EP2328555A2 - Compositions for the treatment of neoplastic diseases - Google Patents

Compositions for the treatment of neoplastic diseases

Info

Publication number
EP2328555A2
EP2328555A2 EP09785003A EP09785003A EP2328555A2 EP 2328555 A2 EP2328555 A2 EP 2328555A2 EP 09785003 A EP09785003 A EP 09785003A EP 09785003 A EP09785003 A EP 09785003A EP 2328555 A2 EP2328555 A2 EP 2328555A2
Authority
EP
European Patent Office
Prior art keywords
docetaxel
composition
pvp
taxane
solid dispersion
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09785003A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jacob Hendrik Beijnen
Johannes Henricus Matthias Schellens
Johannes Moes
Bastiaan Nuijen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Netherlands Cancer Institute
SLOTERVAART PARTICIPATIES BV
Original Assignee
Netherlands Cancer Institute
SLOTERVAART PARTICIPATIES BV
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
Priority claimed from PCT/GB2008/002854 external-priority patent/WO2009027644A2/en
Application filed by Netherlands Cancer Institute, SLOTERVAART PARTICIPATIES BV filed Critical Netherlands Cancer Institute
Publication of EP2328555A2 publication Critical patent/EP2328555A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to pharmaceutical compositions.
  • compositions for the treatment of neoplastic disease are particularly useful.
  • oral anticancer drug in oral form provides a number of advantages.
  • the availability of an oral anticancer drug is important when treatment must be applied chronically to be optimally effective e.g., the 5-fluorouracil (5-FU) prodrugs (e.g. capecitabine) and drugs that interfere with signal transduction pathways or with the angiogenesis process [I].
  • oral drugs can be administered on an outpatient basis or at home, increasing convenience and patient quality of life, and possibly decreasing costs by reducing hospital admissions [2]. Therefore, it is advantageous to try to administer anticancer drugs orally.
  • the oral administration of drugs is convenient and practical.
  • anticancer drugs unfortunately have a low and variable oral bioavailability [I].
  • Typical examples are the widely used taxanes, docetaxel and paclitaxel, which have an oral bioavailability of less than 10% [3, 4].
  • Several other anticancer agents with higher bioavailability demonstrate higher variability. Examples include the topoisomerase I inhibitors, the vinca alkaloids, and mitoxantrone [1, 5, 6].
  • the variable bioavailability may result in unanticipated toxicity or decreased efficacy when therapeutic plasma levels are not achieved.
  • Hellriegel et al. demonstrated in a study that the plasma levels after oral administration are generally more variable than after i.v.
  • Adequate oral bioavailability is important when the period of drug exposure is a major determinant of anticancer therapy [8]. Adequate oral bioavailability is also important to prevent high local drug concentrations in the gastro-intestinal tract that may give local toxicity.
  • a problem associated with the prior art is that it has not been possible to develop an oral composition comprising a taxane in which the taxane has a high bioavailability with low variability.
  • Clinical studies with oral paclitaxel [e.g. 3] and oral docetaxel [e.g. 9] have been executed by the inventors where the i.v. taxane formulations (also containing excipients such as Cremophor EL and ethanol, or polysorbate 80 and ethanol) were ingested orally. Nausea, vomiting and an unpleasant taste are frequently reported by the patients.
  • PVP-K30 only increased the solubility of docetaxel to about 0.8 ⁇ g/ml after 20 minutes and to a maximum of about 4.2 ⁇ g/ml after about 300 minutes (see Figure 2).
  • Glycerol monostearate hardly increased the solubility of docetaxel at all.
  • the solubility and dissolution rate of docetaxel was not increased to a particularly high level.
  • a drug In order to achieve good oral bioavailability, a drug must have a relatively high solubility and dissolution rate so that there is a high enough amount of the drug in solution available for absorption within the first about 0.5 to 1.5 hours.
  • the present invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane, a hydrophilic carrier and a surfactant, wherein the amorphous taxane is prepared by a solvent evaporation method.
  • composition of the invention is that the solubility of the taxane, the rate of dissolution of the taxane and/or the amount of time which the taxane remains in solution before starting to crystallise is increased to a surprising degree. These factors result in a significant increase in the bioavailability of the taxane. It is thought that this is due, at least in part, to the taxane being in a more amorphous state compared to the apparent amorphous taxane produced by other methods which are unlikely to be truely amorphous. Crystalline taxanes have very low solubilities.
  • the carrier helps to maintain the taxane in an amorphous state. Further, when the taxane is placed in aqueous media, the carrier helps to maintain the taxane in a supersaturated state in solution. This helps to stop the taxane from crystallising or increases the length of time before the taxane starts to crystallise in solution. Therefore, the solubility and dissolution rate of the taxane remain high. Further, the carrier gives good physical and chemical stability to the composition. It helps to prevent the degradation of the taxane and also helps to prevent the substantially amorphous taxane from changing to a more crystalline structure over time in the solid state. The good physical stability ensures the solubility of the taxane remains high.
  • the surfactant also helps to maintain the taxane in an amorphous state when placed in aqueous media and, surprisingly, substantially increases the solubility of the taxane compared to compositions comprising an amorphous taxane and a carrier.
  • substantially amorphous means that there should be little or no long range order of the position of the taxane molecules. The majority of the molecules should be randomly orientated. A completely amorphous structure has no long range order and contains no crystalline structure whatsoever; it is the opposite of a crystalline solid. However, it can be hard to obtain a completely amorphous structure for some solids. Therefore, many "amorphous" structures are not completely amorphous but still contain a certain amount of long range order or crystallinity. For example, a solid may be mainly amorphous but have pockets of crystalline structure or may contain very small crystals so that it is bordering on being truly amorphous.
  • the term "substantially amorphous” encompasses solids which have some amorphous structure but which also have some crystalline structure as well.
  • the crystallinity of the substantially amorphous taxane should be less than 50%.
  • the crystallinity of the substantially amorphous taxane is less than 40%, even more preferably, less than 30%, more preferably still, less than 25%, even more preferably, less than 20%, more preferably still, less than 15%, even more preferably, less than 12.5%, more preferably still, less than 10%, even more preferably, less than 7.5%, more preferably still, less than 5% and most preferably, less than 2.5%. Since crystalline taxanes have low solubility, the lower the crystallinity of the substantially amorphous taxane, the better the solubility of the substantially amorphous taxane.
  • the substantially amorphous taxane can be prepared using any suitable solvent evaporation method. Suitable solvent evaporation methods are, for example, spray drying and vacuum drying as described in [18]. Preferably, the solvent evaporation method is spray drying. Surprisingly, it has been found that preparing the amorphous taxane using a solvent evaporation method, in particular spray drying, results in the composition having a particularly good solubility, dissolution rate and/or remains in solution for longer before starting to crystallise compared to compositions prepared using other methods. This is thought to be due to the solvent evaporation method producing a more amorphous taxane compared to other methods.
  • the composition for oral administration is in a solid form.
  • the solid composition can be in any suitable form as long as the taxane is in a substantially amorphous state.
  • the composition can comprise a physical mixture of amorphous taxane, carrier and surfactant.
  • the carrier and/or the surfactant are also in a substantially amorphous state.
  • the taxane and carrier are in the form of a solid dispersion.
  • solid dispersion is well known to those skilled in the art and means that the taxane is partly molecularly dispersed in the carrier. More preferably, the taxane and carrier are in the form of a solid solution.
  • solid solution is well known to those skilled in the art and means that the taxane is substantially completely molecularly dispersed in the carrier. It is thought that solid solutions are more amorphous in nature than solid dispersions. Methods of preparing solid dispersions and solid solutions are well known to those skilled in the art [11, 12]. Using these methods, both the taxane and carrier are in an amorphous state. When the taxane and carrier are in the form of a solid dispersion or solution, the solubility and dissolution rate of the taxane is greater than a physical mixture of amorphous taxane and carrier.
  • the crystallinity of the solid dispersion or solution should be less than 50%.
  • the crystallinity of the solid dispersion or solution is less than 40%, even more preferably, less than 30%, more preferably still, less than 25%, even more preferably, less than 20%, more preferably still, less than 15%, even more preferably, less than 12.5%, more preferably still, less than 10%, even more preferably, less than 7.5%, more preferably still, less than 5% and most preferably, less than 2.5%.
