WO2012095438A1 - Particules et suspensions d'antibiotiques céphalosporine - Google Patents

Particules et suspensions d'antibiotiques céphalosporine Download PDF

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Publication number
WO2012095438A1
WO2012095438A1 PCT/EP2012/050335 EP2012050335W WO2012095438A1 WO 2012095438 A1 WO2012095438 A1 WO 2012095438A1 EP 2012050335 W EP2012050335 W EP 2012050335W WO 2012095438 A1 WO2012095438 A1 WO 2012095438A1
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WO
WIPO (PCT)
Prior art keywords
liquid medium
suspension
cephalosporin
particles
diafiltration
Prior art date
Application number
PCT/EP2012/050335
Other languages
English (en)
Inventor
Hans Peter Niedermann
Heiko Bothe
Original Assignee
Intervet International 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 Intervet International B.V. filed Critical Intervet International B.V.
Publication of WO2012095438A1 publication Critical patent/WO2012095438A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite

Definitions

  • the invention pertains to a method of making particles, particularly crystalline particles, of cefquinome or other cephalosporin antibiotics, and to a method of making
  • the invention also pertains to the use of diafiltration in making particles and suspensions of cephalosporin antibiotics, particularly of
  • Cefquinome is a cephalosporin antibiotic used for humans and animals, inter alia, to treat bovine respiratory disease, Pasteurella infections in pigs, and many other applications where a high antibacterial activity is desired.
  • Cefquinome generally comes as an acid addition salt, preferably a sulfate.
  • the cefquinome sulfate has a chemical structure of the following formula:
  • the drug is presented inter alia as an injection preparation, typically in the form of suspensions, e.g. in ethyl oleate or in the type of esters of saturated coconut and palm kernel oil-derived caprylic and capric fatty acids and glycerine or propylene glycol, known by the trade name of Miglyol.
  • an antibacterial agent in the form of small particles of a narrow particle size range is advantageous compared to coarser material.
  • a practically feasible size distribution of such small particles is, e.g.,
  • cefquinome generally yields stable products, a desire exists to even further improve cefquinome particles in terms of physical stability and to provide cefquinome suspensions that are stable, particularly with reference to lower vulnerability for sedimentation. Moreover, the foregoing should preferably be realized on the basis of cefquinome particles that satisfy the aforementioned size distribution.
  • particles of a cefquinome acid addition salt are prepared by first making a suspension of cefquinome acid addition salt, and precipitating the salt from said suspension.
  • cephalosporin antibiotics it is generally desired to provide the drug in the form of particles, particularly crystalline particles, of a relatively small size, and of a desired size distribution.
  • the cephalosporin antibiotics particles are ultimately formulated into a drug product, preferably in the form of a suspension of said particles.
  • the final drug product is a suspension, in a pharmaceutically acceptable liquid medium such as ethyl oleate, of the crystalline particles as produced in the desired particle size at an earlier stage of the process.
  • the overall process therefore requires not only the controlled precipitation of the particles, but also isolation, drying, packaging, transportation, and formulation. It would be desired to be able to dispense with one or more of the steps in between the formation of the particles (viz. in a suspension) and the production of the final formulation (also a suspension).
  • the invention in one aspect, presents a method of making a composition comprising particles of a cephalosporin antibiotic, wherein the cephalosporin is initially produced in the form of a suspension in a first liquid medium, wherein the suspension is subjected to cross-flow filtration against a further liquid medium, said further liquid medium being selected from media behaving as an anti-solvent for the cephalosporin and pharmaceutically acceptable media capable of retaining the cephalosporin as a suspension.
  • the invention provides the use of a diafiltration method in the production of particles, particularly crystalline particles of a cephalosporin antibiotic.
  • the invention provides a method of isolating cephalosporin antibiotics particles from a solution or suspension in a liquid medium by the addition of an anti-solvent for the antibiotic, wherein anti-solvent is added by means of diafiltration.
  • the invention provides a method of making a pharmaceutical formulation comprising a suspension of a cephalosporin antibiotic in a pharmaceutically acceptable liquid medium, wherein the formulation is made from a crystalline suspension in a processing liquid medium, and wherein said pharmaceutically acceptable liquid medium is substituted for said processing liquid medium by means of diafiltration.
  • the invention pertains to the use of liquid medium exchange by diafiltration, in the preparation of suspensions of cephalosporin antibiotics.
  • Fig. 1 shows a schematic set-up of an embodiment of the invention in which diafiltration is used in the generation of cephalosporin particles.
