WO2021009504A1 - Nouvelles formulations - Google Patents

Nouvelles formulations Download PDF

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Publication number
WO2021009504A1
WO2021009504A1 PCT/GB2020/051692 GB2020051692W WO2021009504A1 WO 2021009504 A1 WO2021009504 A1 WO 2021009504A1 GB 2020051692 W GB2020051692 W GB 2020051692W WO 2021009504 A1 WO2021009504 A1 WO 2021009504A1
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compound
formula
particles
pharmaceutical formulation
formulation
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PCT/GB2020/051692
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English (en)
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Jacob Westman
Thomas Edlund
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Balticgruppen Bio Ab
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Publication of WO2021009504A1 publication Critical patent/WO2021009504A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 present invention relates to pharmaceutical formulations, and the use of such formulations in medicine.
  • the present invention relates to oral formulations which have been obtained by a process which involves wet milling of the active ingredient and which comprise an enteric coating.
  • AMP-activated protein kinase is a protein kinase enzyme that consists of three protein sub-units and is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g. glucose deprivation). Activation of AMPK increases processes that generate adenosine 5'-triphosphate (ATP) (e.g., fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but are not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced.
  • ATP adenosine 5'-triphosphate
  • AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced.
  • AMPK thus is a protein kinase enzyme that plays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is coupled to glucose lowering effects and triggers several other biological effects, including the inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and the reduction of hyperinsulinemia.
  • AMPK is a preferred target for the treatment of the metabolic syndrome and especially type 2 diabetes.
  • AMPK is also involved in a number of pathways that are important for many different diseases (e.g. AMPK is also involved in a number of pathways that are important in CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).
  • AMPK is also involved in a number of pathways that are important in cancer. Several tumour suppressors are part of the AMP pathway. AMPK acts as a negative regulator of the mammalian TOR (mTOR) and EF2 pathway, which are key regulators of cell growth and proliferation. The deregulation may therefore be linked to diseases such as cancer (as well as diabetes). AMPK activators may therefore be of utility as anti-cancer drugs.
  • mTOR mammalian TOR
  • EF2 pathway which are key regulators of cell growth and proliferation.
  • the deregulation may therefore be linked to diseases such as cancer (as well as diabetes).
  • AMPK activators may therefore be of utility as anti-cancer drugs.
  • 4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1 ,2,4-thiadiazol-5-yl]benzamide i.e. the compound of formula I
  • the compound of formula I was found to be useful in the treatment of disorders or conditions which are ameliorated by the activation of AMPK.
  • the compound of formula I may therefore be useful in the treatment of cancer, diabetes, hyperinsulinemia and associated conditions, a condition/disorder where fibrosis plays a role, sexual dysfunction, osteoporosis and neurodegenerative diseases.
  • An enteric coating is a barrier that is applied to an oral medication to prevent dissolution or disintegration of the medication in the gastric environment. Enteric coatings help to protect drugs from the acidity of the stomach, to protect the stomach from any detrimental effects of the drug (e.g. irritation of the stomach lining), and delay release of the drug until it reaches the upper tract of the intestine. Enteric coatings are discussed in MD. Saiful Islam et al. IJPPR. Human, 2016; Vol. 6 (3): 141-159.
  • the inventors have now found a formulation of the compound of formula I that is surprisingly effective in increasing the bioavailability (with reduced variation) of said compound in vivo.
  • the pharmaceutical formulation is obtained by a process which involves wet milling to produce particles comprising said compound or a mixture containing said compound; and wherein the formulation comprises an enteric coating on said formulation or on said particles.
  • the compound of formula I may be referred to as 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-1 ,2,4-thiadiazol-5-yl]benzamide.
  • This compound name was derived using the commercially available software package Autonom (brand of nomenclature software provided as an add-on for use in the Symyx Draw 2.1 (TM) office suite marketed by MDL Information Systems).
  • the compound of formula I may be prepared in accordance with techniques that are well known to those skilled in the art.
  • the compound of formula I may be made in accordance with the techniques described in international patent application WO 2011/004162, and all of its content is hereby incorporated by reference.
  • the compound of formula I is a solid under ambient conditions, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof.
  • milling refers to an operation where mechanical energy is applied (e.g. through grinding) to reduce the particle size of a solid sample (e.g. granules). For example, coarse particles may be broken down to finer ones, such that the average particle size is reduced.
  • Milling is regarded as a ‘top-down’ approach to the production of fine particles.
  • a drug solid may be cut by sharp blades (e.g. cutter mill), impacted by hammers, subjected to high pressure homogenisation, or crushed or compressed by the application of pressure (e.g. roller-mill or pestle and mortar).
  • pressure e.g. roller-mill or pestle and mortar
  • particles produced by such methods remain relatively coarse.