  • the surfactant can be in a physical mixture with the solid dispersion or solution.
  • the composition comprises a taxane, carrier and surfactant in the form of a solid dispersion or, more preferably, a solid solution.
  • the advantage of having all three components in a solid dispersion or solution is that it enables the use of a lower amount of surfactant to achieve the same improvement in solubility and dissolution rate.
  • the taxane, carrier and surfactant are all in a substantially amorphous state.
  • Solid dispersions or solid solutions of taxane and carrier; or taxane, carrier and surfactant can be produced using any suitable solvent evaporation method, as described above.
  • the solid dispersion or solid solution is prepared by spray drying.
  • preparing the solid dispersion or solid solution using a solvent evaporation method, in particular spray drying results in the composition having particularly good solubility characteristics so that the taxane has a good solubility, dissolution rate and/or remains in solution for longer before starting to crystallise compared to compositions prepared using other methods. This is thought to be due to the solvent evaporation method producing a composition in which all the components are in a more amorphous state compared to other methods. In other methods, it has been found that one or more of the components may still have some crystalline nature which is thought to result in the composition having reduced solubility characteristics and/or physical stability in solution.
  • the composition can be contained in a capsule for oral administration.
  • the capsule can be filled in a number of different ways.
  • the amorphous taxane may be prepared by spray drying, powdered, combined with the carrier and surfactant, and then dispensed into the capsule.
  • the composition can be compressed into tablets.
  • the amorphous taxane may be prepared by spray drying, powdered, mixed with the carrier and surfactant (and optionally other excipients), and then an appropriate amount compressed into a tablet.
  • Taxanes are diterpene compounds which originate from plants of the genus Taxus (yews). However, some taxanes have now been produced synthetically or semi synthetically. Taxanes inhibit cell growth by stopping cell division and are used in treatment of cancer. They stop cell division by disrupting microtubule formation. They may also act as angiogenesis inhibitors.
  • taxane includes all diterpene taxanes, whether produced naturally or artificially, functional derivatives and pharmaceutically acceptable salts or esters which bind to tubulin.
  • Taxanes containing groups to modify physiochemical properties are also included within the present invention.
  • polyalkylene glycol such as polyethylene glycol
  • saccharide conjugates of taxanes with improved or modified solubility characteristics, are included.
  • the taxane of the composition can be any suitable taxane as defined above.
  • Preferred taxanes are docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.
  • BMS-275183 is a C-3'-t-butyl-3'-N-t-butyloxycarbonyl analogue of paclitaxel [10]. More preferably, the taxane is selected from docetaxel, paclitaxel, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.
  • the hydrophilic carrier of the composition is an organic compound capable of at least partial dissolution in aqueous media at pH 7.4 and/or capable of swelling or gelation in such aqueous media.
  • the carrier can be any suitable hydrophilic carrier which ensures that the taxane remains in an amorphous state in the composition and increases the solubility and dissolution rate of the taxane.
  • the carrier is polymeric.
  • the carrier is selected from: polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinylalcohol (PVA); crospovidone (PVP-CL); polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-VA); cellulose derivatives such as methylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate; polyacrylates; polymethacrylates; sugars, polyols and their polymers such as mannitol, sucrose, sorbitol, dextrose and chitosan; and cyclodextrins. More preferably, the carrier is selected from PVP, PEG and PVP-VA, more preferably still, the carrier is selected from PVP and PVP-VA. In one embodiment, the carrier is PVP. In an alternative embodiment, the carrier is PVP-VA
  • the carrier is PVP
  • it can be any suitable PVP [16] to act as a carrier and to help keep the taxane in an amorphous state.
  • the PVP may be selected from PVP-K12, PVP-KI5, PVP-K17, PVP- K25, PVP-K30, PVP-K60, PVP-K90 and PVP-K120.
  • the PVP is selected from PVP-K30, PVP-K60 and PVP-K90.
  • the PVP is PVP-K30.
  • the carrier is PEG
  • it can be any suitable PEG [16] to act as a carrier and to help keep the taxane in an amorphous state.
  • the PEG may be selected from PEGl 500, PEG6000 and PEG20000.
  • the PEG is selected from PEG 1500 and PEG6000, and most preferably, the PEG is PEGl 500.
  • the carrier is PVP-VA
  • it can be any suitable PVP-VA [16] to act as a carrier and to help keep the taxane in an amorphous state.
  • the PVP-VA may be PVP-VA 64.
  • the composition can contain any suitable amount of the carrier relative to the amorphous taxane so that the carrier maintains the amorphous taxane in its amorphous state.
  • the taxane to carrier weight ratio is between about 0.01:99.99 w/w and about 75:25 w/w.
  • the taxane to carrier weight ratio is between about 0.01:99.99 w/w and about 50:50 w/w, even more preferably, between about 0.01:99.99 w/w and about 40:60 w/w, more preferably still, between about 0.01 :99.99 w/w and about 30:70 w/w, even more preferably, between about 0.1:99.9 w/w and about 20:80 w/w, more preferably still, between about 1 :99 w/w and about 20:80 w/w, even more preferably, between about 2.5:97.5 w/w and about 20:80 w/w, more preferably still, between about 2.5:97.5 w/w and about 15:85 w/w, even more preferably, between about 5:95 w/w and about 15:85 w/w and most preferably, about 10:90 w/w.
  • the surfactant can be any suitable pharmaceutically acceptable surfactant and such surfactants are well known to those skilled in the art.
  • the surfactant can be an anionic, cationic or non-ionic surfactant.
  • the surfactant is a cationic or anionic surfactant. More preferably, the surfactant is an anionic surfactant.
  • the surfactant preferably has an HLB (hydrophilic lipophilic balance) value of greater than about 2. More preferably, the HLB value is grater than about 4, more preferably still, the HLB value is greater than about 10, even more preferably, the HLB value is greater than about 14, more preferably still the HLB value is greater than about 20, even more preferably, the HLB value is greater than about 25, more preferably still the HLB value is greater than about 30, and most preferably, the HLB value is greater than about 35. Preferably, the HLB value should be less than about 45.
  • HLB hydrophilic lipophilic balance
  • the surfactant is selected from triethanolamine, sunflower oil, stearic acid, monobasic sodium phosphate, sodium citrate dihydrate, propylene glycol alginate, oleic acid, monoethanolamine, mineral oil and lanolin alcohols, methylcellulose, medium-chain triglycerides, lecithin, hydrous lanolin, lanolin, hydroxypropyl cellulose, glyceryl monostearate, ethylene glycol pamitostearate, diethanolamine, lanolin alcohols, cholesterol, cetyl alcohol, cetostearyl alcohol, castor oil, sodium dodecyl sulphate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyxoyethylene alkyl ethers, poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl benzo
  • the surfactant is selected from sodium dodecyl sulphate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyxoyethylene alkyl ethers, poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl bezoate, benzalkonium chloride, benzethonium chloride, hypromellose, non-ionic emulsifying wax, anionic emulsifying wax and triethyl citrate (these compounds are indicated as being surfactants in the Handbook of Pharmaceutical Excipients (4 th Edition, editors: RC Rowe, PJ Sheskey, PJ Weller)).
  • SDS sodium dodecyl sulphate
  • sorbitan esters sorbitan fatty acid esters
  • polyoxyethylene stearates polyoxyethylene sorbit
  • the surfactant is selected from sodium dodecyl sulphate (SDS), sorbitan esters (sorbitan fatty acid esters), and polyoxyethylene sorbitan fatty acid esters.
  • the surfactant can be cetylpyridinium chloride (CPC).
  • the surfactant is selected from SDS, CPC, polyoxyethylene (20) sorbitan monooleate (polysorbate 80) and polysorbitan monooleate.
  • the surfactant is selected from SDS, CPC and polysorbate 80. More preferably, the surfactant is selected from SDS and CPC. Most preferably, the surfactant is SDS.
  • the weight ratio of surfactant, to taxane and carrier combined is between about 1 :99 w/w and about 50:50 w/w, more preferably, between about 1 :99 w/w and about 44:56 w/w, even more preferably, between about 1:99 w/w and about 33:67 w/w, more preferably still, between about 2:98 w/w and about 33:67 w/w, even more preferably, between about 2:98 w/w and about 17:83 w/w, more preferably still, between about 5:95 w/w and about 17:83 w/w and most preferably, about 9:91 w/w.