  • Fig. 2 shows a schematic set-up of an embodiment of the invention in which diafiltration is used in directly converting a sterile cephalosporin suspension as obtained in a particle generation step, into a drug product (suspension formulation in a pharmaceutically acceptable liquid medium).
  • the invention is based on the judicious recognition to use diafiltration as a method for exchange of liquid media, in the preparation of suspensions of cephalosporin antibiotics.
  • the method can be applied either in the working-up of the cephalosporin from its synthesis so as to obtain the
  • cephalosporin in particulate form, or in the direct production of a drug product comprising the cephalosporin, wherein the step of first isolating particles can be bypassed.
  • cephalosporins are a class of beta-lactam antibiotics generally being considered derivatives of 7-aminocephalosporanic acid. Many cephalosporins are on the market. The non-proprietary names generally start with "cef” (and sometimes ceph). Preferred cephalosporins include cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, ceftiofur, cephapirin, cefotaxime, cefadroxil, cephalexin, cefovectin, cefazolin, cephalothin, and cefquinome. More preferably the cephalosporin is cefquinome, and most preferably a cefquinome acid addition salt.
  • a suitable acid is added to the betaine solution.
  • These acids can be organic or inorganic, monobasic or dibasic acids, with mineral acids being preferred.
  • cefquinome acid addition salts include cefquinome dihydrochloride, cefquinome dihydroiodide, cefquinome sulfate, cefquinome-6-hydroxy naphthoate, cefquinome-naphthoate, cefquinome 2,4 dihydroxy benzoate.
  • the most preferred salt is the cefquinome sulfate.
  • Cephalosporins generally come as suspensions in a pharmaceutically acceptable liquid medium, particularly in the form of a suspension in an oily base, being a vegetable oil or a mineral oil or mixtures thereof, e.g. peanut oil, castor oil, ethyl oleate, liquid paraffin, MCT oil (see below) or, Miglyol® (see below).
  • the base preferably comprises a pharmaceutical acceptable low viscosity oily medium, such as medium chain triglyceride or a mixture of medium chain triglycerides.
  • MCT oil Medium chain triglycerides
  • MCT oil have fatty acid chains of 6 - 12 carbon atoms and for the medically refined grades of MCT oil each chain has 8 - 10 carbon atoms.
  • the MCT oil may comprise either triglycerides of the C8-C10 fatty acids, or propylene glycol diesters of these fatty acids or a mixture of both triglycerides and propylene glycol diesters.
  • these C8 -C10 fatty acids are fully saturated, such as n-caprylic and n-capric acids.
  • These are conveniently prepared by the commercial fractionating of naturally occurring vegetable (e.g. coconut) oil to give mainly C8-10 fatty acids followed by esterification of these acids with a chosen alcohol. Fractionated vegetable oil having the desired composition is commercially available.
  • Proprietary examples of such oils are Miglyol® 812 as capric/caprylic triglycerides and Miglyol® 840 as propylene glycol dicaprylate/caprate.
  • the suspension is made by first making solid particles, preferably crystalline particles, which are isolated, dried, micronized, packaged, and transported and, ultimately, rendered into a
  • the micronization step can be avoided, via the process of copending application no PCT/EP2010/060376.
  • the step of particle generation is conducted in such a way as to obtain a suspension of crystalline particles of the desired particle-size distribution.
  • the step of particle generation will result in a suspension (particularly a sterile suspension)
  • the liquid medium of the suspension will have to be changed in favor of an anti-solvent in order to have the particles precipitate (e.g. acetone in the case of cefquinome sulfate).
  • This step and the relatively high amounts of anti-solvent needed, considerably reduces the batch size at which the cephalosporin particles can be produced.
  • the present inventors have found a way of adding the anti-solvent by means of diafiltration (cross-flow filtration). An advantage hereof is that a much lower amount of anti-solvent is required, and the particles can be produced at desired commercial batch sizes.
  • the invention is a method of making a composition comprising particles of a cephalosporin antibiotic, wherein the cephalosporin is initially produced in the form of a suspension in a first liquid medium, wherein the suspension is subjected to cross-flow filtration against a further liquid medium, and wherein said further liquid medium is selected from media behaving as an anti-solvent for the cephalosporin.
  • Anti-solvents are known, and when a cephalosporin is given, it is within the ambit of the average skills of the artisan to select suitable anti-solvents.
  • a suitable anti-solvent is acetone or a mixture of water and acetone wherein acetone is the major component.
  • the composition of the further liquid medium can be changed as desired during the process, e.g. by gradually increasing the amount of acetone in the case of using a mixture of water and acetone as an anti-solvent.
  • the composition comprising particles of a cephalosporin antibiotic in fact comprises the isolated (precipitated) particles as such.
  • the further liquid medium is selected from