  • Technological advancements in milling equipment have enabled the production of ultrafine drug particles down to the micron (i.e. the pm unit range) or even sub-micron (e.g. the nm unit range) dimensions.
  • a milling process may be broadly characterised as being either a dry milling process or a wet milling process.
  • ‘Dry milling’ refers to a process in which a drug is milled in its dry state, i.e. in the absence of a liquid medium (e.g. in the substantial absence of water). In the dry state, the drug can be milled alone, or in the presence of pharmaceutically acceptable excipients. Other abrasive materials, such as salts, may be present during the milling process to aid in the particle size reduction. The mechanical energy imparted by dry milling fosters interactions between the drug (and/or excipient) particles via van der Waals forces or hydrogen bonding.
  • the term‘wet milling’ refers to a process in which a drug is milled in the presence of a liquid medium (e.g. water).
  • the drug particles are dispersed in a solution (often containing a surfactant and/or stabilizer) and the subsequent suspension is then subjected to milling energy.
  • the drug concentration in the suspension typcially ranges from about 5% to about 40% (weight per volume of the suspension).
  • the drug particle size is reduced by the shear forces generated by the movement of the milling apparatus.
  • the drug particles are ground between moving pearls (i.e. balls or beads), moved by an agitator, resulting in a nanosuspension.
  • moving pearls i.e. balls or beads
  • Different sized coated mill ing pearls of glass, stainless steel, zirconium dioxide or highly crosslinked polystyrene resin-coated beads may be used.
  • excipients e.g. surfactants, polymers, and the like
  • suitable excipients are important for stabilising smaller sized particles and for maintaining the shelf- life of the final product.
  • Commonly used excipients that may be mentioned include sugar alcohols (e.g. mannitol), amino acids (e.g. L-leucine), cellulose derivatives (e.g. hydroxypropylmethyl cellulose (HMPC) , hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and carboxymethylcellulose sodium salt), polymers (e.g.
  • PVP polyvinylpyrrolidone
  • PVP polyvinylpyrrolidone
  • PVC polyvinyl alcohol and Carbopol® 981
  • vitamin derivatives e.g. vitamin E-TPGS (D-a-tocopherol polyethylene glycol 1000 succinate)
  • surfactants e.g. sodium lauryl sulfate, docusate, Tween® 80 and Plantacare® 2000 UP
  • poloxamers e.g. Pluronic® F68 and Pluronic® F127
  • polysaccharides e.g. sodium alginate.
  • the wet milling time depends on many factors such as solid content, surfactant/stablizer concentration, hardness, suspension viscosity, temperature, energy inputs and size of the milling media.
  • the wet milling time may vary from minutes to hours or days depending on the particle size desired.
  • wet milling may be performed using techniques, apparatus and conditions that are known in the art, including, for example, using a planetary mill.
  • a planetary mill (such as a Pilverisette 7 Premium Line) usually comprises a vessel filled with (e.g. zirconia) beads. The material to be milled is placed inside the vessel, which is made to rotate or vibrate at a particular speed or frequency. The movement of the vessel causes the balls to collide with each other and the matrial to be milled. Size reduction of the drug particles is caused by impact and attritive forces received from the beads.
  • the skilled person would appreciate that various aspects of the millling process, such as the milling time, milling speed (rotation speed), excipient misture, suspension volumne, etc. may be varied in order to achieve the desired particle size.
  • the wet milling is performed in a planetary mill at about 700 rpm for about 20 minutes.
  • the formulation of the invention is obtained by a process which involves wet milling.
  • a process which involves wet milling will be understood to mean a process which involves a step of wet milling particles (comprising or consisting of the compound of formula I) so that the average particle size of the wet milled product is less than the average particle size of any product that has been produced by processes known in the art but which has not been milled.
  • the term“pharmaceutical formulation is obtained by a process which involves wet milling to produce particles comprising said compound” refers to a pharmaceutical formulation per se of the compound of formula I which has been prepared using any process which involves a step of wet milling particles of said compound of formula I, or a mixture containing said compound e.g. according to the processes described therein.
  • Solidification techniques transform drug particle suspensions, e.g. as obtained directly from a wet-milling process, into solid dosage forms such as tablets, capsules, and pellets.
  • the solvent from drug particle suspension can be removed using drying processes such as fluid bed coating / granulation, spray drying and freeze drying. Transformation into a solid dosage form helps increase the storage stability of the drug.
  • Matrix formers e.g., mannitol and cellulose derivatives
  • particle size distribution refers to the relative number of particles present according to size in a solid sample, such as a powder, a granular material, or particles dispersed in a fluid. Particle size distribution affects the properties of a solid sample (e.g. a powder, and the like) in many ways. We have found that the reduction of the average particle size results in a surprising improvement in the bioavailability of the resulting pharmaceutical product when the compound of formula I is combined with an enteric coating.