  • the weight ratio of surfactant to taxane is preferably between about 1:100 w/w and about 60:1 w/w, more preferably, between about 1:50 w/w and about 40:1 w/w, even more preferably, between about 1:20 w/w and about 20:1 w/w, more preferably still, between about 1:10 w/w and about 10:1 w/w, even more preferably, between about 1:5 w/w and about 5:1 w/w, more preferably still, between about 1 :3 w/w and about 3:1 w/w, even more preferably, between about 1 :2 w/w and about 2: 1 w/w and most preferably, about 1 : 1 w/w.
  • the composition comprises an enteric coating.
  • Any suitable enteric coating can be used, for example, cellulose acetate phthalate, polyvinyl acetate phthalate and suitable acrylic derivates, e.g. polymethacrylates.
  • An enteric coating prevents the release of the taxane in the stomach and thereby prevents acid-mediated degradation of the taxane. Furthermore, it enables targeted delivery of the taxane to the intestines where the taxane is absorbed, thus ensuring that the limited time during which the taxane is present in solution (before crystallisation takes place) is only spent at sites where absorption is possible.
  • the composition may further comprise one or more additional pharmaceutically active ingredients.
  • one or more of the additional pharmaceutically active ingredients is a CYP3A4 inhibitor.
  • Suitable CYP3A4 inhibitors are grapefruit juice or St. John's wort (or components of either), ritonavir, lopinavir or imidazole compounds, such as ketoconazole.
  • the CYP3A4 inhibitor is ritonavir.
  • the pharmaceutically active ingredient(s) can be included into the composition as a physical mixture.
  • the pharmaceutically active ingredient(s) can be in an amorphous form.
  • the pharmaceutically active ingredient(s) can be in an amorphous form in a physical mixture with the other amorphous and/or non-amorphous components.
  • it can be in a solid dispersion, or preferably a solid solution, with the taxane; with the taxane and carrier; or with the taxane, carrier and surfactant.
  • the additional pharmaceutically active ingredient(s) is in an amorphous state, or is in a solid dispersion or solid solution, it should be prepared using a solvent evaporation method, for example, spray drying.
  • the composition When the composition is in a tablet form and comprises one or more additional pharmaceutically active ingredients, the one or more additional pharmaceutically active ingredients are preferably in the same tablet as the amorphous taxane, i.e. in a single tablet with the other components.
  • the pharmaceutical composition may comprise additional pharmaceutically acceptable excipients, adjuvants and vehicles which are well known to those skilled in the art.
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminium stearate, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate and wool fat.
  • ion exchangers alumina, aluminium stearate
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silic
  • compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, a powder or coated granules. Tablets may be formulated to be immediate release, extended release, repeated release or sustained release. They may also, or alternatively, be effervescent, dual-layer and/or coated tablets. Capsules may be formulated to be immediate release, extended release, repeated release or sustained release. Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • binders for tablets and capsules, other pharmaceutical excipients that can be added are binders, fillers, filler/binders, adsorbents, moistening agents, disintegrants, lubricants, glidants, and the like. Tablets and capsules may be coated to alter the appearance or properties of the tablets and capsules, for example, to alter the taste or to colour coat the tablet or capsule.
  • the present invention also provides the above composition for use in therapy.
  • the present invention provides the above composition for use in the treatment of neoplastic disease.
  • the neoplastic disease treated by the present invention is preferably a solid tumour.
  • the solid tumour is preferably selected from breast, lung, gastric, colorectal, head & neck, oesophageal, liver, renal, pancreatic, bladder, prostate, testicular, cervical, endometrial, ovarian cancer and non-Hodgkin's lymphoma (NHL).
  • the solid tumour is more preferably selected from breast, gastric, ovarian, prostate, head & neck and non-small cell lung cancer.
  • neoplastic diseases that may be treated by the present invention are multiple myeloma, chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML) and Kapsoi's sarcoma. Furthermore, the disease range includes myelodysplasia syndromes (MDS).
  • the present invention also provides a method of treatment of a neoplastic disease, the method comprising the administration, to a subject in need of such treatment, of an effective amount of the above composition.
  • the method is used to treat a human subject.
  • the present invention also provides a method of preparing the above composition comprising the steps of: preparing an amorphous taxane using a solvent evaporation method; and combining the amorphous taxane with a hydrophilic carrier and a surfactant to produce the composition.
  • the amorphous taxane can be produced by any suitable solvent evaporation method, for example, as described above.
  • the amorphous taxane is produced by spray drying.
  • the preparation of the amorphous taxane, and the combining thereof with the carrier and/or surfactant may be carried out in a single step, e.g. where the taxane and the carrier and/or the surfactant are subjected to amorphosing treatment together (for example to form a solid dispersion or solution).
  • the method comprises the steps of preparing a solid dispersion comprising the taxane and the hydrophilic carrier, and combining the solid dispersion with the surfactant.
  • the method comprises the step of preparing a solid dispersion comprising the taxane, the hydrophilic carrier and the surfactant.
  • the present invention provides a pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a hydrophilic carrier, wherein the substantially amorphous taxane is prepared by spray drying.
  • the present invention also provides a method of preparing a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a hydrophilic carrier, the method comprising the steps of: preparing an amorphous taxane by spray drying; and combining the amorphous taxane with a hydrophilic carrier to produce the composition.
  • the advantage provided by this composition is that the solubility of the taxane, the rate of dissolution of the taxane and/or the amount of time which the taxane remains in solution before starting to crystallise is increased to a surprising degree. It is thought that this is because the solvent evaporation method produces an even more amorphous taxane compared to other methods of producing amorphous taxanes in which the taxane is unlikely to be truely amorphous. It is thought that the more amorphous nature of the taxane provides the increased solubility characteristics.
  • compositions comprising an amorphous taxane, a carrier and a surfactant are the same as for the composition comprising an amorphous taxane, a carrier and a surfactant.
  • the composition comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by spray drying preferably further comprises a surfactant.
  • the preferred embodiments of the taxane, the carrier, the crystallinity of the taxane, the ratio of taxane to carrier, the state of the taxane and carrier, etc. are as defined above.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a taxane, a hydrophilic carrier and a surfactant, in solution.
  • a pharmaceutical composition comprising a taxane, a hydrophilic carrier and a surfactant, in solution.
  • a pharmaceutical composition comprising a taxane, a hydrophilic carrier and a surfactant, in solution.
  • the pharmaceutical composition may be in the form of a drinking solution for administration to a subject.
  • the pharmaceutical composition can be placed in capsules, for example, gelatin capsules to form liquid filled capsules containing the solution.
  • the composition can be obtained by dissolving the solid composition described above in a suitable solvent. Therefore, in one embodiment, the composition is obtainable by dissolving the solid composition described above in a suitable solvent such as triacetin. In one embodiment, the solvent is an aqueous solvent.
  • the invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane and one or more pharmaceutically acceptable excipients, wherein the substantially amorphous taxane is prepared by spray drying.
  • Figure 1 shows the results of a dissolution test of paclitaxel solid dispersions versus paclitaxel physical mixtures (conditions: 900 mL WfI, 37 0 C, 75 rpm);
  • Figure 2 shows the results of a dissolution test of paclitaxel (PCT) solid dispersion capsules with and without sodium dodecyl sulphate (conditions: 900 mL WfI, 37 0 C, 75 rpm);
  • Figure 3 shows the results of a dissolution test of paclitaxel solid dispersions with sodium dodecyl sulphate incorporated in the solid dispersion or added to the capsule (conditions: 500 mL WfI, 37 0 C, 75 rpm (100 rpm for SDS added to the capsules));
  • Figure 4 shows the results of a dissolution test of paclitaxel solid dispersions with various carriers (conditions: 500 mL WfI, 37 0 C, 100 rpm);
  • Figure 5 shows the results of a solubility test of paclitaxel/PVP-K17 solid dispersions with various drug-carrier ratios (conditions: 25 mL WfI, 37 0 C, 7200 rpm);
  • Figure 6 shows the results of a dissolution test of paclitaxel solid dispersions in various media (conditions: 500 mL FaSSIF (light grey), 37 0 C, 75 rpm; or 500 mL SGF sp and 629 mL SIF sp , 37 0 C, 75 rpm (dark grey));
  • Figure 7 shows the docetaxel solubility of five different formulations (see table 13).
