WO1999025343A1 - Granules comprising clavulanate and one or more excipients - Google Patents

Granules comprising clavulanate and one or more excipients Download PDF

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Publication number
WO1999025343A1
WO1999025343A1 PCT/EP1998/007225 EP9807225W WO9925343A1 WO 1999025343 A1 WO1999025343 A1 WO 1999025343A1 EP 9807225 W EP9807225 W EP 9807225W WO 9925343 A1 WO9925343 A1 WO 9925343A1
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WO
WIPO (PCT)
Prior art keywords
granules
clavulanate
anyone
excipients
potassium clavulanate
Prior art date
Application number
PCT/EP1998/007225
Other languages
French (fr)
Inventor
Jan Willem Groenendaal
Original Assignee
Gist-Brocades B.V.
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 Gist-Brocades B.V. filed Critical Gist-Brocades B.V.
Priority to JP52751299A priority Critical patent/JP2001516365A/en
Priority to CN98801549A priority patent/CN1242705A/en
Priority to AU13379/99A priority patent/AU1337999A/en
Priority to PL98334517A priority patent/PL334517A1/en
Priority to EP98956907A priority patent/EP0973520A1/en
Priority to BR9806280-8A priority patent/BR9806280A/en
Priority to CA002272402A priority patent/CA2272402A1/en
Publication of WO1999025343A1 publication Critical patent/WO1999025343A1/en
Priority to NO993467A priority patent/NO993467L/en

