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
• • 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
  • A61K9/14—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
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/06—Antiabortive agents; Labour repressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/04—Solvent extraction of solutions which are liquid
  • B01D11/0403—Solvent extraction of solutions which are liquid with a supercritical fluid
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/04—Solvent extraction of solutions which are liquid
  • B01D11/0403—Solvent extraction of solutions which are liquid with a supercritical fluid
  • B01D11/0407—Solvent extraction of solutions which are liquid with a supercritical fluid the supercritical fluid acting as solvent for the solute
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/04—Solvent extraction of solutions which are liquid
  • B01D11/0403—Solvent extraction of solutions which are liquid with a supercritical fluid
  • B01D11/0411—Solvent extraction of solutions which are liquid with a supercritical fluid the supercritical fluid acting as solvent for the solvent and as anti-solvent for the solute, e.g. formation of particles from solutions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D11/00—Solvent extraction
  • B01D11/04—Solvent extraction of solutions which are liquid
  • B01D11/0488—Flow sheets

Definitions

• This invention relates to methods for coformulating an active substance and an oligomeric or polymeric excipient. It also relates to the paniculate products of such methods.
• SEDSTM Solution Enhanced Dispersion by Supercritical fluids
• WO-95/01221 and (in modified versions) in WO-96/00610, WO- 98/36825, WO-99/44733 and WO-99/59710. It has been found that this technique may be used to produce novel coformulation products, especially of pharmaceutically active ingredients with oligomer or polymer excipients, having advantageous physicochemical characteristics.
• amorphous phase drugs can also be difficult to control the morphology of the drug in the system, ie, the relative proportions of its crystalline and (more soluble, and hence generally preferred) amorphous phases.
• amorphous phase drugs even in the presence of polymeric excipients, to be meta-stable with respect to the crystalline phase.
• an amorphous drug can revert to its crystalline form, with consequent changes in its dissolution profile.
• the degree of instability may depend on storage temperature (in particular with respect to the glass transition temperature, Tg, of the amorphous solid) and humidity, and on relative drug and excipient concentrations. It can also be affected to some degree by the choice of excipient, and even by the manner in which the drug polymer mixture was prepared. (See references [1] - [5].)
• An active substance such as a drug should have stable characteristics under "normal" storage conditions, typically at room temperature and for shelf lives of at least two years. Thus for pharmaceuticals, standards are being developed which require stability for reasonable periods at 25°C. Previous attempts to coformulate drugs with excipients have generally failed to achieve an amorphous phase active with such a high level of stability; in many cases recrystallisation has been observed within days, if not hours ([1] - [5], supra).
• Matsumoto and Zografi [6] claim more recently to have stabilised the amorphous phase of the drug indomethacin, using poly vinyl pyrrolidone (PVP) as an excipient. They report storage periods of up to 20 weeks at 30°C without recrystallisation, for coformulations containing up to 95% indomethacin. The properties of the system are explained in terms of hydrogen bonding between the drug and polymer, which disrupts the drug dimers associated with the crystalline phase.
• PVP poly vinyl pyrrolidone
• the products of the present invention are coformulations of an active substance, typically a pharmaceutically active substance, with an oligomeric or polymeric material. They contain significant amounts of the active substance in its amorphous form, the stability of which can be much greater than in analogous prior art coformulations. They can be used in particular in the design and manufacture of drug delivery systems, to control drug release and/or enhance bioavailability.
• a coformulation of an active (preferably a pharmaceutically active) substance and an oligomeric or polymeric material in which between 80 and 100% of the active substance is present in an amorphous as opposed to crystalline form, wherein the amorphous phase active substance is stable, with respect to its crystalline form(s), for at least three months after its preparation when stored at between 0 and 10°C, conveniently 6°C. It is preferably also stable, for the same period, when stored at 25°C.
• stable is meant that, over the specified time period, there is no significant change in the X-ray diffraction (XRD) pattern of the coformulation and, where appropriate (ie, where measurable) in its differential scanning calorimetry (DSC) profile. There is preferably no significant change in the dissolution profile of the coformulated active substance. In other words, there is little or no detectable change in the amount of any crystalline form(s) present after the specified time period, preferably less than 10%, more preferably less than 1%, most preferably less than 0.1% change with respect to the initial amount. Yet more preferably, the coformulation contains no detectable crystalline active substance both pre- and post-storage.
• XRD X-ray diffraction
• DSC differential scanning calorimetry
• the coformulation may need to be stored in a protective atmosphere if it is particularly sensitive to humidity.
• Low humidity levels preferably a moisture-free environment or at least between 0 and 5% relative humidity (RH) may be achieved in conventional ways, for instance by storing in moisture resistant packaging or in a desiccator.
• the amorphous phase active substance is preferably stable for at least six, more preferably nine or twelve months after its preparation, and is most preferably stable for at least eighteen, twenty four or thirty six months after its preparation.