  • A anhydrous docetaxel
  • B amorphous docetaxel
  • C physical mixture of anhydrous docetaxel, PVP-K30 and SDS
  • D physical mixture of amorphous docetaxel, PVP-K30 and SDS
  • E solid dispersion of amorphous docetaxel, PVP-K30 and SDS (dissolution conditions: ⁇ 6 mg docetaxel, 25 mL WfI, 37 0 C, 720 rpm);
  • Figure 8 shows docetaxel solubility of solid dispersions with different carriers (see table 13).
  • E Solid dispersion of amorphous docetaxel, PVP-K30 and SDS;
  • F Solid dispersion of amorphous docetaxel, HP ⁇ -CD and SDS. (Dissolution conditions: ⁇ 6 mg Docetaxel, 25 mL WfI, 37 0 C, 720 rpm);
  • Figure 9 shows docetaxel solubility of solid dispersions with PVP of various chain lengths (see table 13).
  • E solid dispersion of amorphous docetaxel, PVP-K30 and SDS;
  • G solid dispersion of amorphous docetaxel, PVP-K12 and SDS;
  • H solid dispersion of amorphous docetaxel, PVP-K17 and SDS;
  • I solid dispersion of amorphous docetaxel, PVP-K25 and SDS;
  • J solid dispersion of amorphous docetaxel, PVP-K90 and SDS.
  • Figure 10 shows docetaxel solubility of solid dispersions with various drug loads (see table 13).
  • E 1/11 docetaxel; K: 5/7 docetaxel; L: 1/3 docetaxel; M: 1/6 docetaxel; N: 1/21 docetaxel.
  • D solution conditions: ⁇ 6 mg Docetaxel, 25 mL WfI, 37 °C, 720 rpm);
  • Figure 11 shows the dissolution results in terms of the relative amount of docetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS, compared to literature data of a solid dispersion of docetaxel and PVP-K30 (Chen et al, [13]);
  • Figure 12 shows the dissolution results in terms of the absolute amount of docetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS, compared to literature data of a solid dispersion of docetaxel and PVP-K30 (Chen et al, [13]);
  • Figure 13 shows the results of a dissolution test of docetaxel capsules (15 mg docetaxel (DXT) per capsule with PVP-K30 + SDS) compared with literature data (Chen et al. [13]).
  • Figure 14 shows the dissolution results in terms of the absolute amount of docetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS.
  • the dissolution test was carried out in Simulated Intestinal Fluid sine Pancreatin (SIFsp);
  • Figure 15 shows the dissolution results in terms of the relative amount of docetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS.
  • the dissolution test was carried out in Simulated Intestinal Fluid sine Pancreatin (SIFsp);
  • Figure 16 shows the docetaxel pharmacokinetic curves of a patient who received docetaxel and ritonavir simultaneously in a first cycle.
  • Figure 17 shows the pharmacokinetic curves of four patients who received a liquid formulation of docetaxel and/or a solid dispersion comprising docetaxel (referred to as MODRA);
  • Figure 18 shows the pharmacokinetic curves of patients receiving the liquid oral formulation of docetaxel compared to the patients receiving the solid oral formulation of docetaxel (MODRA);
  • Figure 19 shows pharmacokinetic curves after i.v. and oral administration of docetaxel. Both i.v. and oral docetaxel administration was combined with administration of ritonavir. N.B. The calculated bioavailability is corrected for the administered dose.
  • Figure 23 shows the X-ray powder diffraction patterns of lyophilized and crystalline docetaxel.
  • Figure 24 shows the DSC thermograms of lyophilized and crystalline docetaxel.
  • Figure 25 shows the X-ray powder diffraction spectra of physical mixtures of crystalline and amorphous docetaxel.
  • Figure 26 shows the DSC thermograms of physical mixtures of crystalline and amorphous docetaxel.
  • Figure 27 shows the peak area at 165 0 C in the total heat flow thermogram vs. the crystalline docetaxel content.
  • the black line is the linear regression line with an R 2 of 0.990.
  • Figure 28 shows the X-ray powder diffraction patterns of lyophilized and crystalline paclitaxel.
  • Figure 29 shows a DSC thermogram of lyophilized and crystalline paclitaxel.
  • Figure 30 shows X-ray powder diffraction patterns of docetaxel, PVP-K30 and SDS.
  • Figure 31 shows DSC thermograms of PVP-K30, SDS and docetaxel.
  • Figure 32 shows X-ray powder diffraction spectra of a physical mixture and solid dispersion with 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS.
  • Figure 33 shows DSC thermograms of a physical mixture and solid dispersion with 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS.
  • Figure 34 shows X-ray powder diffraction spectra of solid dispersions produced by lyophilization and spray drying.
  • Figure 35 shows DSC thermograms of solid dispersions produced by lyophilization and spray drying.
  • Figure 41 shows a DSC thermogram of amorphous (spray dried) and crystalline ritonavir.
  • Figure 42 shows a DSC thermogram of spray dried solid dispersion powder of the combination of docetaxel, ritonavir, PVP-K30 and SDS.
  • Figure 43 shows the dissolution profile of docetaxel/ritonavir/PVP-K30/SDS capsules in 1000 mL 0.1 N HCl at 37 0 C and 50 RPM.
  • a solid dispersion of 20% paclitaxel in PVP-K 17 was prepared by dissolving 100 mg of paclitaxel in 10 mL t-butanol and 400 mg PVP-Kl 7 in 6.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1 for conditions).
  • the resulting powder mixture was encapsulated (see table 2).
  • a physical mixture was prepared by mixing 5 mg anhydrous paclitaxel with 20 mg PVP, 125 mg lactose, 30 mg sodium dodecyl sulphate, and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated.
  • Table 3 formulation of 5 mg paclitaxel/PVP-K17 h sical mixture capsules
  • the amorphous state of the carrier enables thorough mixing of the carrier and taxane.
  • the carrier prevents crystallization during storage as well as during dissolution in aqueous media.
  • a solid dispersion was prepared by dissolving 100 mg of Paclitaxel in 10 mL t-butanol and 400 mg PVP-K 17 in 6.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K 17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • Table 5 formulation of 5 mg paclitaxel/PVP-K17 solid dispersion without sodium dodecyl sulphate ca sules
  • Both capsule formulations were tested in 900 mL of Water for Injection maintained at 37 0 C in a USP 2 (paddle) dissolution apparatus with a rotation speed of 75 rpm. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
  • a solid dispersion was prepared by dissolving 600 mg of Paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17/ water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • Paclitaxel 40% solid dispersion in PVP-K 17 and sodium dodecyl sulphate 10% A solid dispersion was prepared by dissolving 250 mg of Paclitaxel in 25 mL t-Butanol, and 375 mg PVP-Kl 7 and 62.5 mg sodium dodecyl sulphate (SDS) in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K 17/sodium dodecyl sulphate/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • Table 7 formulation of 25 m aclitaxel7PVP-K17 solid dis ersion ca sules
  • Table 8 formulation of 25 m aclitaxel/PVP-K 17 solid dis ersion ca sules
  • a solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 375 mg PVP-K12 in 16.67 mL water. The pacJitaxel/t-butanol solution was added to the PVP-K12 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1). Paclitaxel 40% solid dispersion in PVP-K 17
  • a solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60 mL t-butanol and 900 mg PVP-K 17 in 40 mL water. The paclitaxel/t-butanol solution was added to the PVP-Kl 7 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • a solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-Butanol and 375 mg PVP-K30 in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K30 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • Paclitaxel 40% solid dispersion in HP-cvclodextrin A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 375 mg HP- cyclodextrin in 16.67 mL water. The paclitaxel/t-butanol solution was added to the HP-cyclodextrin water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • Table 9 formulation of 25 m aclitaxel/carrier solid dis ersion ca sules
  • the chain length of the polymeric carrier determines the time to crystallization in aqueous environments.
  • Paclitaxel 10% solid dispersion in PVP-K17 A solid dispersion was prepared by dissolving 100 mg of paclitaxel in 10 mL t-butanol and 900 mg PVP-K 17 in 40 mL water. The paclitaxel/t-butanol solution was added to the PVP-K 17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • a solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 750 mg PVP-K17 in 16.67 mL water.
  • the paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring.
  • the final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL.
  • t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • a solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 6.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • a solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 83 mg PVP- K17 in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • a solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol.