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to granules of clavulanate containing excipients and a process to prepare the same.
  • crystalline Mactam antibiotic powder itself is not suitable for the manufacturing of tablets and capsules containing oral grade /? ⁇ lactam antibiotics because the crystalline material has no satisfactory flowability and density so that controlled dosage per tablet or capsule is not guaranteed. Therefore, normally a granulate is produced by mixing the crystalline product ( 1 -1 50 ⁇ m) with other components as binders and fillers in a wet or dry granulation process. For preparing granules of potassium clavulanate, the situation is even more complex due to its hygroscopic nature and instability at already relative low humidities during the granulation process.
  • German patent application DE 2251 250 a process for relatively small tablets containing a high amount of antibiotic using a granulate prepared with a small amount (5-1 5%) of excipients (e.g. crystalline cellulose, binder, talc) has been described.
  • European patent EP 281 200 describes a pharmaceutical granulate comprising 35-45 wt% microcrystalline cellulose prepared by wet granulation, which granulate disintegrates quickly when immersed in water.
  • the antibiotic has been described to be mixed with excipients (e.g.
  • International patent application WO 971 7960 also describes an oral 5 composition containing clavulanate and amoxicillin in which a metal salt desiccant, for example sodium, calcium or magnesium chloride has been added in order to increase the stability of potassium clavulanate.
  • European patent EP 0002574 describes the preparation of particles comprising an anhydrous salt of clavulanic acid dispersed in a semi-synthetic polymer binder o of low water vapour permeability.
  • WO 9427557 a process has been claimed for the preparation of thermal infusion granules of clavulanate. These thermal infusion granules have been prepared by compacting blends of clavulanate, a hydrophobic waxy material, optionally excipients, milling, screening and, subsequently, subjecting the same to 5 thermal infusion.
  • wet granulation Difficulties one may encounter by using wet granulation are in the first place decomposition of potassium clavulanate because of use of water and/or organic solvents combined with elevated temperature during granulation. Besides that the use of organic solvents is restricted by governmental rules o concerning environmental protection. Furthermore, the wet granulation process is labour intensive, expensive and time consuming because of the large number of processing steps like mixing, granulating, wet sieving, drying etc. and a lot of energy is needed to dry the wet granules. Besides this, the granules produced by wet granulation are rather porous and high bulk volumes 5 are not or difficult to reach, whereby it is often not possible to achieve high dosages in gelatin capsules.
  • binder dissolved in a binder solution or dry mixed with the compound to be granulated usually gives problems with a homogeneous distribution because of its sticking nature. This results in an inhomogeneous composition which can cause differences in dissolution and/or o tablet hardness between dosage forms of various batches and therefore differences in bioavailability. Difficulties one may encounter by using dry granulation together with amoxicillin trihydrate are decomposition of potassium clavulanate because of a too high water activity during roller compaction or slugging developed by amoxicillin trihydrate.
  • the present invention provides granules of clavulanate containing inert excipients which are preferably substantially free of solvents with the provisio that the clavulanate has not been dispersed in a polymeric binder of low water vapour permeability.
  • the clavulanate granules are preferably potassium clavulanate and the inert excipient is a cellulose, preferably microcrystalline cellulose, more preferably with a water activity of less than 0.2 at 25°C, most preferably Avicel ® PH 1 1 2.
  • the ratio of potassium clavulanate related to microcrystalline cellulose such as Avicel ® PH 1 1 2 is 1 : 5 - 0.2 wt%, preferably 1 : 2-0.5 wt% and more preferably about 1 : 1 wt%.
  • These granules are of a particle size between 50 ⁇ m and 1 500 ⁇ m, preferably between 1 25 ⁇ m and 1 000 ⁇ m.
  • the process comprises of feeding, for example, potassium clavulanate powder and inert excipients to a roller compactor to produce compacts, followed by milling said compacts to give granules.
  • These granules are, then, sieved with a sieving device to separate the granules from fine particles, preferably fine particles of ⁇ 1 50 ⁇ m, more preferably fine particles of ⁇ 1 25 ⁇ m.
  • the sieving device comprises a tumbler or vibratory sieving machine, preferably a tumbler sieving machine equipped with an air jet system. The fine particles are optionally recirculated to the roller compactor.
  • the present invention also provides a pharmaceutical composition prepared from blending granules of potassium clavulanate of the invention together with crystals or granules of amoxicillin trihydrate optionally containing excipients and specific excipients specifically used for the preparation of compositions of oral dosage forms like tablets with or without coating, disperse tablets, chewable tablets and oral dry suspension.
  • a pharmaceutical composition prepared from blending granules of potassium clavulanate of the invention together with crystals or granules of amoxicillin trihydrate optionally containing excipients and specific excipients specifically used for the preparation of compositions of oral dosage forms like tablets with or without coating, disperse tablets, chewable tablets and oral dry suspension.
  • the granulation method wherein clavulanate with inert excipients are used, consists of dry granulation by using compaction forces to build up agglomerates. This may be performed by slugging or roller compacting. The compacts are milled and, then, sieved with a sieving device. The separation of fine particles from coarse granules may be carried out by a dry air sieving procedure. In dry air sieving, the milled compacts are placed on the sieve and air is blown through the bed of milled compacts to separate the granules from the fine particles.
  • the sieving device comprises preferably an air jet system using air with a relative humidity of ⁇ 30%, preferably ⁇ 20% and a temperature between 1 5 and 25 °C. Furthermore, the sieving device can be coupled directly to the roller compactor or stands separately from the same.
  • this granulation method results in granules with a satisfactory particle size distribution, viz. between 50 ⁇ m and 1 500 ⁇ m, preferably between 1 25 ⁇ m and 1 000 ⁇ m.
  • these granules are preferably substantially free of organic solvents and/or water, because during the process of compaction use of these solvents is usually avoided. The only traces of solvent(s) which may be present in the said granules are already present in the starting compound.
