preferably sealed by gelatin bands or the like.
  • said orally administrable pharmaceutical dosage form according to the invention is in the form of a capsule.
  • the pharmaceutical formulation of the present invention can be prepared as drug powder suspension or syrup for oral administration.
  • b-lactam antibiotic as used herein shall mean antibiotic and shall include amoxicillin and cephalosporin antibiotics.
  • amoxicillin as used herein shall mean amoxicillin, or any pharmaceutically acceptable salt thereof, in particular amoxycillin trihydrate and (crystallized) sodium amoxycillin, without distinction and unless otherwise indicated.
  • clavulanic acid as used herein shall mean clavulanic acid, or a pharmaceutically acceptable salt thereof.
  • salts include potassium, sodium, lithium, calcium and magnesium salts. Potassium clavulanate is the most preferred in the present invention.
  • effective amount means an amount necessary to achieve a selected result.
  • the present invention provides a method for preparing pharmaceutical formulation by direct compression of granules of amoxicillin trihydrate and clavulanic acid.
  • the method is carried out in an environment with a relative humidity of 20% or lower and at a temperature between 20 and 25°C because decomposition process in clavulanic acid starts with small amount of water as reaction product.
  • the present invention provides a granulation method by granulating clavulanic acid with pH independent hydrophobic polymer and hydrophilic plasticizer having a weight gain 1 to 10%, preferably 1 to 6%.
  • the granulated clavulanic acid is blended with granules of amoxicillin trihydrate, low moisture grade microcrystalline cellulose, disintegrant, glidant, and lubricant and is compressed into tablet with moisture barrier film coating.
  • the present invention provides a wet granulation method by separately granulating amoxicillin trihydrate and clavulanic acid.
  • the particles of clavulanic acid are partially covered with pH independent hydrophobic polymer in presence of hydrophilic plasticizer in a non-aqueous system in rapid mixer granulator.
  • Amoxicillin crystals/granules are sieved, and other excipients are added to the mixture and clavulanic acid added extra granularly.
  • the mixture thus prepared may be filled into sachets, glass or plastic bottles or the mixture is compressed into tablets.
  • the present invention provides drug powder suspension comprising granules of clavulanic acid and crystals of amoxicillin trihydrate along with pharmaceutically acceptable excipients such as a sweetener, a viscosity enhancer, heavy and light colloidal silicon dioxide, a flavor, a filler, and a pH modifier.
  • the drug powder suspension is processed in an environment with relative humidity of 15 to 20% at a temperature between 20 and 25°C.
  • the present invention provides dry powder syrup comprising cellulose diluted potassium clavulanate granulated with pH independent hydrophobic polymer in the presence of hydrophilic plasticizer.
  • the present invention provides a pharmaceutical formulation containing granules of clavulanic acid and a cephalosporin antibiotic along with other pharmaceutically acceptable excipients.
  • cephalosporin as used herein shall mean cephalosporin antibiotic and may include, but not limited to, cefpodoxime proxetil, cefuroxime axetil, cefixime trihydrate, cefadroxil, cefatrizine, ceftibuten, cefalexin, cephradine and cefaclor.
  • the cephalosporin used in the present invention is cefpodoxime proxetil. In another embodiment, the cephalosporin used in the present invention is cefuroxime axetil.
  • the present invention provides a process for the preparation of a pharmaceutical formulation which comprises
  • step (b) blending granules of amoxicillin trihydrate with granules of clavulanic acid of step (a),
  • step (c) blending extra granular excipients with step (b),
  • step (d) compressing mixture of step (c) into tablets
  • Manufacturing process is carried out at RH in the range of 15 to 20% and temperature in the range of 20 to 25°C.
  • RH in the range of 15 to 20% and temperature in the range of 20 to 25°C.
  • Table 1 Tablets of the following composition were prepared
  • Crystals of Amoxicillin trihydrate, potassium clavulanate, sodium starch glycolate dried, microcrystalline cellulose dried and colloidal silicon dioxide were mixed in bin blender and sieved through mesh no. 20. Presifted magnesium stearate added into blender and mixed for 2 minutes. Dry mix blend was slugged using roll compactor or compression machine, the slugs were milled through 2mm screen using Comill. Presfited magnesium stearate added to milled granules and granules were compressed. The compressed tablet coated with film coat with the weight gain of 5% w/w. The final weight of film coated tablet is 1050mg.
  • the percentage clavulanic acid dissolved both in plain clavulanic acid and granulated clavulanic acid is similar in film coated tablet.
  • Dry powder suspension filled into HDPE container and exposed to temperature between 20 and 25°C and the relative humidity less than 20%.
  • the container cap was open for 6 days and assay was performed to evaluate the degradation of clavulanic acid.
  • Open exposure study of potassium clavulanate comprised oral dry suspension results are disclosed in below table
  • Table 11 Dispersible Tablet of the following composition was prepared Cellulose diluted potassium clavulanate granulated with binder ethyl cellulose and polyethylene glycol dried and milled through screen 1.5mm. Cefpodoxime proxetil granulated with ethyl cellulose as taste masking polymer. Granules of Cefpodoxime Proxetil, potassium clavulanate, croscarmellose sodium dried, microcrystalline cellulose dried, sucralose, orange flavor, colorant and aerosil were sifted through # 40 mixed in bin blender. Presfited magnesium stearate added to milled granules and granules were compressed into tablet.
  • Table 14 Tablets of the following composition were prepared Table 15: Dissolution for granulated clavulanic acid
  • the percentage of hydrophilic plasticizer to pH independent hydrophobic polymer was selected from 10% to 20% and a trail without hydrophilic plasticizer. In absence of plasticizer dissolution was slow and with 20% of plasticizer dissolution was found fast. On hold study in ambient condition with 20% of hydrophilic plasticizer significant colour change observed with granulated clavulanic acid. Interestingly with 10% of hydrophilic plasticizer, no colour change was observed. With 10% of hydrophilic plasticizer, process found to be satisfactory, and release of clavulanic acid found to be satisfactory. With 10% of PEG, the degradation of clavulanic acid was found to be least.
  • ethyl cellulose 3% was used for granulating clavulanic acid and during coating process, colour change was observed.
  • ethyl cellulose 10% & 13% was used for granulating clavulanic acid and it was observed that while compression, disintegrating and dissolution were out of specification.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formulations pharmaceutiques comprenant des granules d'acide clavulanique préparées par granulation d'acide clavulanique avec un polymère hydrophobe indépendant du pH et un plastifiant hydrophile dans un solvant non aqueux. L'invention concerne également des formulations pharmaceutiques de granules d'acide clavulanique et d'antibiotique bêta-lactame. Le pourcentage de plastifiant hydrophile et de polymère hydrophobe indépendant du pH utilisé dans la formulation pharmaceutique détermine le taux de dissolution et de stabilité pour l'acide clavulanique.
PCT/IN2021/050415 2020-05-16 2021-04-28 Formulation pharmaceutique contenant des granules stables d'acide clavulanique Ceased WO2021234724A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN202041020750 2020-05-16
IN202041020750 2020-05-16
IN202141019313 2021-04-27
IN202141019313 2021-04-27