  • the paclitaxel/t-butanol solution was added to 16.67 mL water under constant stirring.
  • the final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL.
  • t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • Dissolution test An amount of solid dispersion powder, equal to approximately 4 mg Paclitaxel, was placed in a 50 mL beaker. A magnetic stirring bar and 25 mL water was added to the beaker. The solution was stirred at 720 rpm. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
  • the amount of carrier relative to the amount of drug determines the time to crystallization in aqueous environments.
  • Paclitaxel 40% solid dispersion in PVP-K 17 and sodium dodecyl sulphate 10%
  • a solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol, and 375 mg PVP-K 17 and 62.5 mg sodium dodecyl sulphate (SDS) in 16.67 mL water.
  • the paclitaxel/t-butanol solution was added to the PVP-K 17/sodium dodecyl sulphate/water solution under constant stirring.
  • the final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
  • Table 10 formulation of 25 mg paclitaxel/PVP-K17/SDS solid dispersion capsules
  • the capsules were in duplo subjected to two different dissolution tests.
  • the first test was a two tiered dissolution test, consisting of two hours of dissolution testing in 500 mL simulated gastric fluid without pepsin (SGF sp ; see table 1 1) followed by two hours of dissolution testing in 629 mL simulated intestinal fluid without pepsin (SIF sp ; see table 11).
  • the second test was conducted in 500 mL fasted state simulated intestinal fluid (FaSSIF; see table 12) medium for four hours.
  • An enteric coating will prevent release of the taxane in the stomach, thereby preventing degradation of the active components. Furthermore, it will enable targeted delivery to the intestines where the taxane is absorbed, thus ensuring that the limited time the taxane is present in solution (before crystallization takes place), is only spent at sites where absorption is possible.
  • Anhydrous docetaxel was used as obtained from ScinoPharm, Taiwan.
  • Docetaxel was amorphized by dissolving 300 mg of Docetaxel anhydrate in 30 mL of t-butanol. The docetaxel/t-butanol solution was added to 20 mL of Water for Injection (WfI) under constant stirring.
  • WfI Water for Injection
  • the final mixture was transferred to a stainless steel lyophilisation box (Gastronorm size 1/9), t-butanol and water were subsequently removed by lyophilisation (see table 14).
  • Solid dispersions were obtained by dissolving 300 mg docetaxel anhydrate in 30 mL of t-butanol, and corresponding amounts of carrier and surfactant (see table 13) in 20 mL of Water for Injection.
  • the docetaxel/t-butanol solution was added to the carrier/surfactant/Wfl solution under constant stirring.
  • the final mixture was transferred to a stainless steel lyophilisation box (Gastronorm size 1/9), t-butanol and water were subsequently removed by lyophilisation (see table 14).
  • HP ⁇ -CD is hydroxypropyl - ⁇ -cyclodextrin
  • Results Formulation A (pure docetaxel anhydrate) reaches a maximum concentration of approximately 12 ⁇ g/mL (4.7% total docetaxel present) after 5 minutes of stirring and reaches an equilibrium concentration of approximately 6 ⁇ g/mL (2%) after 15 minutes of stirring.
  • Formulation B (pure amorphous docetaxel) reaches a maximum of 32 ⁇ g/mL (13%) after 0.5 minutes, from 10 to 60 minutes the solubility is comparable to formulation A.
  • Formulation C (physical mixture of anhydrous docetaxel, PVP-K30 and SDS) reaches a concentration of approximately 85 ⁇ g/mL (37%) after 5 minutes. Between 15 and 25 minutes, the docetaxel concentration sharply declines from 85 ⁇ g/mL (37%) to 30 ⁇ g/mL (12%), after which it further declines to 20 ⁇ g/mL (9%) at 60 minutes.
  • Formulation D (physical mixture of amorphous docetaxel, PVP-K30 and SDS) reaches a maximum docetaxel concentration of 172 ⁇ g/mL (70%) after 7.5 minutes. Between 7.5 and 20 minutes, the amount of docetaxel in solution drops to 24 ⁇ g/mL (10%). At 60 minutes, the equilibrium concentration of 19 ⁇ g/mL (7%) is reached.
  • Formulation E solid dispersion of amorphous docetaxel, PVP-K30 and SDS has the highest maximum concentration of 213 ⁇ g/mL (90%) which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution rapidly declines resulting in an equilibrium concentration of 20 ⁇ g/mL (8%) after 45 minutes.
  • AIi formulations initially show a higher solubility, which decreases to an equilibrium solubility after 45 to 60 minutes of stirring.
  • the decrease in solubility is caused by the crystallization of docetaxel as a result of the supersaturated solution.
  • the degree of supersaturation is dependent on the physical state of the drug, i.e. whether it is amorphous or crystalline.
  • PVP-K30 is the carrier, the supersaturated state is maintained for longer so that the solubility of the docetaxel does not decrease as quickly.
  • the results show that using amorphous docetaxel significantly increases the solubility of docetaxel compared to anhydrous crystalline docetaxel.
  • amorphous docetaxel shows a relatively high dissolution rate, peaking at about 5 to 7.5 minutes.
  • Formulation E solid dispersion of amorphous docetaxel, PVP-K30 and SDS has a highest maximum concentration of 213 ⁇ g/mL (90% of total docetaxel present) which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution rapidly declines, resulting in an equilibrium concentration of 20 ⁇ g/mL (8%) after 45 minutes.
  • Formulation F solid dispersion of amorphous docetaxel, HP ⁇ -CD and SDS reaches a maximum docetaxel concentration of approximately 200 ⁇ g/mL (81%) after about 2 minutes. Between 5 and 10 minutes, the amount of docetaxel in solution drops to a value of 16 ⁇ g/mL (6%) and after 45 minutes, an equilibrium concentration of 11 ⁇ g/mL (4%) is reached.
  • Formulation G (PVP-K 12) reaches a maximum docetaxel concentration of 206 ⁇ g/mL (77% of the total docetaxel present) after 5 minutes. Between 5 and 30 minutes, the amount of docetaxel in solution decreases to 20 ⁇ g/mL (7%) and at 45 minutes, the docetaxel concentration is 17 ⁇ g/mL (6%).
  • Formulation H reaches a maximum docetaxel concentration of 200 ⁇ g/mL (83%) after 5 minutes and maintains this concentration up to 10 minutes of stirring, after which the amount of docetaxel in solution rapidly drops to 44 ⁇ g/mL (18%) at 15 minutes and 22 ⁇ g/mL (9%) at 30 minutes.
  • the equilibrium concentration between 45 and 60 minutes is approximately 21 ⁇ g/mL (8%).
  • Formulation I (PVP-K25) reaches a maximum docetaxel concentration of 214 ⁇ g/mL (88%) after 5 minutes of stirring.
  • the amount of docetaxel in solution decreases between 10 and 30 minutes to 22 ⁇ g/mL (9%) and at 60 minutes, the concentration of docetaxel is ] 9 ⁇ g/mL (8%).
  • Formulation E has a maximum docetaxel concentration of 213 ⁇ g/mL (90%) which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution rapidly declines, resulting in an equilibrium concentration of 20 ⁇ g/mL (8%) after 45 minutes.
  • Formulation J (PVP-K90) reaches a maximum docetaxel concentration of 214 ⁇ g/mL (88%) after 10 minutes of stirring. At 15 minutes, the amount of docetaxel in solution is still 151 ⁇ g/mL (61%). After 60 minutes, the docetaxel concentration has declined to 19 ⁇ g/mL (7%).
  • Formulation N (1/21 docetaxel by weight of total composition; 5:95 w/w docetaxel to PVP) reaches a maximum docetaxel concentration of 197 ⁇ g/mL (79% of total docetaxel present) after 10 minutes. After 15 minutes, the amount of docetaxel in solution is still 120 ⁇ g/mL (48%) and between 15 and 30 minutes, the docetaxel concentration decreases to 24 ⁇ g/mL (12%). At 60 minutes the docetaxel concentration is 20 ⁇ g/mL (8%).
  • Formulation E (1/11 docetaxel by weight of total composition; 10:90 w/w docetaxel to PVP) has a maximum concentration of 213 ⁇ g/mL (90%) which is reached after 5 minutes. Between 10 and 30 minutes, the amount of docetaxel in solution rapidly declines and reaches an equilibrium concentration of 20 ⁇ g/mL (8%) after 45 minutes.