  • the present technique eliminates problems in granulation processes due to heat and moisture because potassium clavulanate should be processed in an environment with a relative humidity of 20% or lower at a temperature between 20 and 25 °C because higher humidities start decomposition processes with small amounts of water as reaction products which on their turn continue the decomposition reaction. Since potassium clavulanate is dry granulated together with an inert excipient, preferably Avicel ® PH 1 1 2 this has strongly reduced the run-away hazard in comparison with that of the unblended potassium clavulanate. The unblended potassium clavulanate is classified as highly flammable, both according to the European notification directories and the UN transport recommendations.
  • the blend potassium clavulanate in the concentration with Avicel ® PH 1 1 2 1 : 1 weight ratio is not flammable.
  • the inert excipients with sufficient binding properties also increase the flowability of the blend with potassium clavulanate to improve the flow through the compacting equipment.
  • the dry granulation of potassium clavulanate according to the present invention results in granules with a sufficient high density. This is an advantage because potassium clavulanate is always used in admixture with amoxicillin in relatively high dosages resulting in large tablets. A too low density of the granules would further enlarge the large, difficult swallowable tablets.
  • the clavulanate granules also allow for disintegration of dosage forms into primary drug particles followed by a high dissolution rate because no wet binders are used. This is especially important when dispersable tablets are produced which should have a disintegrating time less than a few minutes.
  • the resulting potassium clavulanate granules showing excellent flow properties and almost no dust can be mixed with amoxicillin, preferably amoxicillin granules as mentioned in European patent application No. PCT/EP 98/05902 filed on 27-08-1 998, which granules possess the same particle size forming a mixture of both granules not susceptible to segregation.
  • clavulanate powder for instance potassium clavulanate and the excipients, for instance Avicel® PH 1 1 2 with a water activity of less than 0.2 measured at a temperature of 25 ° C
  • the compact materials are milled and, thereafter, sieved by using an air jet system.
  • the sieving device is coupled directly to the roller compactor in order to avoid extra steps or stands separately.
  • the fine particles preferably the material ⁇ 1 25 ⁇ m, are recycled to the roller compacting process.
  • the granules of clavulanate preferably of potassium clavulanate in combination with granules of amoxicillin, preferably of amoxicillin trihydrate as described in European patent application No. PCT/EP 98/05902 indicated above can be used for all formulations to produce chew, swallow, disperse, effervescent or normal tablets of all sizes, forms and weights, also to fill hard gelatin capsules and to formulate dry syrups and for administering drugs with the help of a dose sipping device. To produce tablets, only excipients have to be mixed with the granules and tablets can be pressed.
  • the granules can directly be filled into capsules or when fast running capsules filling machines are used, some lubricant like magnesium stearate can be mixed with the granules to facilitate the filling process.
  • flavours To formulate dry oral syrups, flavours, bulking agents such as sugars and preservatives are often used. These excipients are mixed with the granules and bottles for multi dosage use or sachets for single dosage use. Optionally a premix of excipients is prepared and filled into bottles or sachets after which the granules are added separately.
  • the granules can be placed over a support in a tube having a liquid inlet end and a liquid outlet end; excipients can also be placed over the support, together with the drug granules.
  • Oral administration of therapeutical agents with the help of a dose sipping device has been described in European patent application EP 383503.
  • Slugs were pressed with a thickness of about 3 mm, and a hardness of about 25 N measured with an Erweka ® TBH28 hardness tester.
  • the slugs were crushed using an Erweka T32 tablet crusher followed by a milling process using a Peppink ® N 1 00 hammer mill equipped with a 3 mm sieve.
  • the milled material (30 g) was treated as presented below:
  • the coarse particles and the fines were separated from the milled material using a Retsch Vibro vibrating-sieve working with a vibration amplitude of 2 mm, during 1 0 minutes, and using a 1 000 ⁇ m and a 1 25 ⁇ m sieve.
  • the amount of fines ⁇ 1 25 ⁇ m was 1 9 % w/w.
  • the amount of coarse particles > 1 000 ⁇ m was 8 % w/w.
  • the yield of granules between 1 25 and 1 000 ⁇ m was 73 % w/w.
  • the flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
  • the granules flowed freely through a funnel with an aperture of 1 2 mm but not through 8 mm, which indicates just sufficient flowability.
  • the coarse particles and the fines were separated from the milled material using an Alpine ® 200LS-N air-sieve working with an under pressure of 2000 Pa during 3 minutes, and using a 1 000 and a 1 25 ⁇ m sieve.
  • the used air had a relative humidity of ⁇ 20% and a temperature of 25°C.
  • the amount of fines ⁇ 1 25 ⁇ m was 42 % w/w.
  • the amount of coarse particles > 1 000 ⁇ m was 7 % w/w.
  • the yield of granules between 1 25 and 1 000 ⁇ m was 51 % w/w.
  • the flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
  • the granules flowed freely through a funnel with an aperture of 5 mm but not through 2.5 mm, which indicates good flowability.
  • Potassium clavulanate powder was mixed with microcrystalline cellulose (Avicel ® PH 1 1 2), with a water activity of less than 0.2 at 25 °C. The mixture was fed to a roller compactor. The produced compacts were milled and sieved with an air jet system using a sieve with apertures of 1 50 ⁇ m. The particles ⁇ 1 50 ⁇ m were recycled to the roller compactor.
  • the amount of fines ⁇ 1 50 ⁇ m was 32 % w/w.
  • the amount of coarse particles > 1 000 ⁇ m was 5 % w/w.
  • the yield of granules between 1 50 and 1000 ⁇ m was 63 % w/w.
  • the flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
  • amoxycillin trihydrate granules were prepared as follows:
  • Amoxicillin trihydrate powder was fed to a Fitzpatrick roller compacter type Chilsonator 4L X 1 0D.
  • the used rolls had a diameter of 25.4 cm and a roll wide of 1 0.2 cm, the roll surface was sinus waved grooved, the roll gap was 3.1 mm.
  • the roll speed was 1 1 rpm
  • the horizontal feeder speed was 1 7 rpm
  • the applied roll pressure 1 1 00 psi.
  • the compacts were milled using a Minox sieve type MTS 1 200 equipped with an air jet system.
  • the sieve applied had a diameter of 1 20 cm and apertures of 1 50 ⁇ m.
  • the air was escaping upwards from a rotating perforated blade fixed horizontal under the sieve. By this action the fine particles were blown off from the coarse particles and sucked downwards through the sieve to the receiver by the action of an under pressure.
  • the fines ⁇ 1 50 ⁇ m were recycled from the receiver to the roller compacting process, the material > 1 50 ⁇ m, collected from the 1 50 ⁇ m sieve, was the final product.