• a coformulation according to the mvention is typically an intimate mixture of the active substance dispersed in a "matrix" of the oligomer or polymer excipient, in which the solubility characteristics of the active substance are modified due to the presence of the excipient.
• the dissolution rate of the active substance will be enhanced by coformulating it, but in some cases (for instance of use in "controlled release” drug formulations) it may be inhibited.
• the products of the present invention when made by a SEDSTM process, tend not only to be more stable but also generally less cohesive, more free flowing (having discrete particles) and easier to handle and process, than analogous coformulations made according to more conventional methods (in particular prior art coformulations containing amorphous or even semi-crystalline actives, which can have extremely poor handling properties).
• the products of the invention can also be made with particle sizes down to between 0.1 and 1 ⁇ m, with relatively narrow size distributions.
• Another advantage of the products of the present invention is that they can generally be prepared in the absence of additional surfactants, which many prior art coformulations require as stabilisers. They also usually contain significantly reduced levels of residual solvents. Moreover, since they are precipitated rapidly from homogeneous active/excipient solutions, they tend to contain more uniform active distributions, a characteristic which is especially important when formulating low dosage drugs.
• the coformulations of the invention are preferably prepared by a SEDSTM process, from one or more "target solutions" containing the active substance and/or the oligomeric or polymeric material.
• SEDSTM-coformulated products can contain higher levels of amorphous phase active than is often possible using prior art production methods, and more significantly that the amorphous phase is more stable, with respect to reversion to the crystalline phase, than in conventionally produced coformulations. This may be due to increased intimacy of the active substance/excipient mix, and/or to reduced levels of residual solvent, although we do not wish to be bound by these theories. It may also be the case that the SEDSTM method involves such rapid particle formation that neither the drug nor the excipient molecules are able to group themselves with any degree of order as they precipitate.
• SEDSTM may be used to prepare such coformulations is surprising in view of earlier literature on the process.
• WO-95/01221 there are examples of drug/polymer coformulations (salmeterol xinafoate and hydroxypropyl cellulose), but although these apparently demonstrate "disturbance" of crystallinity, it is clear from the appended DSC/XRD data that significant amounts of the crystalline drug are still present.
• SEDSTM is a fast precipitation process, which might otherwise have been expected to produce amorphous solids, in fact it has been shown to force the majority of organic compounds into a crystalline state.
• the addition of a polymer might be expected, as in Examples 0 and 16 of WO-95/01221, to reduce crystallinity levels, but it would not be predicted to achieve 100% amorphous drug systems, particularly at the relatively high drug loadings now found to be possible (in the past, high levels of polymer (80% or greater) tend to have been needed to give any significant reduction in crystallinity [2]).
• the products of the invention have significantly improved long term stability (with respect to active re-crystallisation), which could not have been predicted from the prior art.
• a SEDSTM process is meant a particle formation technique as described in WO-95/01221, WO-96/00610, WO-98/36825, WO-99/44733 and/or WO-99/59710, in which a supercritical or near-critical (preferably supercritical) fluid anti-solvent is used simultaneously both to disperse, and to extract a fluid vehicle from, a solution or suspension of a target substance.
• a supercritical or near-critical (preferably supercritical) fluid anti-solvent is used simultaneously both to disperse, and to extract a fluid vehicle from, a solution or suspension of a target substance.
• SEDSTM is also a one-step process; it can be used to precipitate both the active substance and the excipient at the same time, either from the same or from separate "target" solutions or suspensions, the target solution(s)/suspension(s) being co- introduced into a particle formation vessel with the anti-solvent, preferably through a coaxial nozzle with an appropriate number of concentric passages.
• the anti-solvent used in the SEDSTM process is preferably supercritical carbon dioxide, although others (eg, as mentioned in the earlier SEDSTM literature) may be used instead or in addition.
• the oligomeric (which includes dimeric) or polymeric material may be any suitable excipient for the active substance, of whatever molecular weight and whether hydrophilic - such as a polyethylene glycol, hydroxypropyl methyl cellulose (HPMC) or polyvinyl pyrrolidone (PVP) - or hydrophobic - such as an ethyl cellulose (EC). It may be a biodegradable oligomer or polymer such as a polylactide or glycolide or a polylactide/glycolide. It may be crystalline, semi-crystalline or amorphous. It may be a homo- or co-oligomer/polymer, synthetic or naturally occurring.
• oligomeric or polymeric materials suitable in particular for coformulation with pharmaceutically active substances include but are not limited to: a) traditional "natural" source materials, their derivatives and their synthetic analogues, such as acacia, tragacanth, alginates (for instance calcium alginate), alginic acid, starch, agar, carrageenan, xanthan gum, chitosan, gelatin, guar gum, pectin, amylase or lecithin.
• traditional "natural" source materials such as acacia, tragacanth, alginates (for instance calcium alginate), alginic acid, starch, agar, carrageenan, xanthan gum, chitosan, gelatin, guar gum, pectin, amylase or lecithin.