  • the preferred embodiment uses the diafiltration of the suspension of cephalosporin particles to add the eventual liquid medium of the drug product, i.e. the aforementioned oily liquid.
  • composition comprising particles of a cephalosporin antibiotic is a pharmaceutical composition in the form of a suspension of the
  • cephalosporin antibiotic in a pharmaceutically acceptable liquid medium.
  • this embodiment of the invention allows a direct step from a sterile crystal suspension towards a final drug product suspension.
  • these liquid media may or may not be sufficiently miscible with each other so as to conduct the diafiltration. In the latter case it is preferred to conduct an additional diafiltration with an intermediate (second) liquid medium, that is miscible with both the first liquid medium (in which the crystals are produced) and the further liquid medium (the pharmaceutically acceptable liquid medium in the drug product).
  • second liquid medium that is miscible with both the first liquid medium (in which the crystals are produced) and the further liquid medium (the pharmaceutically acceptable liquid medium in the drug product).
  • Miglyol® (30) 35% acetone (0,32) 50% liquid paraffin (110-230) 15% yes ethyloleate (6.5) 25% acetone (0,32) 25% liquid paraffin (110-230) 50% yes ethyloleate (6.5) 22% acetone (0,32) 30% liquid paraffin (110-230) 48% yes
  • a cephalosporin suspension is subjected to cross-flow filtration against a further liquid medium, said further liquid medium being selected from media behaving as an anti-solvent for the cephalosporin and pharmaceutically acceptable media capable of retaining the cephalosporin as a suspension.
  • the pharmaceutically acceptable liquid medium will generally not be a solvent for the cephalosporin, as it retains a suspension thereof. It will also be understood, in view of the above embodiment to make use of an intermediate liquid medium, that the invention encompasses the indirect exchange of the liquid medium in the initially obtained suspension with the final pharmaceutically acceptable liquid medium.
  • Cross-flow filtration is a known technique, normally used for entirely different purposes. Typical uses include waste-water treatment, the production of purified water or salt water purification. A typical use in pharmaceutical industry is for the enrichment of a fermentation slurry. A further typical use in health care environment is the well known dialysis of human blood.
  • diafiltration is a membrane based separation that is used to reduce, remove or exchange salts and other small molecule contaminant from a process liquid or dispersion. The process essentially involves passing a feed flow across a membrane filter on one side, and passing a clean liquid across the membrane filter on the other side, in the opposite direction.
  • This type of filtration is typically selected for feeds containing a high proportion of small particle size solids (where the permeate is of most value) because solid material can quickly block (blind) the filter surface with dead-end filtration.
  • the process fluid is typically diluted by a factor of two using "clean" liquid, brought back to the original concentration by filtration, and the whole process repeated several times to achieve the required concentration contaminant.
  • the "clean" liquid is added at the same rate as the permeate flow.
  • Cross-flow filtration refers to the fact that the majority of the feed flow travels tangentially across the surface of a filter, rather than into the filter. The principle advantage of this is that the filter cake (which can blind the filter) is substantially washed away during the filtration process, increasing the length of time that a filter unit can be operational. It can be a continuous process, unlike batch-wise dead-end filtration.
  • the technique is used in the invention to precipitate solids (viz. cephalosporin particles), which in classical filtration would mean keeping them as a retentate.
  • the technique is used to transfer cephalosporin from one suspension to another, which is entirely incomparable with normal (filtration-type) used of diafiltration.
  • the filter will preferably be a ceramic membrane.
  • filters are known, and are made of, e.g., silicon, silicon nitride, silicon oxynitride, silicon carbide, silicides, alumina, zirconium oxide, magnesium oxide, chromium oxide, titanium oxide, titanium oxynitride, titanium nitride, yttrium barium copper oxides, or as composite membrane, made of polymer membranes based on polyvinylalcohols, polyimides, polyacrylamides, polysiloxanes, polydimethylsiloxanes, ethylene-propylene diene, polynorbonene, polyoctenamer, polyurethane, butadiene, nitrile butadiene rubber, polyethylene, polypropylene, polyvinylidene difluoride, derivatives and mixtures thereof, on an inorganic (e.g. ceramic or zeolithe) surface layer
  • the filter membranes can have
  • the membrane has pores, which presents the skilled person with the choice of a pore size.
  • the lower limit in the present invention is 1 nm diameter.
  • the upper limit is 10 ⁇ .
  • the diafiltration process can be conducted in equipment known in the art.