Abstract

Granules of clavulanate containing inert excipients for pharmaceutical formulations have been provided for. Also a process to prepare the same by employing a sieving device preferably using an air jet system has been described.

Description

GRANULES COMPRISING CLAVULANATE AND ONE OR MORE EXCIPIENTS
The present invention relates to granules of clavulanate containing excipients and a process to prepare the same.
Technological background and field of invention
It is generally known that crystalline Mactam antibiotic powder itself is not suitable for the manufacturing of tablets and capsules containing oral grade /?~lactam antibiotics because the crystalline material has no satisfactory flowability and density so that controlled dosage per tablet or capsule is not guaranteed. Therefore, normally a granulate is produced by mixing the crystalline product ( 1 -1 50 μm) with other components as binders and fillers in a wet or dry granulation process. For preparing granules of potassium clavulanate, the situation is even more complex due to its hygroscopic nature and instability at already relative low humidities during the granulation process.
In German patent application DE 2251 250, a process for relatively small tablets containing a high amount of antibiotic using a granulate prepared with a small amount (5-1 5%) of excipients (e.g. crystalline cellulose, binder, talc) has been described. European patent EP 281 200 describes a pharmaceutical granulate comprising 35-45 wt% microcrystalline cellulose prepared by wet granulation, which granulate disintegrates quickly when immersed in water. Also, in PCT applications WO 91 1 6893 and WO 921 9227, for example, the antibiotic has been described to be mixed with excipients (e.g. an effervescent couple of excipients or intra-granular disintegrant, flavour, magnesium stearate) for granulation using slugging or a roller compactor for compacting. Thereafter, the granules have been sieved to the desired particle size and finer material is recycled to the compaction process. In PCT application WO 9528927, a pharmaceutical tablet formulation having a structure comprising compacted granules of amoxicillin and clavulanate in a weight ratio of 6: 1 to 8: 1 , excipients and having a coating of polymers has been described.
International patent application WO 971 7960 also describes an oral 5 composition containing clavulanate and amoxicillin in which a metal salt desiccant, for example sodium, calcium or magnesium chloride has been added in order to increase the stability of potassium clavulanate. European patent EP 0002574 describes the preparation of particles comprising an anhydrous salt of clavulanic acid dispersed in a semi-synthetic polymer binder o of low water vapour permeability. In International patent application WO 9427557 a process has been claimed for the preparation of thermal infusion granules of clavulanate. These thermal infusion granules have been prepared by compacting blends of clavulanate, a hydrophobic waxy material, optionally excipients, milling, screening and, subsequently, subjecting the same to 5 thermal infusion.
Difficulties one may encounter by using wet granulation are in the first place decomposition of potassium clavulanate because of use of water and/or organic solvents combined with elevated temperature during granulation. Besides that the use of organic solvents is restricted by governmental rules o concerning environmental protection. Furthermore, the wet granulation process is labour intensive, expensive and time consuming because of the large number of processing steps like mixing, granulating, wet sieving, drying etc. and a lot of energy is needed to dry the wet granules. Besides this, the granules produced by wet granulation are rather porous and high bulk volumes 5 are not or difficult to reach, whereby it is often not possible to achieve high dosages in gelatin capsules. Finally the binder dissolved in a binder solution or dry mixed with the compound to be granulated usually gives problems with a homogeneous distribution because of its sticking nature. This results in an inhomogeneous composition which can cause differences in dissolution and/or o tablet hardness between dosage forms of various batches and therefore differences in bioavailability. Difficulties one may encounter by using dry granulation together with amoxicillin trihydrate are decomposition of potassium clavulanate because of a too high water activity during roller compaction or slugging developed by amoxicillin trihydrate.
It has been found that directly after roller compaction the water activity of compacted amoxicillin trihydrate was increased from 0.1 5 to 0.25 for the powder to 0.35 to 0.45 for the compacts. Furthermore it has been found with Dynamic Vapour Sorption Analyses that potassium clavulanate starts to decompose at relative humidities of 20% and higher at ambient temperatures because of volatile decomposition products formed. Difficulties one may encounter by storing and transporting mixtures of granulated amoxicillin trihydrate and potassium clavulanate are decomposition of potassium clavulanate because of a too high water activity in the mixture developed by the granulated amoxicillin trihydrate. Furthermore, during transportation and processing of mixtures of granulated amoxicillin trihydrate and potassium clavulanate powder, segregation will take piace because of the difference in particle size resulting in inhomogeneous mixtures.
It has been found that during a long period after dry or wet granulation of amoxicillin trihydrate this material still shows water activity of 0.2 to 0.5 that is too high for stable storage conditions of potassium clavulanate. It also has been found that this too high value of water activity was developed by only 0.2 to 0.5 w/w% of free, not crystal bound, water that was detected by Differential Thermal Analyses. Also the active ingredient may dissolve partially in the granulation solution, which after drying will cause a decreased disintegration and dissolution of these granules that are therefore less suitable for tablets, especially disperse tablets.
Surprisingly it is found that granules comprising potassium clavulanate and an inert excipient are relatively stable. Such granules have nowhere been described or suggested in the prior art. Summary of the invention