  • the particle size distribution of a solid sample may be measured using techniques that are well known in the art.
  • the particle size distribution of a solid sample may be measured by laser diffraction, dynamic light scattering, image analysis (e.g. dynamic image analysis), sieve analysis, air elutriation analysis, optical counting, electro-resistance counting, sedimentation, laser obscuration and acoustic (e.g. ultrasound attenuation) spectroscopy.
  • image analysis e.g. dynamic image analysis
  • sieve analysis air elutriation analysis
  • optical counting e.g. electro-resistance counting
  • sedimentation e.g. laser obscuration
  • acoustic e.g. ultrasound attenuation
  • Particle size distributions also may be determined based on results from sieve analysis.
  • Sieve analysis presents particle size information in the form of an S-curve of cumulative mass retained on each sieve versus the sieve mesh size.
  • the most commonly used metrics when describing particle size distributions are D-values (D10, D50 & D90) which are the intercepts for 10%, 50% and 90% of the cumulative mass.
  • the particle size distribution of the present invention is preferably defined using one or more of such values.
  • D-values essentially represent the diameter of the sphere which divides the sample's mass into a specified percentage when the particles are arranged on an ascending mass basis.
  • the D10 value is the diameter at which 10% of the sample's mass is comprised of particles with a diameter of less than this value.
  • the D50 value is the diameter of the particle that 50% of a sample's mass is smaller than and 50% of a sample's mass is larger than.
  • the D v 50 is the maximum particle diameter below which 50% of the sample volume exists - also known as the median particle size by volume.
  • the D v 10 and D v 90 are the maximum particle diameter below which 10% and 90% of the sample volume exists. Commonly reported percentiles are the D v 10, D v 50 and D v 90.
  • Formulations of the invention may further be characterised by the average diameter (also referred to as the Z-average diameter) of the wet milled particles of the compound of formula I.
  • the Z-average diameter of the particles may be measured in the suspension comprising the wet milled particles, e.g. by dynamic light scattering.
  • Z-average diameter refers to the harmonic intensity averaged particle diameter of a sample of particles measured by dynamic light scattering.
  • the Z-average is derived from a Cumulants analysis of the measured correlation curve, wherein a single particle size is assumed and a single exponential fit is applied to the autocorrelation function.
  • a formulation comprising particles containing the compound of formula I, wherein said particles have a Z-average diameter of less than about 1000 nm, and wherein the formulation comprises an enteric coating on said formulation or on said particles.
  • the particle size distribution parameters mentioned above may be applicable, individually or in combination, to any given formulation.
  • the particle size distribution of a formulation comprising particles containing the compound of formula I may be measured after the wet-milling by dynamic light scattering, using, for example a particle size analyser (such as a Malvern ZetaSizer Nano). Where such a process involves the dispersion of the substance to be analysed, a suitable amount of a dispersion agent may be used, for example water.
  • a particle size analyser such as a Malvern ZetaSizer Nano
  • the present invention also encompasses a pharmaceutical formulation comprising particles containing the compound of formula I with any of the particle size distributions defined herein, regardless of the process by which the formulation is produced.
  • a formulation comprising particles containing the compound of formula I, wherein said particles have a particle size distribution defined by a Z-average diameter of less than about 1000 nm; and wherein the formulation comprises an enteric coating on said formulation or on said particles, preferably where the particle size distribution has been measured after the particles have been wet-milled.
  • the pharmaceutical formulation of the second aspect of the invention comprises particles of the compound of formula I with any of the particular particle size distributions described herein, wherein the particles are obtained by a process which involves wet milling said compound or a mixture containing said compound. Therefore, in a particular embodiment of the second aspect of the invention, the particles are obtained by a process which involves wet milling said compound or a mixture containing said compound.
  • Formulations according to the first and second aspects of the invention are herein referred to as“formulations of the invention”.
  • the pharmaceutical formulations of the invention may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • the compound of formula I is the sole active pharmaceutical ingredient in the particles, or in the formulations of the invention.
  • Wet milling is useful for producing particles that are generally smaller in size than those obtained from dry milling.
  • Particular particle size distributions that may be mentioned in the context of the present invention include those with a Z-average diameter value of from about 20 nm to about 800 nm; a Z-average diameter of from about 20 nm to about 600 nm; a Z-average diameter of from about 25 nm to about 200 nm; or a Z-average diameter of from about 25 nm to about 100 nm.
  • the particles comprising of the compound of formula I present in a formulation of the invention may have a Z-average diameter of about 20 nm, about 25 nm, about 30 nm, about 35 nm, about 40 nm, about 45 nm, about 50 nm, about 100 nm, about 110 nm, about 120 nm, about 130 nm, about 140 nm, about 150 nm, about 200 nm, about 250 nm, about 300 nm, about 350 nm, about 400 nm, about 500 nm, about 550 nm, about 600 nm, about 700 nm, about 800 nm, about 900 nm or about 1000 nm.