Publications (1)

Publication Number Publication Date
WO2021234724A1 true WO2021234724A1 (fr) 2021-11-25

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Application Number Title Priority Date Filing Date
PCT/IN2021/050415 Ceased WO2021234724A1 (fr) 2020-05-16 2021-04-28 Formulation pharmaceutique contenant des granules stables d'acide clavulanique

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005099672A1 (fr) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Formulation pharmaceutique a liberation modifiee contenant de l'amoxicilline et du clavulanate
US7217430B2 (en) * 1999-04-13 2007-05-15 Beecham Pharmaceuticals (Pte) Limited Compositions and methods of treatment comprising amoxicillin and potassium clavulanate with xanthan
WO2008029351A2 (fr) * 2006-09-04 2008-03-13 Ranbaxy Laboratories Limited Formulation à libération modifiée comprenant de l'amoxicilline et un clavulanate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7217430B2 (en) * 1999-04-13 2007-05-15 Beecham Pharmaceuticals (Pte) Limited Compositions and methods of treatment comprising amoxicillin and potassium clavulanate with xanthan
WO2005099672A1 (fr) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Formulation pharmaceutique a liberation modifiee contenant de l'amoxicilline et du clavulanate
WO2008029351A2 (fr) * 2006-09-04 2008-03-13 Ranbaxy Laboratories Limited Formulation à libération modifiée comprenant de l'amoxicilline et un clavulanate

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