The present invention provides granules of clavulanate containing inert excipients which are preferably substantially free of solvents with the provisio that the clavulanate has not been dispersed in a polymeric binder of low water vapour permeability. The clavulanate granules are preferably potassium clavulanate and the inert excipient is a cellulose, preferably microcrystalline cellulose, more preferably with a water activity of less than 0.2 at 25°C, most preferably Avicel® PH 1 1 2. The ratio of potassium clavulanate related to microcrystalline cellulose such as Avicel® PH 1 1 2 is 1 : 5 - 0.2 wt%, preferably 1 : 2-0.5 wt% and more preferably about 1 : 1 wt%. These granules are of a particle size between 50 μm and 1 500 μm, preferably between 1 25 μm and 1 000 μm.
Furthermore, a process to prepare said granules has been provided for. The process comprises of feeding, for example, potassium clavulanate powder and inert excipients to a roller compactor to produce compacts, followed by milling said compacts to give granules. These granules are, then, sieved with a sieving device to separate the granules from fine particles, preferably fine particles of < 1 50 μm, more preferably fine particles of < 1 25 μm. The sieving device comprises a tumbler or vibratory sieving machine, preferably a tumbler sieving machine equipped with an air jet system. The fine particles are optionally recirculated to the roller compactor.
The present invention also provides a pharmaceutical composition prepared from blending granules of potassium clavulanate of the invention together with crystals or granules of amoxicillin trihydrate optionally containing excipients and specific excipients specifically used for the preparation of compositions of oral dosage forms like tablets with or without coating, disperse tablets, chewable tablets and oral dry suspension. Detailed description of the invention
The granulation method, wherein clavulanate with inert excipients are used, consists of dry granulation by using compaction forces to build up agglomerates. This may be performed by slugging or roller compacting. The compacts are milled and, then, sieved with a sieving device. The separation of fine particles from coarse granules may be carried out by a dry air sieving procedure. In dry air sieving, the milled compacts are placed on the sieve and air is blown through the bed of milled compacts to separate the granules from the fine particles. The sieving device comprises preferably an air jet system using air with a relative humidity of < 30%, preferably < 20% and a temperature between 1 5 and 25 °C. Furthermore, the sieving device can be coupled directly to the roller compactor or stands separately from the same.
The application of this granulation method results in granules with a satisfactory particle size distribution, viz. between 50 μm and 1 500 μm, preferably between 1 25 μm and 1 000 μm. Moreover, these granules are preferably substantially free of organic solvents and/or water, because during the process of compaction use of these solvents is usually avoided. The only traces of solvent(s) which may be present in the said granules are already present in the starting compound. Furthermore, the present technique eliminates problems in granulation processes due to heat and moisture because potassium clavulanate should be processed in an environment with a relative humidity of 20% or lower at a temperature between 20 and 25 °C because higher humidities start decomposition processes with small amounts of water as reaction products which on their turn continue the decomposition reaction. Since potassium clavulanate is dry granulated together with an inert excipient, preferably Avicel® PH 1 1 2 this has strongly reduced the run-away hazard in comparison with that of the unblended potassium clavulanate. The unblended potassium clavulanate is classified as highly flammable, both according to the European notification directories and the UN transport recommendations. The blend potassium clavulanate in the concentration with Avicel® PH 1 1 2 1 : 1 weight ratio is not flammable. The inert excipients with sufficient binding properties also increase the flowability of the blend with potassium clavulanate to improve the flow through the compacting equipment. Moreover, the dry granulation of potassium clavulanate according to the present invention results in granules with a sufficient high density. This is an advantage because potassium clavulanate is always used in admixture with amoxicillin in relatively high dosages resulting in large tablets. A too low density of the granules would further enlarge the large, difficult swallowable tablets. The clavulanate granules also allow for disintegration of dosage forms into primary drug particles followed by a high dissolution rate because no wet binders are used. This is especially important when dispersable tablets are produced which should have a disintegrating time less than a few minutes. Thus, the resulting potassium clavulanate granules showing excellent flow properties and almost no dust can be mixed with amoxicillin, preferably amoxicillin granules as mentioned in European patent application No. PCT/EP 98/05902 filed on 27-08-1 998, which granules possess the same particle size forming a mixture of both granules not susceptible to segregation. For the preparation of clavulanate granules, a certain amount of clavulanate powder, for instance potassium clavulanate and the excipients, for instance Avicel® PH 1 1 2 with a water activity of less than 0.2 measured at a temperature of 25 ° C, is fed to a roller compactor. The compact materials are milled and, thereafter, sieved by using an air jet system. The sieving device is coupled directly to the roller compactor in order to avoid extra steps or stands separately. The fine particles, preferably the material < 1 25 μm, are recycled to the roller compacting process.
The granules of clavulanate, preferably of potassium clavulanate in combination with granules of amoxicillin, preferably of amoxicillin trihydrate as described in European patent application No. PCT/EP 98/05902 indicated above can be used for all formulations to produce chew, swallow, disperse, effervescent or normal tablets of all sizes, forms and weights, also to fill hard gelatin capsules and to formulate dry syrups and for administering drugs with the help of a dose sipping device. To produce tablets, only excipients have to be mixed with the granules and tablets can be pressed. To fill hard gelatin capsules no excipients are necessary, the granules can directly be filled into capsules or when fast running capsules filling machines are used, some lubricant like magnesium stearate can be mixed with the granules to facilitate the filling process.