  • the equipment will comprise a filtration unit (1) comprising a tubular or disc diafiltration membrane (2), an inlet (3) for the flow (a) of liquid to be subjected to diafiltration, an outlet (4) for a flow of retentate (b) and an outlet (5) for a flow of permeate (c); said filtration unit comprises fluid connections (flows a and c above) with a mixing unit (6), comprising a vessel (7) provided with an agitator (8), an inlet (9) for a flow of anti-solvent (d), in the figure indicated with reference to acetone, an inlet (10) for the flow of permeate (c), and an outlet (11) for a flow of liquid (a), i.e. a suspension, from the vessel (7) to the filtration unit (1), driven by a pump unit (12).
  • a filtration unit (1) comprising a tubular or disc diafiltration membrane (2), an inlet (3) for the flow (a) of liquid to be subjected to diafiltration, an outlet (4) for
  • Fig. 1 the equipment is presented for use in generating cefquinome (or other cephalosporin antibiotic) crystalline particles, with reference to the use of acetone as the anti-solvent flow (d) and comprising a valve (13) allowing the flow of liquid (a) to either be led to a separation unit (not shown) so as to obtain solid particles, or to the filtration unit (1) for further diafiltration.
  • Fig. 2 the aforementioned equipment is presented for use in generating a cefquinome (or other cephalosporin antibiotic) drug product (suspension), with reference to the use of a choice of carrier liquids as the anti-solvent flow (d) and wherein the valve (13) allows the flow of liquid (a) to either be led to a drug product filling line (not shown), or to the filtration unit (1) for further diafiltration.
  • the invention in one aspect, also relates to the use of a diafiltration method in the production of particles of a cephalosporin antibiotic.
  • cephalosporin drug products requires a step of adjusting particle size, and requires a step of formulating the drug product as a suspension in a pharmaceutically acceptable liquid.
  • the former step generally requires the use of liquids, such as acetone, that are not pharmaceutically acceptable.
  • the use of a diafiltration method according to the invention presents a much more economical process, with a lower risk of losing sterility in intermediate process steps, than in classical processes where cephalosporin particles first need to be isolated, and later reformulated.
  • the invention also pertains to the use of liquid medium exchange by diafiltration, in the preparation of suspensions of
  • the invention relates to a method of making a pharmaceutical formulation comprising a suspension of a cephalosporin antibiotic in a pharmaceutically acceptable liquid medium, wherein the formulation is made from a crystalline suspension in a processing liquid medium, and wherein said pharmaceutically acceptable liquid medium is substituted for said processing liquid medium by means of diafiltration.
  • the invention also pertains to a method of isolating cephalosporin antibiotics particles from a solution or suspension in a liquid medium (particularly a sterile suspension), by the addition of an anti-solvent for the antibiotic, wherein anti-solvent is added by means of diafiltration.
  • cephalosporin antibiotics the production of a suspension of particles, notably of crystalline cephalosporin, it is important that sterility be
  • the invention presents a method of making particles of a
  • cephalosporin antibiotic particularly cefquinome
  • the diafiltration can be with anti-solvent, in which case a precipitate is obtained of particles as such.
  • the diafiltration can also be with a pharmaceutically acceptable suspension medium. In that case several process steps of isolating, drying, transporting of particles can be avoided, because the suspension resulting from the synthesis of the particles is directly turned into a final drug product formulation.
  • the diafiltration trials were done based on a cefquinome sulfate suspension with contents of 7,5-8% cefquinome sulfate in a mixture of acetone and water with a ratio of 2: 1. as described in (PCT/EP2010/060376).
  • the suspension was given to a jacketed and stirrable reservoir. By switch on the pump the loop was started.
  • the desired temperature could be controlled by cooling the jacketed vessel. According to the valve position the permeate was recirculated into the reservoir or discharged during the concentration step and diafiltration step.
  • D diafiltration factor
  • the time needed for concentration and diafiltration was half the time as for the appropriate experiments, due to doubling the specific surface area per suspension volume. No scale up effect was detected.
  • Example 7
  • Example 7 was performed according to example 1 , using ceramic discs with a porosity of 60 nm and an appropriate equipment. 6.1 L of the crystal suspension was diafiltrated with 25 L of acetone, resulting in a calc. water content of lower than 1 %. The final suspension was filtrated with a filtration rate of ⁇ 0.1 min/g.
  • Example 8
  • Cefalonium-dihydrat was suspended in acetone: water 2: 1 , resulting in a suspension of 10% cefalonium-dihydrat related to water.
  • the diafiltration process was carried out with the same filter equipment as described in example 7.
  • the initial suspension for this experiment had a content of 7.5-8% Cefquinome sulfate in a mixture of acetone and water with a ratio of 2: 1.
  • Membrane type porosity 150 kD; area 220 cm 2
  • the resulting ethyloleate suspension had an acetone content ⁇ 0.2%, water content ⁇ 0.4 % and a cefquinome sulphate content of 8.6%.