• celluloses and cellulose derivatives such as alkyl (for instance methyl or ethyl) cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose, sodium carboxy methyl cellulose, microcrystalline cellulose or microfine cellulose.
• HPC hydroxypropyl cellulose
• hydroxy acids such as lactic and glycolic acids.
• acrylates and their derivatives such as the "Eudragit' TM polymers, methacrylic acids, or methacrylates such as methyl methacrylate.
• hydrated silicas such as bentonite or magnesium aluminium silicate.
• vinyl polymers such as polyvinyl chloride, polyvinyl alcohols, polyvinyl acetates, polyvinyl pyrrolidones, cross-linked polyvinyl pyrrolidones or carboxy vinyl copolymers.
• polymeric surfactants such as polyoxyethylene or polyoxypropylene, or polyalkylene oxides such as polyethylene oxides,
• phospholipids such as DMPC (dimyristoyl phosphatidyl choline), DMPG
• i) carbohydrates such as lactose, dextrans, cyclodextrins or cyclodextrin derivatives.
• j) dendrimeric polymers such as those based on 3,5 hydroxy benzyl alcohol.
• poly(orthoester)s and poly(orthoester)/poly(ethylene glycol) copolymers including block copolymers, such as are described in US-5,968,543 and US- 5,939,453, also derivatives of such polymers, also such polymers with incorporated esters of short chain ⁇ -hydroxy acids or glycolic-co-lactic acid copolymers.
• Suitable oligomers/polymers are listed in the literature on drug delivery systems, for example the report by Brocchini in World Markets Series "Business Briefing", Drug Delivery Supplement [7].
• the oligomeric or polymeric material is preferably either a cellulosic material such as EC, HPC or HPMC (including cellulose derivatives), a vinyl polymer such as a polyvinyl pyrrolidone, a polyoxyalkylene (eg, polyoxyethylene or polyoxypropylene) polymer or copolymer or a polylactide or glycolide (including lactide/glycolide copolymers).
• a cellulosic material such as EC, HPC or HPMC (including cellulose derivatives)
• a vinyl polymer such as a polyvinyl pyrrolidone
• a polyoxyalkylene eg, polyoxyethylene or polyoxypropylene
• a polyoxyalkylene eg, polyoxyethylene or polyoxypropylene
• a polylactide or glycolide including lactide/glycolide copolymers
• the active substance may be a single active substance or a mixture of two or more active substances. It may be monomeric or polymeric, organic (including organometallic) or inorganic, hydrophilic or hydrophobic. It may be a small molecule, for instance a synthetic drug like paracetamol, or a larger molecule such as a (poly)peptide, an enzyme, an antigen or other biological material. It preferably comprises a pharmaceutically active substance, although many other active substances, whatever their intended function (for instance, herbicides, pesticides, foodstuffs, nutriceuticals, etc.), may be coformulated with oligomers or polymers in accordance with the invention.
• the active substance may be a material having low aqueous solubility, for which coformulation with an oligomeric or polymeric excipient can increase the aqueous dissolution rate and hence facilitate delivery.
• SEDSTM may be used to coformulate an active substance with an oligomer or polymer even when their respective hydrophilicities are significantly different. Such pairings might previously have been thought incompatible for coformulation. Examples include coformulations of relatively polar actives such as paracetamol, theophylline or ascorbic acid with hydrophobic polymers such as ethyl cellulose.
• a second aspect of the present invention provides a coformulation of (i) an active substance selected from the group consisting of paracetamol, ketoprofen, indomethacin, carbamazepine, theophylline and ascorbic acid and (ii) an oligomeric or polymeric material, in which between 80 and 100% of the active substance is present in an amorphous as opposed to crystalline form, and in which the active substance represents at least 10% of the coformulation, provided that if the active substance is indomethacin or theophylline, the oligomeric or polymeric material is not polyvinyl pyrrolidone.
• a coformulation according to the invention preferably between 80 and 100%, more preferably between 90 and 100% or between 95 and 100%, most preferably 100%, of the active substance is present in an amorphous as opposed to crystalline form.
• the active substance preferably represents at least 1%, more preferably at least 2% or 5% or 10% or 20% or 25% or 30% or 35% or 40% or 50% or 60% or 70% or 80% or 90% of the system.
• products according to the invention can contain high loadings of the active substance, of which all or substantially all is present as a single amorphous phase.
• Percentage concentrations are weight for weight unless otherwise stated. Wftere the active substance is indomethacin and the excipient is ethyl cellulose (EC), preferably between 95 and 100% of the indomethacin is present in an amorphous form, and the indomethacin represents at least 10%, more preferably at least 20% or 25% or 30% or 35%, of the coformulation.
• EC ethyl cellulose
• the active substance is indomethacin and the excipient is hydroxypropyl methyl cellulose (HPMC), preferably between 95 and 100% of the indomethacin is present in an amorphous form, and the indomethacin represents at least 10%, more preferably at least 20% or 25% or 30% or 35% or 40%, of the coformulation.