To formulate dry oral syrups, flavours, bulking agents such as sugars and preservatives are often used. These excipients are mixed with the granules and bottles for multi dosage use or sachets for single dosage use. Optionally a premix of excipients is prepared and filled into bottles or sachets after which the granules are added separately.
For dose sipping devices, for example, the granules can be placed over a support in a tube having a liquid inlet end and a liquid outlet end; excipients can also be placed over the support, together with the drug granules. Oral administration of therapeutical agents with the help of a dose sipping device has been described in European patent application EP 383503.
The invention will now be described with reference to the following Examples, which are provided purely for illustrative purposes.
Example 1
Preparation of a granulate using slugging and conventional vibration sieving on a small scale
During the preparation procedures the temperature was between 20 and 25 °C and the relative humidity < 20%. Potassium clavulanate powder
( 1 00 g) was mixed with microcrystalline cellulose (Avicel® PH 1 1 2)( 1 00 g) using a Turbula® T2C mixer during 10 minutes. Magnesium stearate ( 1 g) was added and mixed during 2 minutes. The powder mixture was fed to a Korsch EK-0 excenter tablet press equipped with a die and an upper and lower flat punch with a diameter of 1 6 mm.
Slugs were pressed with a thickness of about 3 mm, and a hardness of about 25 N measured with an Erweka® TBH28 hardness tester. The slugs were crushed using an Erweka T32 tablet crusher followed by a milling process using a Peppink® N 1 00 hammer mill equipped with a 3 mm sieve.
The milled material (30 g) was treated as presented below:
The coarse particles and the fines were separated from the milled material using a Retsch Vibro vibrating-sieve working with a vibration amplitude of 2 mm, during 1 0 minutes, and using a 1 000 μm and a 1 25 μm sieve.
The amount of fines < 1 25 μm was 1 9 % w/w.
The amount of coarse particles > 1 000 μm was 8 % w/w.
The yield of granules between 1 25 and 1 000 μm was 73 % w/w. The flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
The granules flowed freely through a funnel with an aperture of 1 2 mm but not through 8 mm, which indicates just sufficient flowability.
Example 2
Preparation of a granulate using slugging and air sieving on a small scale
The milled material (30 g) of example 1 was treated as presented below:
The coarse particles and the fines were separated from the milled material using an Alpine® 200LS-N air-sieve working with an under pressure of 2000 Pa during 3 minutes, and using a 1 000 and a 1 25 μm sieve. The used air had a relative humidity of < 20% and a temperature of 25°C. The amount of fines < 1 25 μm was 42 % w/w. The amount of coarse particles > 1 000 μm was 7 % w/w.
The yield of granules between 1 25 and 1 000 μm was 51 % w/w.
The flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
The granules flowed freely through a funnel with an aperture of 5 mm but not through 2.5 mm, which indicates good flowability.
It is obvious that the air-sieve method separates the fines much more efficient from the coarse particles than the conventional vibrating sieve resulting in a much better flowability of the granules and lower dust content.
Example 3
Preparation of a granulate using roller compaction and air sieving on larger scale
During the preparation procedures the temperature was between 20 and 25 °C and the relative humidity < 20%. Potassium clavulanate powder was mixed with microcrystalline cellulose (Avicel® PH 1 1 2), with a water activity of less than 0.2 at 25 °C. The mixture was fed to a roller compactor. The produced compacts were milled and sieved with an air jet system using a sieve with apertures of 1 50 μm. The particles < 1 50 μm were recycled to the roller compactor.
The amount of fines < 1 50 μm was 32 % w/w.
The amount of coarse particles > 1 000 μm was 5 % w/w. The yield of granules between 1 50 and 1000 μm was 63 % w/w.
The flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
The granules flowed freely through a funnel with an aperture of 5 mm but not through 2.5 mm, which indicates good flowability. Example 4
Preparation of disperse tablets of granules of potassium clavulanate and granules of amoxicillin trihydrate
During the preparation procedures the temperature was between 20 and 25 °C and the relative humidity < 20%. Potassium clavulanate granules ( 1 .52 kg), with a potency of 41 .1 % clavulanic acid, prepared according to example 3, amoxicillin trihydrate granules (2.925 kg), with a potency of 85.5% amoxicillin, 0.095 kg sodium starch glycolate (Explotab®), 0.047 kg magnesium stearate and 0.1 62 kg microcrystalline cellulose (Avicel® PH 1 1 2) were mixed.
About 5000 round, flat tablets were pressed using a Korsch EKO excenter tablet press with the following characteristics: weight 950 mg, diameter 1 8 mm, thickness 6 mm, hardness between 1 1 0 and 1 50 N, disintegration in water of 20°C in less than 60 seconds, dissolution of the labelled amount of amoxicillin within 30 minutes by using the method as described in the U.S. Pharmacopoeia XXIII 1 994, The United States Pharmacopeial Convention Inc. Rochville MD, USA.
The amoxycillin trihydrate granules were prepared as follows:
Amoxicillin trihydrate powder was fed to a Fitzpatrick roller compacter type Chilsonator 4L X 1 0D. The used rolls had a diameter of 25.4 cm and a roll wide of 1 0.2 cm, the roll surface was sinus waved grooved, the roll gap was 3.1 mm. The roll speed was 1 1 rpm, the horizontal feeder speed was 1 7 rpm, the vertical feeder speed 450 rpm and the applied roll pressure 1 1 00 psi.
The compacts were milled using a Minox sieve type MTS 1 200 equipped with an air jet system. The sieve applied had a diameter of 1 20 cm and apertures of 1 50 μm. The air was escaping upwards from a rotating perforated blade fixed horizontal under the sieve. By this action the fine particles were blown off from the coarse particles and sucked downwards through the sieve to the receiver by the action of an under pressure.
The fines < 1 50 μm were recycled from the receiver to the roller compacting process, the material > 1 50 μm, collected from the 1 50 μm sieve, was the final product.