  • Said Z-average diameter values preferably relate to particles that have been wet milled and that comprise the compound of formula I and further excipients (e.g. PVP K30, Na-docusate and/or mannitol).
  • the particles comprising of the compound of formula I particles have a particle size distribution defined by a Z- average diameter of from about 20 nm to about 800 nm.
  • the particles comprising the compound of formula I may have a Z-average diameter of from about 25 nm to about 200 nm.
  • the particles comprising the compound of formula I may have a Z-average diameter of from about 25 nm to about 100 nm.
  • the product obtained by the wet milling process may be converted into a solid form, e.g. using any of the solidification processes disclosed herein, including fluid bed coating / granulation, spray drying and freeze drying. Other techniques for removing the liquid medium known to the person skilled in the art may be used. Where solidification is achieved using freeze-drying, for example, the particle size distribution may change. Such freeze-dried products, and products that have been solidified by other processes, are included within the scope of the invention.
  • the particle size distribution may be characterised by a D v 50 of from about 5 pm to about 100 pm, from about 10 pm to about 90 pm, from about 20 pm to about 80 pm, from about 30 pm to about 70 pm, or from about 40 pm to about 60 pm. More specifically, the particles consisting of the compound of formula I present in a formulation of the invention may have a particle size distribution defined by a D v 50 of about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 25 pm, about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, about 60 pm, about 70 pm, about 80 pm, about 90 pm, or about 100 pm. Said particle size distributions preferably relate to particles that comprise of the compound of formula I and suitable excipients known in the art. These particle size distributions relate to particles that have been subjected to a freeze-thaw cycle after they have been wet milled.
  • Formulations of the invention may also be defined by the average Pdl (polydispersity index) of the particles.
  • the polydispersity index of the particles indicates the degree of particle size homogeneity in a suspension. On the nanoscale, the Pdl is always less than 1.
  • a Pdl of less than 0.2 indicates a mono-dispersed suspension, whereas a Pdl greater than 0.7 is an indication of a broad particle size distribution or of particle aggregation.
  • Pdl values that may be mentioned in the context of the present invention include those that are less than about 0.9, less than about 0.8, less than about 0.7, less than about 0.6 or less than about 0.5. More specifically, the particles comprising of the compound of formula I present in a formulation of the invention may have a particle size homogeneity defined by Pdl of about 0.5, about 0.6 or about 0.7. Said Pdl values preferably relate to particles that have been wet milled and that comprise the compound of formula I and further excipients (e.g. PVP K30, Na-docusate and/or mannitol).
  • the compound of formula I is not considered to be acid labile, and protection from exposure to stomach acid has therefore not been found to be necessary for oral formulations containing the compound of formula I. Nevertheless, it has surprisingly been found that the use of an enteric coat can improve the pharmacokinetic properties of formulations containing this compound, particularly when the compound has been wet milled to produce a particle size distribution as described herein.
  • the pharmaceutical formulations of the invention therefore comprise an enteric coating.
  • An“enteric coating” is a substance (e.g. a polymer) that is applied on the surface of an oral medication (e.g.
  • enteric coatings are stable at the highly acidic pH found in the stomach, but break down rapidly in the relatively basic pH of the small intestine. Therefore, enteric coatings prevent release of the active ingredient in the medication until the medication reaches the small intestine e.g. the duodenum, the jejunum and the ileum. The use of an enteric coating may therefore allow for targeted release of an active ingredient in the small intestine.
  • the enteric coating is present on surface of the formulation of the invention (e.g. on the surface of a tablet, a capsule or pellets), or the particles comprising said compound of formula I are coated with the enteric coating.
  • the formulation comprises enteric coated particles of the compound of formula I and the formulation is in a form that does not necessarily have (but preferably does have) an enteric coating on the overall formulation, e.g. an uncoated tablet containing coated particles.
  • Any enteric coating known to the skilled person may be used in the present invention.
  • Particular enteric coating materials that may be mentioned include those which comprise beeswax, shellac, an alkylcellulose polymer resin (e.g. ethylcellulose polymers, carboxymethylethylcellulose, or hydroxypropyl methylcellulose phthalate) or an acrylic polymer resin (e.g.
  • acrylic acid and methacrylic acid copolymers methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate), poly(methyl methacrylate)
  • references herein to particular aspects of the invention (such as the first aspect of the invention, i.e. referring to a pharmaceutical formulation of the compound of formula I obtained by wet milling particles of said compound, and wherein the formulation comprises an enteric coation on said formuation or on said particles) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention.