  • Formulation M (1/6 docetaxel by weight of total composition; 20:80 w/w docetaxel to PVP) has a docetaxel concentration of 196 ⁇ g/mL (80%) after 10 minutes of stirring.
  • the amount of docetaxel in solution decreases between 10 and 30 minutes to 25 ⁇ g/mL (10%) and at 60 minutes, the concentration of docetaxel is 18 ⁇ g/mL (7%).
  • Formulation L (1/3 docetaxel by weight of total composition; 40:60 w/w docetaxel to PVP) reaches a docetaxel concentration of 176 ⁇ g/mL (71%). Between 10 and 15 minutes, the amount of docetaxel in solution rapidly drops to 46 ⁇ g/mL (18%) and after 60 minutes, the amount of docetaxel in solution is 18 ⁇ g/mL (7%).
  • Formulation K (5/7 docetaxel by weight of total composition; 75:25 w/w docetaxel to PVP) reaches a maximum docetaxel value of 172 ⁇ g/mL (71%) after 5 minutes of stirring. Between 5 and 10 minutes, the docetaxel concentration sharply declines to 42 ⁇ g/mL (17%) and after 60 minutes, a docetaxel concentration of 18 ⁇ g/mL (7%) is reached.
  • the composition of Chen et al. can dissolve a maximum of about 80% of the 5 mg docetaxel in the composition in 900 ml water. It took over 5 hours to reach this maximum.
  • the docetaxel, PVP-K30 and SDS composition dissolved 100% of the 15 mg docetaxel in about 60 minutes.
  • the docetaxel capsules reach a solubility of 28 ⁇ g/ml (>90 % solubility).
  • the solid dispersion described by Chen et al. (docetaxel + PVP K30) reaches a solubility of 4.2 ⁇ g/ml (lower than 80 % of the 5 mg docetaxel solid dispersion tested for dissolution in 900 ml).
  • the capsule formulation thus reaches a 6.6 fold better solubility with a higher dissolution rate (maximum reached after 30 minutes versus 90-120 minutes by Chen).
  • Figures 14 and 15 show that nearly 100% of the docetaxel dissolved. This is equivalent to an absolute docetaxel concentration of about 29 ⁇ g/ml and is achieved in about 30 minutes. Thus, the composition provides a relatively high solubility in a relatively short period of time.
  • Docetaxel dose 30 mg for all patients (with the exception of patient 306 who received 20 mg docetaxel).
  • the 30 mg dose was prepared as follows: 3.0 mL Taxotere® premix for intravenous administration (containing 10 mg docetaxel per ml in polysorbate 80 (25% v/v), ethanol (10% (w/w), and water) was mixed with water to a final volume of 25 mL. This solution was orally ingested by the patient with 100 mL tap water,
  • Formulation E from the previous example (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) was selected for further testing in the clinical trial.
  • a new batch of formulation E was produced by dissolving 1200 mg docetaxel anhydrate in 120 mL of t-butanol, and 10800 mg PVP-K30 and 1200 mg SDS (see table 13) in 80 mL of Water for Injection.
  • the docetaxel/t-butanol solution was added to the PVP-K30/SDS ⁇ V ⁇ solution under constant stirring.
  • the final mixture was transferred to a stainless steel lyophilisation box (Gastronorm size 1/3), t-butanol and water were subsequently removed by lyophilisation (see table 14).
  • a total of 60 gelatine capsules of size 0 were filled with an amount of solid dispersion equivalent to 15 mg docetaxel, an HPLC assay was used to determine the exact amount of docetaxel per mg of solid dispersion. The assay confirmed that the capsules contained 15 mg docetaxel.
  • Patient Treatment Patients 301 , 302, 303, 304 and 305 received only liquid formulation.
  • Patient 306 received 20 mg docetaxel as liquid formulation + ritonavir in the first cycle and in the second cycle the same medication but with extra ritonavir 4 hours after docetaxel ingestion.
  • Patients 307, 308, 309 and 310 received liquid formulation and/or MODRA. Cycles were administered in a weekly interval.
  • Tlast time at which last sample for measurement docetaxel concentration was taken (in h)
  • AUC last AUC calculated until Cone last (ng.h/mL)
  • AUC inf AUClast + extrapolation to infinity (ng.h/mL)
  • Patients 301, 302, 303, 304, 305, 307, 309 and 310 received the liquid formulation.
  • the mean, and the 95% confidence interval for the mean of the AUC (extrapolated to infinity) is : 1 156 (+ 348) ng*h/mL.
  • the inter-individual variability is 85 %.
  • the pharmacokinetic curves are depicted in Figure 16.
  • Patient 307, 308, 309 and 310 received liquid formulation and/or MODRA.
  • the pharmacokinetic curves are depicted in Figure 17.
  • AUC inf (95% confidence interval of the mean): 1156 (808-1504) ng*h/ml Inter-individual variability: 85% (n 8)
  • AUCi nf 95% confidence interval of the mean: 768 (568-968) ng*h/ml
  • Inter-individual variability: 29% (n 4)
  • Intra-individual variability: 33% (n 2)
  • the average AUC of MODRA was calculated using the 6 curves from four patients.
  • the first dose of MODRA administered to each patient was used to calculate the inter-individual variability.
  • the intra- individual variability is based on data from patients 307 and 308 who received two doses of MODRA.
  • the tested docetaxel Liquid Formulation results in an AUC value that is approximately 1.5 fold higher than the same dose (30 mg) given in the novel capsule formulation (MODRA).
  • the inter-individual variability of the liquid formulation is high (85%) while the inter-individual variability of the capsule formulation is substantially lower (29%). This is an important feature of the novel capsule formulation and provides a much better predictable docetaxel exposure. Also for safety reasons low inter-individual variability is very much desired in oral chemotherapy regimens.
  • the intra-individual variability (limited data) is in the same order of magnitude as the inter-individual variability.
  • a second boosting dose of 100 mg ritonavir ingested 4 hours after docetaxel administration increases the docetaxel AUC 1.5 fold.
  • Figure 19 shows pharmacokinetic curves after i.v. (20 mg docetaxel as a i.v. 1-hour infusion
  • Formulations produced by spray drying are fully amorphous and have a prolonged duration of the supersaturated state upon dissolution testing compared to formulations produced by lyophilization (see section 7 below).
  • Amorphous nature of docetaxel (section 3): o Lyophilization of docetaxel results in the disappearance of the diffraction peaks in the X-ray powder diffraction spectrum, o Lyophilization of docetaxel results in the disappearance of the endothermic peak near 165 0 C and the appearance of a glass transition near 124 0 C. o The area of the endothermic peak near 165 0 C correlates well with the amount of crystalline material in a physical mixture of amorphous and crystalline docetaxel.
  • paclitaxel Amorphous nature of paclitaxel (section 4): o Lyophilization of paclitaxel results in the disappearance of the diffraction peaks in the X-ray powder diffraction spectrum. o Lyophilization of paclitaxel results in the disappearance of the endothermic peaks near 58, 80 and 163 °C, and the appearance of a endothermic peak near 61 °C and a glass transition near 154 0C.
  • Characterization of solid dispersions of docetaxel (section 5): o Lyophilization of a mixture of docetaxel, PVP-K30 and SDS results in the disappearance of the diffraction peaks belonging to docetaxel in the X-ray powder diffraction pattern, o Diffraction peaks of docetaxel are present in a physical mixture of the solid dispersion components.
  • Characterization of solid dispersions of paclitaxel (section 6): o paclitaxel solid dispersion systems are comparable to docetaxel solid dispersion systems.
  • Crystalline drug was used as obtained from the supplier.
  • Drugs were amorphized by dissolving 300 mg of drug in 30 mL of t-Butanol.
  • the drug/t-Butanol solution was added to 20 mL of Water for Injection (WfI) under constant stirring.
  • the final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9), t-Butanol and water were subsequently removed by lyophilization (see Table 20)
  • Solid dispersions were obtained by dissolving docetaxel in 30 mL of t-Butanol, and corresponding amounts of carrier and surfactant (see Table 19) in 20 mL of Water for Injection.
  • the docetaxel/t- Butanol solution was added to the carrier/surfactant/Wfl solution under constant stirring.
  • the final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9), t-Butanol and water were subsequently removed by lyophilization (see Table 20).