Claims

1 . Granules comprising clavulanate and one or more excipients, with the proviso that the clavulanate has not been dispersed in a polymeric binder of low water vapour permeability.
2. Granules according to claim 1 wherein the clavulanate is potassium clavulanate.
3. Granules according to anyone of the claims 1 or 2 wherein one or more of the excipients is an inert excipient.
4. Granules according to anyone of the claims 1 -3 wherein one or more of the excipients is a cellulose.
5. Granules according to claim 4 wherein the cellulose is a microcrystalline cellulose.
6. Granules according to anyone of the claims 1 -5 wherein the ratio of potassium clavulanate to the inert excipients is 1 : 0.2 - 5 wt%.
7. Granules according to any one of the claims 1 -6 essentially free of solvents.
8. Granules according to anyone of the claims 1 -7 with a particle size between 50 and 1 500 ╬╝m, preferably between 1 25 and 1000 ╬╝m.
9. A process for the preparation of granules defined in anyone of the claims 1 -8, comprising: - feeding a mixture consisting of the powder clavulanate and the excipients to a roller compactor producing compacts, - milling the compacts to produce granules,
- sieving the granules with a sieving device optionally coupled to the roller compactor to separate the granulates from fine particles of < 1 50 ╬╝m, preferably < 1 25 ╬╝m, - optionally recirculating said fine particles to the roller compactor.
1 0. A process according to claim 9 wherein the sieving device comprises an air jet system.
1 1 . A process according to claim 1 0, wherein the sieving device stands separately from the roller compactor.
1 2. Pharmaceutical composition comprising granules of clavulanate as defined in anyone of the claims 1 -8 and amoxicillin suitable for oral administration.
1 3. Pharmaceutical composition according to claim 1 2 comprising granules of potassium clavulanate and granules of amoxicillin trihydrate.
1 4. Oral dosage forms as tablets, capsules, syrups, sachets, dry instant or ready to use, multiple or single dose produced from granules as defined in anyone of the claims 1 1 -1 3.
1 5. Oral delivery form produced from granules as defined in anyone of the claims 1 1 -1 3 for using as a dose sipping device.
PCT/EP1998/007225 1997-11-17 1998-11-09 Granules comprising clavulanate and one or more excipients WO1999025343A1 (en)

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JP52751299A JP2001516365A (en) 1997-11-17 1998-11-09 Granules containing clavulanate and one or more excipients
CN98801549A CN1242705A (en) 1997-11-17 1998-11-09 Granules comprising clavulanate and one or more excipients
AU13379/99A AU1337999A (en) 1997-11-17 1998-11-09 Granules comprising clavulanate and one or more excipients
PL98334517A PL334517A1 (en) 1997-11-17 1998-11-09 Clavulate and one or more of exicipients containing granules
EP98956907A EP0973520A1 (en) 1997-11-17 1998-11-09 Granules comprising clavulanate and one or more excipients
BR9806280-8A BR9806280A (en) 1997-11-17 1998-11-09 Granules comprising clavulanide and one or more excipients
CA002272402A CA2272402A1 (en) 1997-11-17 1998-11-09 Granules comprising clavulanate and one or more excipients
NO993467A NO993467L (en) 1997-11-17 1999-07-14 Granules comprising clavulanate and one or more excipients

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WO2002049618A1 (en) * 2000-12-21 2002-06-27 Smithkline Beecham P.L.C. Amoxycillin pellets
US6660299B2 (en) 1999-04-13 2003-12-09 Beecham Pharmaceuticals Limited Modified release pharmaceutical formulation comprising amoxycillin
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
AT412344B (en) * 2001-04-12 2005-01-25 Sandoz Ag Pharmaceutical composition useful for reducing rapid degradation of the active ingredient comprises clavulanate, in the form of granulated and hydrophobised particles, and an active ingredient
US7011849B2 (en) 2000-10-12 2006-03-14 Beecham Pharmaceuticals (Pte) Limited Second release phase formulation
AT413983B (en) * 2001-04-12 2006-08-15 Sandoz Ag Pharmaceutical composition useful for reducing rapid degradation of the active ingredient comprises clavulanate, in the form of granulated and hydrophobised particles, and an active ingredient
US7217430B2 (en) 1999-04-13 2007-05-15 Beecham Pharmaceuticals (Pte) Limited Compositions and methods of treatment comprising amoxicillin and potassium clavulanate with xanthan
NO20091714A (en) * 2006-11-10 2009-08-03 Atacama Labs Oy Apparatus for dry granulation and method for producing granules from a powder
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WO2009135948A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a high drug load tablet
US8293272B2 (en) * 2003-05-02 2012-10-23 Globopharm Pharmazeutische Produktions-Und Handelsgesellschaft M.B.H. Solid pharmaceutical preparation containing levothyroxine and/or liothyronine salts
US8581134B2 (en) 2006-11-10 2013-11-12 Giovanni Politi Method and apparatus for dry granulation
WO2014033077A1 (en) * 2012-08-28 2014-03-06 Dsm Sinochem Pharmaceuticals Netherlands B.V. Composition comprising an antibiotic and a beta-lactamase inhibitor, wherein at| least one of them is in the form of mini-tablets
US8951562B2 (en) 2006-11-10 2015-02-10 Atacama Labs Oy Method and apparatus or dry granulation
US11504333B2 (en) 2017-07-05 2022-11-22 Novartis Ag Pharmaceutical composition