  • compositions of the invention have been found to be surprisingly effective at improving (e.g. increasing) the bioavailability of the compound of formula I in vivo compared to a pharmaceutical formulation in which the compound of formula I has not been wet milled. Improvement in bioavailability may be demonstrated by measuring the C max or the area under the curve (AUC) following administration of the pharmaceutical formulation to a subject.
  • the subject is a human.
  • Cmax and“AUC” will be well understood by the person skilled in the art to refer, in this context, to the peak plasma concentration of the compound of formula I after administration (e.g. to a human subject) and the integral of the concentration/time curve post administration of said compound, respectively.
  • the formulation of the invention results in the bioavailability of the compound of formula I being increased compared to the bioavailability of the compound of formula I in a pharmaceutical formulation in which the compound of formula I has not been wet milled or the formulation does not comprise an enteric coating.
  • the variation in the bioavailability of the compound of formula I may additionally or alternatively be reduced compared to the variation in the bioavailability of the compound of formula I in a pharmaceutical formulation in which the compound of formula I has not been wet milled or that does not comprise an enteric coating.
  • the bioavailability of the compound of formula I is increased compared to the bioavailability of the compound of formula I in a pharmaceutical formulation in which the compound of formula I has not been wet milled
  • administration of the formulation of the invention results in a larger systemically available fraction of the compound of formula I in vivo compared to administration of a formulation in which the compound of formula I has not been wet milled.
  • the increase in the amount of compound of formula I that is systemically available following administration of the formulation of the invention as compared to administration of a formulation in which the compound of formula I has not been wet milled e.g.
  • C max or AUC may be at least about 10%, (at least) about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% (i.e. 2-fold), about 150%, about 200% (i.e. 3-fold), about 250%, about 300% (i.e. 4-fold), about 350%, about 400% (i.e. 5-fold), about 450%, about 500% (i.e. 6-fold), about 600% (i.e. 7-fold), about 700% (i.e. 8-fold), about 800% (i.e. 9-fold) or about 900% (i.e. 10-fold).
  • the improvement of the bioavailability provided by the formulations of the invention may be demonstrated using suitable methods known in the art.
  • the improvement in bioavailability may be demonstrated by comparing the AUC data of a subject who has been administered a formulation of the invention with the AUC data of a subject who has been administered a pharmaceutical formulation in which the compound of formula I has not been wet milled or that does not comprise an enteric coating.
  • the inter-individual variation in bioavailability between subjects who have been administered a formulation of the invention is at least about 1 %, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% less compared to the inter-individual variation in the bioavailability of the compound of formula I between subjects who have been administered a formulation in which the compound of formula I has not been wet milled or that does not comprise an enteric coating.
  • the difference between the bioavailability (as represented by the C max or AUC) value for a subject that has been administered a formulation of the invention and the median bioavailability (or the median C max or AUC) value for a population of subjects that have been administered said formulation is not more than 30%, e.g. not more than 25%, not more than 20%, not more than 15%, not more than 10%, not more than 5% of said median bioavailability (or the median C max or AUC) value.
  • the reduction in the variability of bioavailability provided by the formulations of the invention may be determined by suitable methods known in the art.
  • the reduction may be assessed comparing the C max and AUC values of subjects following administration of the formulation.
  • the formulation of the invention will generally be administered as a mixture comprising the compound of formula I and one or more pharmaceutically acceptable excipients.
  • the one or more pharmaceutically acceptable excipients may be selected with due regard to the intended route of administration in accordance with standard pharmaceutical practice.
  • Such pharmaceutically acceptable excipients are preferably chemically inert to the active compound and are preferably have no detrimental side effects or toxicity under the conditions of use.
  • Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief review of methods of drug delivery may also be found in e.g. Langer, Science 249, 1527 (1990).
  • the formulation further comprises at least one pharmaceutically acceptable excipient.
  • the at least one pharmaceutically acceptable excipient may be a lubricant, a binder, a filler, a surfactant, a diluent, an anti adherent, a coating, a flavouring, a colourant, a glidant, a preservative, a sweetener, a disintegrant, an adsorbent, a buffering agent, an antioxidant, a chelating agent, a dissolution enhancer, a dissolution retardant or a wetting agent.
  • Particular pharmaceutically acceptable excipients include mannitol, PVP (polyvinylpyrrolidone) K30, lactose, saccharose, sorbitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredients, as well as disintegrating agents and lubricating agents such as Na-docusate, magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • particles comprising of the compound of formula I may be wet milled, either together or separately, with mannitol, PVP (polyvinylpyrrolidone) K30 and Na-docusate.
  • the formulation comprises PVP K30, Na-docusate and mannitol.
  • Such mixtures may then be processed into blocks, pellets, granules a powder, or compressed into tablets or mini-tablets.