• the active substance is indomethacin and the excipient is polyvinyl pyrollidone (PVP), preferably between 95 and 100% of the indomethacin is present in an amorphous form, and the indomethacin represents at least 20%, more preferably at least 25% or 30% or 40% or 50% or 60% or 65% or 70%, of the coformulation.
• PVP polyvinyl pyrollidone
• the active substance is carbamazepine and the excipient is EC, preferably between 95 and 100% of the carbamazepine is present in an amorphous form, and the carbamazepine represents at least 10%, more preferably at least 20% or 25% or 30%, of the coformulation.
• the active substance is carbamazepine and the excipient is HPMC, preferably between 95 and 100% of the carbamazepine is present in an amorphous form, and the carbamazepine represents at least 10%, more preferably at least 20% or 25% or 30%, of the coformulation.
• the active substance is theophylline and the excipient is EC
• the excipient is EC
• the theophylline represents at least 10%, more preferably at least 20% or 25% or 28% or 30%, of the coformulation.
• the active substance is theophylline and the excipient is HPMC, preferably between 95 and 100% of the theophylline is present in an amorphous form, and the theophylline represents at least 1%, more preferably at least 2% or 5% or 8% or 10%, of the coformulation.
• the active substance is ascorbic acid and the excipient is EC
• the excipient is EC
• the ascorbic acid represents at least 1%, more preferably at least 2% or 5% or 8% or 10% or 15%, of the coformulation.
• the active substance is ascorbic acid and the excipient is HPMC, preferably between 95 and 100% of the ascorbic acid is present in an amorphous form, and the ascorbic acid represents at least 10%, more preferably at least 20% or 25% or 30% or 35% or 40%, of the coformulation.
• HPC hydroxypropyl cellulose
• the active substance is a compound of formula (I) and the excipient is a polyoxyalkylene polymer or copolymer, such as a polyoxypropylene-polyoxyethylene copolymer, preferably between 95 and 100% of the Compound (I) is present in an amorphous form, and the Compound (I) represents at least 5%, more preferably at least 10% or 15% or 20% or 24%, of the coformulation.
• the active substance is a compound of formula (FI):
• SEDSTM can allow formation of the amorphous phase of active substances which have (to our knowledge) previously only been prepared in their crystalline phase(s).
• One example of this is the preparation of paracetamol excipient coformulations.
• a third aspect of the present invention therefore provides a coformulation of paracetamol and an oligomeric or polymeric material, in which between 80 and 100% of the paracetamol is present in an amorphous as opposed to crystalline form, and in which the paracetamol represents at least 1% of the coformulation.
• paracetamol coformulations preferably between 90 and 100%, more preferably between 95 and 100%, most preferably 100%, of the paracetamol is present in its amorphous form.
• the paracetamol preferably represents at least 2%, more preferably at least 5%, most preferably at least 8% or 10% or 20% or 25% or 28% or 30% or 35% or 40% or 50% or 60%, of the coformulation.
• the oligomeric or polymeric material is preferably hydrophobic; most preferably it is an ethyl cellulose.
• the amorphous phase paracetamol is preferably stable, with respect to its crystalline form(s), for at least three months, preferably six months, more preferably nine or twelve or eighteen or twenty four or thirty six months, after its preparation, when stored at between 0 and 10°C. It is preferably also stable, for the same period, when stored at 25°C, more preferably also at 40°C. Aspects of the invention can also provide methods for preparing the above described coformulations, using a SEDSTM process, as well as the use of a SEDSTM process to prepare the coformulations.
• the invention provides the use of a SEDSTM process to prepare a coformulation of an active substance and an oligomeric or polymeric material, in which between 80 and 100% of the active substance is present in an amorphous as opposed to crystalline form, and in which the amorphous phase active substance is stable, with respect to its crystalline form(s), for at least three months after its preparation when stored at between 0 and 10°C. It also provides the use of a SEDSTM process to prepare a coformulation of an active substance and an oligomeric or polymeric material, in which between 80 and 100% of the active substance is present in an amorphous as opposed to crystalline form and in which the active substance represents at least 10% of the coformulation.
• composition containing a coformulation according to the first, second or third aspect of the invention.
• the invention further provides a method for preparing a coformulation of an active (preferably a pharmaceutically active) substance and a hydrophobic oligomeric or polymeric excipient, using a SEDSTM process, in which the active substance and the excipient are chosen so that the difference between their respective total specific solubility parameters, ⁇ s , is between -5 and +5, preferably between -2 and +2 and more preferably zero or close to zero.
• the excipient is preferably a cellulose or cellulose derivative such as an ethyl cellulose.
• the invention provides the products of such a method, and the use of a SEDSTM process in it.
• a further aspect of the invention provides a method for preparing a coformulation of an active (preferably pharmaceutically active) substance and an oligomeric or polymeric excipient, using an anti-solvent-induced particle formation process (preferably a SEDSTM process), wherein, under the operating conditions used, the active substance is soluble in the chosen "anti-solvent” but the excipient is not.