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JP2014062064A (en) * 2012-09-21 2014-04-10 Ohara Yakuhin Kogyo Kk Method of producing tablets containing valsartan
JP6141472B2 (en) * 2016-03-02 2017-06-07 大原薬品工業株式会社 Method for producing valsartan-containing tablets
CN110051637A (en) * 2019-05-21 2019-07-26 葵花药业集团北京药物研究院有限公司 Amoxicillin and clavulanate potassium preparation and preparation method thereof

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Cited By (31)

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Publication number Priority date Publication date Assignee Title
US6660299B2 (en) 1999-04-13 2003-12-09 Beecham Pharmaceuticals Limited Modified release pharmaceutical formulation comprising amoxycillin
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium 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
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
US7011849B2 (en) 2000-10-12 2006-03-14 Beecham Pharmaceuticals (Pte) Limited Second release phase formulation
WO2002049618A1 (en) * 2000-12-21 2002-06-27 Smithkline Beecham P.L.C. Amoxycillin pellets
AT412344B (en) * 2001-04-12 2005-01-25 Sandoz Ag Pharmaceutical composition useful for reducing rapid degradation of the active ingredient comprises clavulanate, in the form of granulated and hydrophobised particles, and an active ingredient
AT413983B (en) * 2001-04-12 2006-08-15 Sandoz Ag Pharmaceutical composition useful for reducing rapid degradation of the active ingredient comprises clavulanate, in the form of granulated and hydrophobised particles, and an active ingredient
US8293272B2 (en) * 2003-05-02 2012-10-23 Globopharm Pharmazeutische Produktions-Und Handelsgesellschaft M.B.H. Solid pharmaceutical preparation containing levothyroxine and/or liothyronine salts
US8968788B2 (en) 2006-11-10 2015-03-03 Atacama Labs Oy Granules, tablets and granulation
US8951562B2 (en) 2006-11-10 2015-02-10 Atacama Labs Oy Method and apparatus or dry granulation
US8052999B2 (en) 2006-11-10 2011-11-08 Atacama Labs Granules, tablets and granulation
US8581134B2 (en) 2006-11-10 2013-11-12 Giovanni Politi Method and apparatus for dry granulation
NO20091714A (en) * 2006-11-10 2009-08-03 Atacama Labs Oy Apparatus for dry granulation and method for producing granules from a powder
NO347305B1 (en) * 2006-11-10 2023-09-04 Atacama Labs Oy Apparatus for dry granulation and method for producing granules from a powder
US10265272B2 (en) 2006-11-10 2019-04-23 Atacama Labs Oy Method and apparatus for dry granulation
EP2081669B1 (en) 2006-11-10 2018-10-17 Atacama Labs Oy Process and apparatus for for producing granules
US9700513B2 (en) 2006-11-10 2017-07-11 Atacama Labs Oy Method and apparatus for dry granulation
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WO2009135950A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a tablet containing excipients
WO2009135948A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a high drug load tablet
WO2009135949A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a very high drug load tablet
WO2009135949A3 (en) * 2008-05-09 2010-10-28 Atacama Labs Oy Process for preparing a very high drug load tablet
WO2009135951A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a tablet comprising metformin
WO2009135951A3 (en) * 2008-05-09 2010-10-28 Atacama Labs Oy Process for preparing a tablet comprising metformin
WO2009135950A3 (en) * 2008-05-09 2010-10-28 Atacama Labs Oy Process for preparing a tablet containing excipients
WO2009135947A2 (en) * 2008-05-09 2009-11-12 Atacama Labs Oy Process for preparing a low drug load tablet
WO2009135947A3 (en) * 2008-05-09 2010-08-19 Atacama Labs Oy Process for preparing a low drug load tablet
WO2014033077A1 (en) * 2012-08-28 2014-03-06 Dsm Sinochem Pharmaceuticals Netherlands B.V. Composition comprising an antibiotic and a beta-lactamase inhibitor, wherein at| least one of them is in the form of mini-tablets
US11504333B2 (en) 2017-07-05 2022-11-22 Novartis Ag Pharmaceutical composition

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TR199901584T1 (en) 2000-01-21
PL334517A1 (en) 2000-02-28
JO2082B1 (en) 2000-05-21
CA2272402A1 (en) 1999-05-27
CO4980893A1 (en) 2000-11-27
CN1242705A (en) 2000-01-26
NO993467D0 (en) 1999-07-14
AU1337999A (en) 1999-06-07
BR9806280A (en) 2000-02-15
NO993467L (en) 1999-07-14
JP2001516365A (en) 2001-09-25
EP0973520A1 (en) 2000-01-26

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