  • Solid dispersions were obtained by dissolving docetaxel in 45 mL of ethanol and 5 mL of WfI. After the drug was completely dissolved, PVP-K30 and SDS (see table 21) were added to the drug/ethanol/Wfl solution under constant stirring. The final mixture was transferred to a flask and ethanol and water were subsequently removed by spray drying (see Table 22).
  • Capsules were produced by weighing an amount of lyophilized solid dispersion powder (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) equivalent to 10-15 mg drug.
  • the solid dispersion powder was grinded with mortar and pestle to a fine powder and encapsulated with a manual capsulation apparatus in size 0 hard gelatin capsules.
  • the amount of docetaxel per capsules was estimated after production by subtracting the net capsule weight from the gross capsule weight and multiplying it by the docetaxel ratio of the solid dispersion powder (see Table 19). The contents of the capsules were confirmed by HPLC quality control.
  • Clinical trial capsules were produced by weighing an amount of lyophilized solid dispersion powder (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) equivalent to 10 mg drug, 110 mg lactose monohydrate and 1.1 mg colloidal silicon dioxide. All components were mixed with mortar and pestle until a homogeneous mixture was obtained. The mixture was encapsulated with a manual capsulation apparatus in size 0 hard gelatine capsules.
  • Tablets (used in section 9) Tablets were produced by weighing an amount of spray dried solid dispersion powder equivalent (1/1 1 docetaxel, 9/11 PVP-K30 and 1/11 SDS) to 20 mg docetaxel, 110 mg lactose monohydrate and 1 10 mg crosslinked polyvinylpyrrolidone. All components were mixed with mortar and pestle until a homogeneous mixture was obtained. The mixture was compacted manually on a excentric press equipped with 13 mm flat tooling. Filling volume was fixed at 13.5 mm and the upper pressure was set at 10.5 mm.
  • Tablets were weighed after compaction and the amount of docetaxel was estimated by multiplying the tablet weight by the product of the weight fraction of drug in the solid dispersion powder (see Table 21) and the weight fraction of the solid dispersion powder in the tablet. The contents of the tablets were confirmed by HPLC quality control.
  • Capsules or tablets were placed in a type 2 (paddle) dissolution apparatus, filled with 500 mL WfI at 37 0C, the rotational speed of the paddle was 75 rpm.
  • Samples were collected at various timepoints, and filtrated using a 0.45 ⁇ m filter before they were diluted 1 :1 with a 1 :4 v/v mixture of methanol and acetonitrile. The filtrated and diluted samples were subsequently analyzed by HPLC-UV (see Table 23).
  • the amount of docetaxel dissolved is either expressed as concentration in ⁇ g/mL or as percentage of the label claim (% RLC).
  • the label claim is the estimated amount of drug present in each capsule or tablet after production. Table 23. Chromato ra hic conditions
  • X-ray powder diffraction measurements were performed on a Phlips X'pert pro diffractiometer equipped with an X-celerator. Samples of approximately 0.5 mm thick were placed in a metal sample holder, placed in the diffractiometer and scanned with the settings depicted in Table 25.
  • Section 1 Effect of the type of surfactant on the dissolution of docetaxel
  • Figure 20 shows that between 0 and 5 minutes the amount of docetaxel dissolved in the formulation with SDS is below 10% RLC, while the amount of docetaxel dissolved in the formulation with CPC and Polysorbate 80 are above 30% RLC. At this time, approximately 17% RLC of the docetaxel in the sorbitan monooleate formulation is dissolved. However after 10 minutes the differences in the dissolved amount of docetaxel between the SDS (63% RLC), CPC (75% RLC) and polysorbate 80 (68% RLC) formulations are markedly reduced, while the release of docetaxel from the sorbitan monooleate formulation remains considerably lower with 48% RLC.
  • the amount of docetaxel released from the formulation with SDS is equal to the amount of docetaxel released from the formulation with CPC.
  • the polysorbate 80 and sorbitan monooleate formulation have lower amounts of docetaxel released, 73% RLC and 63% RLC respectively, but these values are still much higher than the release of docetaxel from the solid dispersion system without an surfactant (37% RLC).
  • the amount of docetaxel released from the CPC and SDS systems are 87% RLC and 89% RLC respectively, the release from the polysorbate 80 and sorbitan monooleate formulations is lower with 77% RLC and 83% RLC respectively.
  • *amount of surfactant in capsules is approximately 10 mg, or 0.02 g/L in 500 mL WfI
  • Section 2 Effect of the amount of surfactant on the dissolution of docetaxel
  • formulation 4-7 solid dispersion powders containing docetaxel (see Table 19, formulation 4-7) were prepared by lyophilization (see Table 20). The amount of SDS varied between the four formulations while the amount of docetaxel and PVP-K30 were kept constant. From each formulation three capsules were produced without any additives and subjected to a dissolution test.
  • Figure 21 and Figure 22 show the results of the dissolution tests. Between 0 and 5 minutes the dissolution of docetaxel is limited in all four formulations. The initial slow dissolution is due to the lag time caused by the dissolution of the capsule shell. After the shell is dissolved, the dissolution of the solid dispersion powders can start. The dissolution of docetaxel from the formulation without an surfactant is considerable slower than the dissolution of docetaxel from the formulation with 1/11 SDS.
  • the 1/11 SDS formulation reaches an amount of docetaxel dissolved of 90% RLC within 30 minutes
  • the formulation without SDS reaches only an amount of docetaxel dissolved of 70% RLC (Relative to Label Claim) after 60 minutes.
  • the variation in the release rate of docetaxel between capsules of the formulation without an surfactant is much higher than the variation between the capsules of the formulation with 1/11 SDS.
  • Figure 20 and 21 also show the difference between various amounts of SDS.
  • the dissolution of docetaxel is already improved by addition of only 1/41 SDS to the solid dispersion system, however there is no clear difference between the dissolution patterns of 1/41 and 1/21 SDS.
  • An amount of 1/1 1 SDS results in the best dissolution pattern of docetaxel compared to 1/21 SDS and 1/41 SDS.
  • Section 3 Amorphous nature of docetaxel
  • DSC differential scanning calorimetry
  • X-ray powder diffraction see Table 25
  • Figure 23 shows the effect of lyophilization on the X-ray powder diffraction pattern of docetaxel.
  • the X-ray diffraction spectrum Before lyophilization of docetaxel the X-ray diffraction spectrum has numerous diffraction peaks between 10 and 40 °2Theta, indicating that docetaxel is in a crystalline state.
  • an amorphous halo is present in the X-ray powder diffraction pattern, indicating that docetaxel is in an amorphous form.
  • Figure 24 shows the effect of lyophilization on the DSC thermogram of docetaxel.
  • the DSC thermogram Before lyophilization of docetaxel the DSC thermogram shows a large endothermic peak at 165 °C, possibly caused by a rearrangement of the crystal structure of docetaxel.
  • the DSC thermogram After lyophilization of docetaxel the DSC thermogram has no endothermic peak at 165 0 C. However, a broad endothermic peak is present around 50 0 C which is caused by the evaporation of water and t-butanol. Furthermore a glass transition can be observed at 124 °C, indication that docetaxel is in an amorphous state.
  • Figure 25 shows X-ray powder diffraction spectra of various mixtures of amorphous (lyophilized) and crystalline docetaxel.
  • a decrease in the crystalline docetaxel content in the mixture results in a decrease in the intensity and number of diffraction peaks in the X-ray powder diffraction spectra.
  • the X-ray diffraction pattern of the mixture with 5% crystalline docetaxel has no diffraction peaks, this indicates that the lowest detectable amount of crystalline docetaxel with X-ray powder diffraction is above 5% w/w (pure drug substance).
  • Figure 26 shows DSC thermograms of various mixtures of amorphous (lyophilized) and crystalline docetaxel.
  • a decrease in the crystalline docetaxel content in the mixture results in a decrease in the size of the endothermic peak at 165 0 C and an increase in the broad endothermic peak around 50 0 C.
  • Figure 27 shows a plot of the peak area at 165 0 C in the total heat flow thermogram vs. the amount of crystalline material in the physical mixture of crystalline and amorphous docetaxel (see Table 18).
  • the amount of crystalline material in the amorphous and crystalline drug is assumed to be 0 and 100% w/w respectively.