• an anti-solvent-induced particle formation process preferably a SEDSTM process
• a preferred "anti-solvent” for this method is supercritical carbon dioxide.
• the active substance is preferably non-polar, as for instance the drug ketoprofen, and the excipient is preferably hydrophilic, for instance HPMC.
• the invention provides the products of such a method, and the use of a SEDSTM process in it.
• a yet further aspect of the invention provides a method for preparing a coformulation of indomethacin and polyvinyl pyrrolidone, using an anti-solvent-induced particle formation process, preferably a SEDSTM process.
• the invention provides the products of such a method, and the use of a SEDSTM process in it.
• SEDSTM can yield active/excipient mixes of sufficient intimacy that the initial "burst" of drug release, which tends to occur in the dissolution profiles of conventional systems, can be inhibited or even prevented.
• Certain coformulations according to the present invention can therefore be used as slow release drug formulations, providing a more uniform rate of drug release without the need for protective coatings or additional reagents. Examples include in particular coformulations of water soluble active substances such as theophylline with relatively hydrophobic excipients such as ethyl cellulose.
• a further aspect of the invention provides a coformulation of an active (preferably a pharmaceutically active) substance and an oligomeric or polymeric excipient, comprising an intimate single-phase mixture of the active substance and the excipient in which between 80 and 100% of the active substance is present in an amorphous as opposed to crystalline form, from which the dissolution rate of the active substance in an aqueous medium is no higher for the first 30 minutes, preferably for the first 60 or 90 or 120 minutes, than it is subsequently.
• Such a coformulation is again preferably prepared by a SEDSTM process.
• COX- 2 selective inhibitor means an organic compound or pharmaceutically acceptable salt or solvate thereof which is capable of selectively inhibiting the COX-2 enzyme over the COX-1 enzyme.
• the COX-2 selective inhibitor may be a diarylheterocycle.
• diarylheterocycle means an organic compound of the diarylheterocycle genus (or a pharmaceutically acceptable salt or solvate thereof), comprising two substituted or unsubstituted phenyl rings each directly attached to adjacent atoms in a five or six- membered heterocycle or both of said phenyl rings directly attached to the same carbon atom of a C ⁇ -3 alkylidene linker, said C 1 .3 alkylidene linker further attached to one atom in said five or six-membered heterocycle.
• the COX-2 selective inhibitor may be a diarylfuranone. As used herein
• diarylfuranone means an organic compound of the diarylfuranone genus (or a pharmaceutically acceptable salt or solvate thereof), comprising two substituted or unsubstituted phenyl rings each directly attached to adjacent carbon atoms in a fiiranone moiety or both of said phenyl rings directly attached to the same carbon atom of a C ⁇ - 3 alkylidene linker, said C ⁇ -3 alkylidene linker further attached to one carbon atom in said furanone moiety.
• the COX-2 selective inhibitor may alternatively be a diarylpyrazole.
• diarylpyrazole means an organic compound of the diarylpyrazole genus (or a pharmaceutically acceptable salt or solvate thereof), comprising two substituted or unsubstituted phenyl rings each directly attached to adjacent atoms in a pyrazole moiety or both of said phenyl rings directly attached to the same carbon atom of a C 1 .3 alkylidene linker, said C).3 alkylidene linker further attached to one atom in said pyrazole moiety.
• the COX-2 selective inhibitor may alternatively be an arylpyridylpyridine.
• arylpyridylpyridine means an organic compound of the arylpyridylpyridine genus (or a pharmaceutically acceptable salt or solvate thereof), comprising one substituted or unsubstituted phenyl ring and one substituted or unsubstituted pyridyl moiety each directly attached to adjacent atoms in a pyridine ring or both said phenyl ring and pyridyl moiety directly attached to the same carbon atom of a C ⁇ -3 alkylidene linker, said C ⁇ - 3 alkylidene linker further attached to one atom in said pyridine ring.
• the COX-2 selective inhibitor is preferably selected from the group consisting of (Z)-3 -[ 1 -(4-bromophenyl)- 1 -(4-methylsulfonylphenyl)methylene] dihydrofuran-2-one, (Z)-3-[ 1 -(4-chlorophenyl)- 1 -(4-methylsulfonylphenyl)methylene] dihydrofiiran-2-one, 4- [5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide, 4-[4- (methylsulfonyl)phenyl]-3-phenyl-2(JH)-furanone and the compound of Formula (HI):
• 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1 H-pyrazol- 1 -yljbenzenesulfonamide is a COX-2 selective inhibitor approved for the treatment of osteoarthritis and rheumatoid arthritis and is marketed in the U.S. under the tradename CELEBREX ® (celecoxib). See, e.g., U.S. 5,466,823 and U.S. 5,563,165, incorporated by reference herein.