  • formulations of the invention may act systemically, and may therefore be administered accordingly using suitable techniques known to those skilled in the art.
  • Formulations as described herein will normally be administered orally, in a pharmaceutically acceptable dosage form.
  • the pharmaceutical formulation of the present invention is preferably an oral pharmaceutical formulation.
  • Formulations of the invention may also be prepared for oral administration in the form of a capsule.
  • capsules such as soft gelatin capsules may be prepared containing a formulation of the invention alone, or together with a suitable vehicle, e.g. vegetable oil, fat etc.
  • hard gelatin capsules may contain the formulation of the invention alone, or in combination with solid powdered ingredients such as a disaccharide (e.g. lactose or saccharose), an alcohol sugar (e.g. sorbitol or mannitol), a vegetable starch (e.g. potato starch or corn starch), a polysaccharide (e.g. amylopectin or cellulose derivatives) or gelling agent (e.g. gelatin).
  • a disaccharide e.g. lactose or saccharose
  • an alcohol sugar e.g. sorbitol or mannitol
  • a vegetable starch e.g. potato starch or corn starch
  • a polysaccharide
  • compositions of the invention include formulations that are provided in the form of a tablet or capsule e.g. for oral administration.
  • the formulation of the invention comprises an enteric coating.
  • the enteric coating is present on surface of the formulation (e.g. on the surface of a tablet or a capsule) or each of the particles comprising the compound of formula I are coated with the enteric coating.
  • the formulation is provided in the form of a capsule or tablet, and the enteric coating is present as an outer layer on said capsule or tablet.
  • the formulation may be in the form of a capsule with an enteric coating, the capsule containing wet milled compound of formula I, or alternatively the wet milled compound of formula I may be compressed into a tablet and the tablet is subsequently coated with an enteric coating.
  • the formulation is provided in the form of a capsule or tablet containing particles comprising the compound of formula I, wherein the particles are coated with the enteric coating.
  • said particles may have a particle size distribution defined by a D v 50 of less than about 100 pm; a D v 50 of from about 20 pm to about 100 pm; a D v 50 of from about 20 pm to about 90 pm; a D v 50 of from about 20 pm to about 50 pm; a D v 50 of from about 50 pm to about 100 pm; or a D v 50 of from about 70 pm to about 90 pm.
  • particles comprising the compound of formula I are first wet milled to obtain the desired particle size distribution. They are then may be coated with an enteric coating. Said coated particles may then be compressed into a tablet or loaded into a (e.g. non- coated) capsule.
  • formulations of the invention may be prepared by a process that involves wet milling the compound of formula I, or a mixture containing said compound, to produce particles with a particle size distribution defined by a D v 50 of less than about 100 pm.
  • a process for preparing a capsule or tablet as defined herein above which process comprises:
  • step (iii) incorporating the particles obtained in step (ii) into a capsule or a tablet.
  • the compound of formula I is mixed with PVP K30, Na-docusate and mannitol prior to wet-milling.
  • the enteric coating may be introduced at any time point, provided the compound of formula I in the resulting formulation is encompassed with the enteric coating.
  • the process may further comprise the step of coating said capsule or tablet with the enteric coating before or after (preferably before) the particles are incorporated into said capsule or tablet.
  • the process may further comprise the step of applying the enteric coating onto the particles prior to the incorporation of said particles into a capsule or tablet.
  • compositions that may be mentioned include those in which the compound of formula I is present in a total amount that is at least 1 % (or at least 10%, at least 30% or at least 50%) by weight of the formulation. That is, the weight ratio of the compound of formula I to the totality of the components (i.e. the compound of formula I and all pharmaceutical excipients, e.g. adjuvants, diluents and carriers) of the pharmaceutical formulation is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50).
  • A“therapeutically effective amount”, an“effective amount” or a“dosage” as used herein refers to an amount of a formulation of the invention that is sufficient to produce a desired effect, which can be a therapeutic and/or beneficial effect.
  • the effective amount or dosage will vary with the age or general condition of the subject, the severity of the condition being treated, the particular agents administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and like factors within the knowledge and expertise of those skilled in the art.
  • a“therapeutically effective amount”,“effective amount” or“dosage” in any individual case can be determined by one of skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation.
  • formulations of the invention may be administered (for example, by way of one or more preparations as described herein) at varying doses, with suitable doses being readily determined by one of skill in the art.
  • the total dosage of the compound of formula I that is to be administered to a subject in need thereof may range from about 0.01 to about 2000 mg/kg of body weight per day (mg/kg/day), about 0.1 to about 500 mg/kg/day, and about 1 to about 100 mg/kg/day.
  • Such dosages may be, for example, oral dosages of the formulations of the invention.