  • the regression line has an determination coefficient of 0.990 and a regression coefficient of 0.995, this confirms that there is a strong correlation between the peak size at 165 0 C and the degree of crystallinity.
  • the peak area of the endothermic peak associated with crystal rearrangement correlates well with the crystalline docetaxel content in physical mixtures of amorphous and crystalline docetaxel.
  • Section 4 Amorphous nature of paclitaxel
  • Figure 28 shows the effect of lyophilization on the X-ray powder diffraction pattern of paclitaxel.
  • the X-ray diffraction spectrum Before lyophilization of paclitaxel the X-ray diffraction spectrum has numerous diffraction peaks between 10 and 40 °2Theta, indicating that paclitaxel is in a crystalline state.
  • an amorphous halo is present in the X-ray powder diffraction pattern, indicating that paclitaxel is in an amorphous form.
  • Figure 29 shows the effect of lyophilization on the DSC thermogram of paclitaxel.
  • the DSC thermogram Before lyophilization of paclitaxel the DSC thermogram shows a large endothermic peak at 58, 80 and 163 0 C. Both the peak at 58 and 80 0 C are caused by the loss of water from the crystal lattice. The endothermic peak at 163 0 C is possibly caused by a rearrangement of the crystal structure of paclitaxel.
  • the DSC thermogram has no endothermic peaks at 58, 80 or 163 0 C, instead a broad endothermic peak at 61 °C and a glass transition at 154 0 C can be observed.
  • Lyophilization of paclitaxel results in a reduction of crystallinity to such a degree that X-ray powder diffraction spectra of lyophilized paclitaxel do not show diffraction peaks, as well as DSC thermograms do not show the endothermic peak associated with crystal rearrangement. Furthermore in the DSC thermogram a glass transition appears. This all is indicative that after lyophilization paclitaxel is in an amorphous state.
  • Docetaxel is crystalline and has numerous diffraction peaks between 10 and 40° 2Theta
  • SDS is crystalline and has sharp diffraction peaks in between 20 and 22 ° 2Theta
  • PVP-K30 is amorphous and has no diffraction peaks.
  • Figure 31 shows the DSC thermograms of the solid dispersion components docetaxel, PVP-K30 and SDS.
  • Docetaxel has a large endothermic peak at 165 0 C, possibly caused by crystal rearrangement.
  • PVP-K30 has a large endothermic peak near 76 °C, caused by the evaporation of water, and a glass transition near 162 0 C caused by the difference in heat capacity between the glassy and rubbery state.
  • SDS has a phase transition near 67 0 C probably caused by a small amorphous fraction, and a large endothermic region between 80 and 120 0 C containing multiple peaks. These peaks are partly caused by melting of the crystalline bulk of SDS and partly caused by unknown non-reversible endothermic events.
  • Figure 32 shows the X-ray diffraction spectra of a physical mixture and a solid dispersion system containing 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS.
  • the diffraction peaks of docetaxel and SDS appear in the X-ray diffraction spectrum of the physical mixture, while the diffraction peaks of docetaxel do not appear in the X-ray diffraction spectrum of the solid dispersion system.
  • Figure 33 shows the DSC thermograms of a physical mixture and a solid dispersion system containing 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS.
  • the thermogram of the physical mixture shows an endothermic dip near 100 °C probably caused by SDS; a small endothermic peak near 162 0 C probably caused by crystalline docetaxel and an glass transition near 164 0 C, probably caused by PVP-K30.
  • the thermogram of the solid dispersion system shows an endothermic peak near 1 13 0 C probably caused by SDS; and a glass transition near 155 °C which is probably caused by the combination of amorphous docetaxel and amorphous PVP-K30.
  • SDS is present in a crystalline state in both the solid dispersion and the physical mixture and causes the diffraction peaks between 20 and 22 °2Theta in the X-ray diffraction spectra of both the solid dispersion and physical mixture, and the endothermic peaks near 100 0 C and 1 13 0 C in the DSC thermograms of the physical mixture and the solid dispersion respectively.
  • Section 6 Characterization of solid dispersions of paclitaxel
  • paclitaxel solid dispersion systems are comparable to docetaxel solid dispersion systems, i.e. paclitaxel is present in an amorphous state after Iyophilization while SDS is not.
  • Section 7 Effect of the production method on the characteristics and performance of docetaxel solid dispersion
  • Figure 34 shows the X-ray powder diffraction spectra of solid dispersions produced by Iyophilization and spray drying.
  • the solid dispersion produced by lyophilisation (freeze drying) is partly crystalline because there are diffraction peaks present in the spectrum between 20 and 22 °2Theta. These diffraction peaks belong to the SDS ( Figure 30).
  • the solid dispersion produced by spray drying is fully amorphous, as can be concluded from the absence of diffraction peaks in the X-ray powder diffraction pattern.
  • Figure 35 shows the DSC thermograms of solid dispersions produced by Iyophilization and spray drying.
  • the thermogram of the solid dispersion produced by Iyophilization shows an endothermic peak near 113 0 C probably caused by SDS; and a glass transition near 155 0 C, which is probably caused by the combination of amorphous docetaxel and amorphous PVP-K30.
  • the solid dispersion produced by spray drying only shows a glass transition near 147 0 C, indicative for a fully amorphous system.
  • Figure 36 shows the dissolution screening curves of solid dispersions produced by Iyophilization and spray drying.
  • the solid dispersion produced by Iyophilization reaches the peak docetaxel concentration after 5 minutes and starts to precipitate.
  • the solid dispersion produced by spray drying reaches the peak docetaxel concentration after 10 minutes and starts to precipitate after 15 minutes.
  • the powder obtained after spray drying is less static and has a more uniform particle size, making it more suitable for further processing compared to the lyophilized product.
  • Section 8 Effect of the type of carrier on the dissolution performance of docetaxel solid dispersions
  • Figure 37 shows the dissolution screening curves of solid dispersion systems containing PVP-K.30, PEG 1500, PEG 6000 or PEG20000. All systems reach a comparable docetaxel peak concentration after 5 minutes, however precipitation of docetaxel already starts after 5 minutes for all three PEG systems. Furthermore, the amount of docetaxel in solution after precipitation is approximately 8 ⁇ g/mL in the PEG containing solid dispersion systems, while the PVP-K30 containing system reaches an amount of docetaxel in solution after precipitation of 20 ⁇ g/mL.
  • Figure 38 shows the dissolution screening curves of solid dispersions containing PVP-K30 or PVP-VA 64.
  • PVP-VA 64 40 ⁇ g/mL
  • PVP- K30 20 ⁇ g/mL
  • Solid dispersion systems containing PEG perform worse in dissolution screening tests than solid dispersion systems containing PVP-K30.
  • Solid dispersion systems containing PVP-VA 64 reach significantly higher concentrations of docetaxel after precipitation than solid dispersion systems containing PVP-K30.
  • paclitaxel has a lower solubility than docetaxel
  • PVP-VA 64 might especially be helpful in paclitaxel containing solid dispersion systems.
  • Figure 39 shows the average dissolution curves of 20 mg docetaxel tablets and 10 mg docetaxel capsules which are currently used in clinical trials.
  • Figure 40 shows the average dissolution rates of the tablets and capsules between 0 and 10 minutes. The tablets show a steady dissolution rate between 0 and 30 minutes until a concentration of 35 ⁇ g/mL is reached. The capsules show a steady dissolution rate between 0 and 10 minutes until a concentration of approximately 16 ⁇ g/mL is reached. Between 0 and 10 minutes the release rate of docetaxel from both capsules and tablets is approximately 0.8 mg/min.
  • Example S Additon of an additional pharmaceutically active ingredient to the docetaxel solid dispersion
  • Ritonavir was dissolved in the ethanol water mixture and spray dried with a Buchi 290 mini spray dryer (see table 27).
  • Figure 41 shows a DSC thermogram of amorphous (spray dried) and crystalline ritonavir.
  • Amorphous ritonavir exhibits a Tg around 25 0 C
  • crystalline exhibits a melting endotherm around 122 0 C. It is concluded that spray drying results in amorphous ritonavir.
  • Figure 42 shows a DSC thermogram of spray dried solid dispersion powder of the combination of docetaxel, ritonavir, PVP-K30 and SDS.
  • the thermogram shows a single Tg around 1 17 0 C and no melting endotherms of ritonavir, docetaxel, PVP-K30 or SDS.

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