Abstract

L'invention concerne un procédé de fabrication de particules d'un antibiotique céphalosporine, en particulier le céfquinome, dans lequel on utilise la diafiltration. La diafiltration peut être effectuée avec un anti-solvant, dans ce cas, un précipité de particules telles quelles est obtenu. La diafiltration peut également être effectuée avec un milieu de suspension pharmaceutiquement acceptable. Dans ce cas, plusieurs étapes de traitement d'isolement, de séchage, de transport de particules peuvent être évitées, puisque la suspension résultant de la synthèse des particules est directement transformée en une formulation de produit médicamenteux final.
PCT/EP2012/050335 2011-01-12 2012-01-11 Particules et suspensions d'antibiotiques céphalosporine WO2012095438A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP11150745.5 2011-01-12
EP11150745 2011-01-12

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WO2012095438A1 true WO2012095438A1 (fr) 2012-07-19

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0280157A2 (fr) 1987-02-25 1988-08-31 Hoechst Aktiengesellschaft Sels d'addition cristallins de dérivés céphem et procédé pour leur préparation
WO2001021290A1 (fr) * 1999-09-17 2001-03-29 Danish Separation Systems As Procede et appareil destines a la diafiltration continue par ecoulement croise
WO2003063877A1 (fr) 2002-02-01 2003-08-07 Akzo Nobel N.V. Composition de cefquinome pour administration intra-mammaire chez le betail
WO2004037265A1 (fr) * 2002-10-25 2004-05-06 Akzo Nobel N.V. Composition pharmaceutique a liberation prolongee
US20060100424A1 (en) 2004-11-08 2006-05-11 Acs Dobfar S.P.A. Process for producing Cefepime and cephalosporin analogues

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0280157A2 (fr) 1987-02-25 1988-08-31 Hoechst Aktiengesellschaft Sels d'addition cristallins de dérivés céphem et procédé pour leur préparation
WO2001021290A1 (fr) * 1999-09-17 2001-03-29 Danish Separation Systems As Procede et appareil destines a la diafiltration continue par ecoulement croise
WO2003063877A1 (fr) 2002-02-01 2003-08-07 Akzo Nobel N.V. Composition de cefquinome pour administration intra-mammaire chez le betail
WO2004037265A1 (fr) * 2002-10-25 2004-05-06 Akzo Nobel N.V. Composition pharmaceutique a liberation prolongee
US20060100424A1 (en) 2004-11-08 2006-05-11 Acs Dobfar S.P.A. Process for producing Cefepime and cephalosporin analogues

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