  • treatment with such formulations may comprise administration of a unit dose formulation containing from about 0.01 mg to about 3000 mg of the compound of formula I, for example from about 0.1 mg to about 2000 mg, or from about 1 mg to about 1000 mg (e.g. from about 10 mg to about 500 mg), of the active ingredient.
  • treatment may comprise administration of the formulation of the invention (including capsules containing said formulation) using a single daily dose.
  • the total daily dosage of the compound of formula I may be administered in divided doses two, three or four times daily (e.g. twice daily with reference to the doses described herein, such as a dose of 100 mg, 250 mg, 500 mg or 1000 mg twice daily).
  • the skilled physician will recognise that the dosage will vary from subject to subject.
  • the formulation of the invention is administered to a subject where the daily dose of the compound of formula I is in the range of from about 1 to about 3000 mg, preferably from about 1 to about 1000 mg.
  • the dose administered to a subject, particularly a human subject, in the context of the present invention should be sufficient to effect a therapeutic response in the subject over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the subject to be treated, and the stage/severity of the disease.
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage which will be most suitable for an individual subject.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • formulations of the invention are useful as pharmaceuticals.
  • Formulations of the invention may be particularly useful in treating a disorder or condition ameliorated by the activation of AMP- activated protein kinase (AMPK).
  • AMPK AMP- activated protein kinase
  • a method of treating a disorder or condition ameliorated by the activation of AMPK comprising administering to a subject in need thereof a therapeutically effective amount of a formulation of the invention or a capsule containing said formulation.
  • the formulation of the invention or a capsule containing said formulation for use in a method of treating a disorder or condition ameliorated by the activation of AMPK.
  • AMPK acetyl-CoA carboxylase
  • cancer will be understood by those skilled in the art to include one or more diseases in the class of disorders that is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion, proliferation or by implantation into distant sites by metastasis.
  • the compound of formula I is capable of inhibiting the proliferation of cancer cells and the metastasis of cancer cells.
  • proliferation we include an increase in the number and/or size of cancer cells.
  • metastasis we mean the movement or migration (e.g. invasiveness) of cancer cells from a primary tumor site in the body of a subject to one or more other areas within the subject's body (where the cells can then form secondary tumors).
  • formulations of the invention may be suitable for use in the treatment of any cancer type, including all tumors (non-solid and, preferably, solid tumors, such as carcinoma, adenoma, adenocarcinoma, blood cancer, irrespective of the organ).
  • the cancer cells may be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and airways, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph glands and gastrointestinal tract.
  • the cancer is selected from the group of colon cancer (including colorectal adenomas), breast cancer (e.g.
  • the cancer is selected from the group of colon, prostate and, particularly, breast cancer.
  • the cancer is a non-solid tumor, it is preferably a hematopoietic tumor such as a leukemia (e.g. Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL).
  • AML Acute Myelogenous Leukemia
  • CML Chronic Myelogenous Leukemia
  • ALL Chronic Lymphocytic Leukemia
  • CLL Chronic Lymphocytic Leukemia
  • diabetes i.e. diabetes mellitus
  • type 1 diabetes insulin-dependent
  • type 2 diabetes insulin-independent
  • formulations of the invention may be suitable for use in the treatment of type 1 diabetes and/or type 2 diabetes.
  • hyperinsulinemia or an associated condition will be understood by those skilled in the art to include hyperinsulinemia, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions such as stroke, systemic lupus erythematosus, neurodegenerative diseases such as Alzheimer’s disease, and polycystic ovary syndrome.
  • Other disease states include progressive renal disease such as chronic renal failure.
  • a condition/disorder where fibrosis plays a role includes (but is not limited to) scar healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis, and cardiovascular fibrosis (including endomyocardial fibrosis), systemic sclerosis, liver cirrhosis, eye macular degeneration, retinal and vitreal retinopathy, Crohn’s/inflammatory bowel disease, post-surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis.
  • Formulations of the invention may also be useful in the treatment of sexual dysfunction (e.g. the treatment of erectile dysfunction).
  • Neurodegenerative diseases that may be mentioned include Alzheimer ' s disease, Parkinson ' s disease and Huntington ' s disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA).
  • SBMA spinal and bulbar muscular atrophy
  • DRPLA dentatorubral and pallidoluysian atrophy
  • SCA spinocerebellar ataxias
  • references to the “treatment” of a particular condition will take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity and/or frequency of occurrence of one or more clinical symptom associated with the condition, as judged by a physician attending a subject having or being susceptible to such symptoms.
  • references to a subject refer to a living subject being treated, or receiving preventative medicine, including mammalian (e.g. human) subjects.
  • references to a subject refer to a human subject.
  • a“subject in need” of the formulation of the invention includes a subject that is suffering a disorder or condition ameliorated by the activation of AMPK.