• 4-[4-(methylsulfonyl)phe ⁇ yl]-3-phenyl-2(5H)-f ⁇ ranone is a COX-2 selective inhibitor approved for the treatment of osteoarthritis, treatment of primary dysmenorrhea and management of acute pain and is marketed in the U.S. under the tradename VIOXX ® (rofecoxib). See e.g., U.S. 5,474, 995, incorporated by reference herein.
• the compound of Formula (II) is a COX-2 selective inhibitor being developed for the treatment of acute and chronic pain. See WO 99/15503 and related applications incorporated by reference herein. These and other COX-2 selective inhibitors falling within the biarylheterocycle genus or more particularly biarylfurananone and biarylpyrazole genera appear to have low aqueous solubility, suggesting suboptimal bioavailability. Their coformulation with oligomeric or polymeric excipients, in accordance with the present invention, can be expected to enhance their bioavailability
• Figure 1 is a schematic illustration of apparatus usable to carry out methods, and obtain products, according to the invention
• Figures 2-5 are SEM (scanning electron microscope) photographs of some of the starting materials and products of Example I below;
• Figures 6 to 8 show dissolution profiles for three of the systems investigated in Example I;
• FIGS 9 to 19 show plots of crystallinity against drug weight fraction for the systems investigated in Example I;
• Figures 20 to 24 are DSC (differential scanning calorimetry) traces for, respectively, crystalline indomethacin and a number of coformulations prepared in Example I, including after 24 months'storage;
• Figures 25 and 26 are plots of ( ⁇ s ⁇ - ⁇ f) against X (see Table 10 below) for some of the systems investigated in Example I;
• Figures 27 and 28 are SEM photographs of some of the products of Example II.
• Figures 29 and 30 are plots of crystallinity against drug weight fraction for the products of Example II; and Figure 31 is a plot of crystallinity against drug weight fraction for the products of Example HI.
• the following experiments demonstrate the use of a SEDSTM process to coformulate various drugs and polymers in accordance with the present invention.
• the physicochemical characteristics of the products in particular the degree (if any) of drug crystallinity, the stability of the amorphous phase and the relative concentrations of the drug and the polymer (ie, the drug "loading"), were tested and where possible manipulated by altering the operating conditions and solvents present.
• the drugs were chosen to cover a broad range of polarities, including the highly apolar ketoprofen and, in ascending order of polarity, indomethacin, carbamazepine, paracetamol, theophylline and ascorbic acid. These drugs were coformulated with both hydrophobic (EC) and hydrophilic (HPMC) polymers.
• Ketoprofen was on the whole too soluble in supercritical carbon dioxide (the chosen anti-solvent) to produce meaningful results, even under moderate processing conditions. Surprisingly, however, it could be retained to a degree when coformulated with HPMC.
• Example IV the drug glibenclamide was coformulated with 75/25 DL-lactide- c ⁇ -caprolactone.
• WO-96/00610, WO-98/36825, WO-99/44733 and/or WO-99/59710 could be used to similar effect.
• the apparatus is shown schematically in Figure 1, in which 1 is a particle formation vessel; 2 is a device (eg, a filter) for retaining the particles formed; 3 is an oven and 4 a back pressure regulator; and 5 is a nozzle for co-introducing, into the vessel 1, a supercritical anti-solvent from source 6 and a target solution from source 7.
• the items labelled 8 are pumps; 9 is a cooler, 10 a heat exchanger and 11 a pulse dampener.
• a recycling system 12 allows solvent recovery at 13 (via needle valve 14), whilst returning carbon dioxide to the cooler 9 for re-use.
• the nozzles employed at 5 were two-passage coaxial nozzles of the general form depicted in Figure 3 of WO-95/01221, typical dimensions being as described in that document.
• Supercritical carbon dioxide was the chosen anti-solvent, introduced into a 50 ml particle formation vessel via the inner nozzle passage.
• a suitable solvent depended on the properties of both drug and polymer, but particularly on the latter because of the potential difficulties of processing polymeric solutions and dispersions.
• Polymeric dispersions can exhibit very high viscosities, even when dilute, whereas in "good” solvents the polymer matrix will relax and loosen, allowing both a greater degree of interaction and a lower viscosity, important respectively for the production of intimate drug/polymer mixtures and for the processing requirements of SEDSTM [8].
• DSC Differential scanning calorimetry
• Crystallinity was derived from the latent heat of fusion ( ⁇ H f ), using the equation:
• the weight fraction of drug in samples was measured with an UltrospecTM 4000 spectrophotometer (Pharmacia Biotech, Cambridge, England), from reconstituted solutions of the samples.
• the absorbance of the polymers was negligible at the wavelengths used.
• Dissolution testing was carried out using a stirred vessel technique and UV analysis.
• the apparatus consisted of a 1 litre round-bottomed vessel maintained at around 37°C in a water bath, stirred by paddle at 60 rpm. The medium was circulated using a peristaltic pump through a 10 mm flow cell. UV readings were taken every 30 seconds using an UltrospecTM 4000 spectrophotometer (supra) and analysed for up to between 30 and 60 minutes.
• Three systems were analysed: paracetamol/HPMC, theophylline EC and indomethacin/HPMC. The conditions for the individual systems were:-
• Paracetamol/HPMC 247 nm, 37+0.5°C, 500 ml distilled water.
• Theophylline/EC 273 nm, 37 ⁇ 1.0°C, 350 ml distilled water.
• Indomethacin/HPMC 235 nm, 37 ⁇ 0.5°C, 400 ml pH 7.00 ⁇ 0.02 0.05M
• the release profile characteristics were compared with physical mixes to give an indication of polymer/drug interaction and possible complex formation.
• the physical mixes were prepared from pre-micronised drug ground (for 1 minute in a pestle and mortar) together with the designated polymer. Samples were transferred to hard gelatine capsules (size 4 clear/clear, weighted by 60:40 tin/lead wire coils) for analysis. The capsules gave no significant absorbance in the analysis region.
• Aerosizer-AerodisperserTM particle size analyser (Example D
• Particle size analysis was carried out using a time-of-flight analyser (AerosizerTM with AerodisperserTM, TSI Inc, USA). This instrument is capable of sizing dry powder samples over the range 0.2-700 ⁇ m. The powder is dispersed in air and the air/particle suspension is expanded through a nozzle into a partial vacuum. The air/particle stream accelerates through a measuring region, where the particles pass through two consecutive laser beams. Smaller particles experience a greater acceleration than larger ones and hence move more rapidly between the two beams. From measurements of the time taken to travel between the beams and the known density of the material, the AerosizerTM software calculates the mean size distribution of particles present in the sample. The data obtained complements SEM observations. No sample preparation is required.
• This instrument uses laser diffraction to determine particle size distributions of solid paniculate materials. It is capable of measuring across the particle size range 0.1- 8750 ⁇ m.
• a dry powder sample is introduced, via a vibrating conveyor feeder, into a dry dispersing unit. Here the powder and any agglomerates present are fully dispersed in air.
• the dispersion of single particles is then propelled by compressed air and fed through the measuring zone, where the particle stream interacts with a monochromatic high energy beam from a He-Ne laser.
• the laser light is diffracted and detected by a multicomponent photodetector.
• the intensity of the diffracted light is then converted into an electrical signal, which is used to calculate the particle size distribution. Again, the data complements SEM observations. No sample preparation is required.
• Compound (I) and (II) loadings were determined by HPLC using UV detection. An isocratic method was followed, employing a single mobile phase (0.1% phosphoric acid.acetonitrile (62:38 v/v), degassed for 20 minutes before use).
• Quantification was by external standardisation. Two stock solutions of Compound (I) with concentrations of 500 ⁇ gml "1 were prepared in the mobile phase. Appropriate volumes were alternately taken and diluted with mobile phase to produce a set of standard calibrants in the nominal range 2 to 10 ⁇ gml "1 . Aliquots of prepared sample solutions, diluted if necessary, were then submitted to HPLC analysis, interspersed with the calibrant solutions. Using the following nominal conditions a chromatogram was generated.
• Cycle time Typically 17 minutes All peak area measurements and calculations were performed using BorwinTM chromatography software Version 1.22.01.
• HPMC Hydroxypropyl methyl Cellulose
• R is H, CH 3 or [CH j CHtOHjCHJ
• the principal operating conditions were manipulated and optimised for each drug/polymer system. Different drug:polymer concentration ratios were also tested. It was found that temperatures in the range 34-50°C and pressures between 80 and 100 bar were preferable for processing these polymers.
• Anti-solven target solution flow rate ratios (into the particle formation vessel) were between 66: 1 and 200: 1, ie, an anti-solvent flow rate of 20 ml/min was used with target solution flow rates of between 0.1 and 0.3 ml min.
• Nozzle outlet internal diameters were between 100 and 500 ⁇ m, 100 ⁇ m being preferred over those greater than 200 ⁇ m.
• a 1 : 1 mixture of ethanol and dichloromethane (or 1 : 1 ethanol/chloroform in the case of PVP) was used as the drug/polymer solvent. This yielded dispersions of suitably low viscosity, enabling processing without significant nozzle blockage. Similarly, ethanol was found to produce low viscosity dispersions for the EC systems.
• a polymer concentration of 0.5% w/v provided a balance between the ability to pump the solution at a moderate back pressure and an acceptably high material throughput.
• the polymers used were selected from the lower molecular weight fractions - 3 cps HPMC, 7 cps EC and PVP of average molecular weight 10,000.
• Figure 2 shows the indomethacin raw material (at 2000x magnification);
• Figure 3 shows the amorphous indomethacin/HPMC product of experimental run RASE 21 (2000x magnification);
• Figure 4 shows the paracetamol raw material (200x magnification) and
• Figure 5 shows the amorphous paracetamol/HPMC product of experimental run RASF 34 (lOOOx magnification).
• Figures 6 to 8 show dissolution profiles for three of the systems investigated, namely paracetamol: HPMC ( Figure 6), theophylline.EC ( Figure 7) and indomethac ⁇ rHPMC ( Figure 8).
• HPMC paracetamol
• EC theophylline.EC
• indomethac ⁇ rHPMC Figure 8
• the labelling corresponds to that used in Tables 2-9 for the various experimental runs;
• X (%) is the maximum concentration of the amorphous phase of the drug prior to the detection of crystallinity.
• there were significant differences in drug release rates between the SEDSTM-coformulated products and purely physical mixes of the relevant drug and polymer suggesting that the products of the present invention had been formed as intimate molecular level dispersions of a drug in a polymer matrix.
• the release of theophylline was significantly inhibited by coformulating it with EC according to the invention, that of paracetamol was also slightly inhibited by coformulation with HPMC, whilst the dissolution rate of indomethacin was increased on coformulation with HPMC (including one sample above the amorphous detected limit).
• Plots of drug crystallinity (determined by DSC) against drug weight fraction are shown in Figures 9 to 19.
• the systems illustrated are ascorbic acid/EC, ascorbic acid/HPMC, carbamazepine/EC, carbamazepine/HPMC, indomethacin/EC, indomethacin/HPMC, indomethacin/PVP, paracetamol/EC, paracetamol/HPMC, theophylline/EC and theophylline/HPMC respectively.
• Example I The medium to long term storage stability of several of the Example I products was investigated. In all cases the physical properties of the samples were unchanged even after up to 24 months' storage; the samples remained free flowing and easy to handle. Chemical stability (in terms of amorphous phase contents) was assessed using
• the drug in its crystalline form exhibits a peak in DSC profiles at 150-165°C, when analysed at a scanning rate of 20°C/min. This peak shifts to lower temperature in coformulated indomethacin/PVP systems.
• Figures 20 and 21 show DSC profiles for, respectively, the crystalline raw material and the indomethacin/PVP system prepared in experimental run RASE 64. The peak at 139°C in Figure 20 indicates the presence of crystalline indomethacin in the sample (which contained 78% w/w indomethacin, with 30% crystallinity).
• the indomethacin/PVP samples prepared in experimental runs were assessed initially and after both 12 and 24 months' storage in a desiccator at between 2 and 8°C.
• the DSC results indicated no crystallinity in any of the samples even after 24 months.
• An example DSC profile for the RASE 63 sample at 24 months is shown in Figure 22; the absence of the 139°C peak indicates an absence of crystalline indomethacin.
• Three theophylline/EC systems were also tested, after storage at ambient temperature and without desiccation.
• Solubility effects A relationship was observed, in the systems containing the hydrophobic polymer ethyl cellulose, between the amorphous phase drug concentration and the total specific solubility - see Table 1) of the reagents. Insofar as could be inferred from the systems studied, the trend was towards the maximum concentration of amorphous phase (and thus also the maximum drug:polymer interaction) being achieved when the ⁇ s of the drug and the polymer were equivalent or substantially so.
• R is H or [-CH j -CH ⁇ H j )-] ⁇ and:
• the reagents used in the experiments were analytical or HPLC grade.
• the solvent used was a mixture of DCM and ethanol (1: 1), which could dissolve both the drug and the polymer together.
• the (HPC + drug) concentration was varied between 0.5 and 4.5% w/v and the DCM: ethanol ratio was altered where appropriate to increase solution saturation. The ethanol helped to lower the viscosity of the HPCdispersion.
• the operating temperature was 35°C (due to the relatively low melting point of the polymer) and the pressure was varied between 75 and 100 bar.
• DCM was used as a solvent for both Compound (I) and the polymer together, with solution concentrations between 1 and 3% w/v.
• the C0 2 anti-solvent flowed at 18 ml/min and the target solution at between 0.1 and 0.2 ml min.
• Table 13 (appended) summarises the operating conditions for each run.
• nozzle outlet diameters of 100, 200, 400 and 750 ⁇ m were employed, and either a 50 ml or in some cases a 500 ml particle formation vessel.
• nozzle blockages were reduced at lower concentrations (eg, about 80% w/w or lower) of Compound (I).
• concentrations eg, about 80% w/w or lower
• Particle agglomeration could generally be reduced by decreasing the process throughput, for instance by reducing the concentration and/or flow rate of the drug/polymer solution (whilst still maintaining a near saturated solution).
• Compound (I) were produced in run 38, using a 2% w/v target solution with a flow rate of 0.15 ml/min. These conditions were used to produce coformulations for dissolution testing, as well as a control batch of pure Compound (I).
• Supercritical nitrogen was used as the anti-solvent, since supercritical carbon dioxide would plasticise the amorphous polymer excipient.
• the glibenclamide was dissolved in methylene chloride.
• the anti-solvent flow rates were between 15 and 25 litres min "1 , those for the drug solution between 0.05 and 0.1 ml min "1 .
• a 500 ml particle formation vessel was used, at an operating temperature of between 35 and 60°C and a pressure of 100 bar.

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