  • formulations of the invention as described herein are capable of improving the bioavailability of the compound of formula I, i.e. by increasing the amount of the compound in the systemic circulation following administration of the formulation to a subject.
  • Formulations of the invention may provide at least a three-fold, a four-fold, a five-fold, six-fold, eight-fold or ten-fold (or greater) increase in the bioavailability of the compound of formula I compared to a formulation that was not obtained using a wet milling process.
  • a surprising increase in bioavailability has been obtained for wet milled products (wherein an enteric coating is present) in comparison to dry milled products.
  • Formulations of the invention may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, other therapies known in the prior art, whether for use in the above-stated indications or otherwise.
  • formulations of the invention may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.
  • Figure 1 shows comparative results of oral pharmacokinetic studies of non-milled (without excipients), dry milled (without excipients) and wet milled (with excipients) compound of formula I, as a suspension and in non-coated and enteric coated capsules.
  • Figure 2 shows comparative results of oral pharmacokinetic studies of non-milled and to dry milled compound of formula I (with excipients) in non-coated and enteric coated capsules.
  • Figures 3 and 4 show absolute and relative C max results for formulations (without excipients) of non-milled and dry milled compound of formula I in non-coated and enteric coated capsules.
  • Figures 5 and 6 show absolute and relative AUC results for formulations (without excipients) of non-milled and dry milled compound of formula I in non-coated and enteric coated capsules.
  • Figures 7 and 8 show absolute and relative C max results for formulations (with excipients) of non-milled, dry milled and wet milled compound of formula I in non-coated and enteric coated capsules.
  • Figures 9 and 10 show absolute and relative AUC results for formulations (with excipients) of non-milled, dry milled and wet milled compound of formula I in non-coated and enteric coated capsules.
  • Figure 11 shows results of oral pharmacokinetic studies of wet-milled compound of formula I administered in non-coated capsules.
  • Figure 12 shows results of oral pharmacokinetic studies of wet-milled compound of formula I administered in enteric coated capsules.
  • Figure 13 shows results of oral pharmacokinetic studies of dry-milled compound of formula I administered in enteric coated capsules.
  • AUCo-t Area under the concentration-time curve from time zero to last quantifiable concentration
  • AUCo- Area under the concentration-time curve from time zero to infinity b.w.: Body weight
  • PVP K30 Polyvinylpyrrolidone K 30
  • Example 1 - dry milled compound of formula I Dry milling was performed for Examples 1a to 1c using an air jet mill (Equipment code: CP-AJM-01 ; Promas engineers) with the following parameters:
  • Example 1c Micronisation was repeated in Example 1c by performing the air jet milling for a second time using the same parameters. This allowed the particle size D90 to be reduced to less than 10 pm.
  • Tween 20 Four drops of Tween 20 were added to 25m L of water and the mixture was sonicated for 3 minutes. 0.05 g of milled material was transferred into a 250ml_ glass beaker. 25 ml_ of the dispersant solution (Tween 20/water mixture) was added to the beaker with continuous swirling for 2 to 3 minutes. The suspension was transferred into the measuring unit and the particle size distribution measurements were conducted in triplicate.
  • Examples 2c and 2d further comprised mannitol.
  • the suspensions were then sampled for particle size distribution measurements.
  • the suspensions were analysed with a Malvern ZetaSizer Nano (Dynamic Light Scattering (DLS) equipment). Approximately 1 mL of nanosuspension was used to fill a disposable micro cuvette. The measurements were run in duplicate. The freeze/thaw samples were analysed with a Malvern Mastersizer 2000 equipped with a Hydro2000pP (A) unit (light scattering (LS) equipment) due to larger particle size. The suspensions were added directly to the volume dispersion unit until an obscuration value between 5-10% was obtained. Measurements were also run in duplicate. The following instrument settings were used for both the DLS and LS:
  • Example 2c was chosen for use in PK studies.
  • All the formulations contained Na-Docusate and PVP K30 in the same proportion (see table 2).
  • the systems with a higher concentration of the active substance (100 mg/ml - example 2a and example 2c) showed a smaller particle size after milling. Changes in particles size after storage for 7 days were not more than ⁇ 10 %.
  • example 2c was selected for the manufacturing of the nanosuspension for having mannitol in the formulation.
  • Mannitol is usually added as co-milling agent to increase coalition between particles favouring particle size reduction during milling. Its effect is not significant at this scale for the formulated example 2a and example 2c, but it might help to reduce the particle size if scale up of the process is necessary at later stages.
  • the effect of mannitol is however noticeable for example 2b and example 2d which have a lower concentration of the active substance (50 mg/ml). A higher concentration of the compound of formula I also increases the mechanical forces during wet-milling thus reducing the particle size of the suspension.
  • Polydispersity index (Pdl) indicates the degree of particle size homogeneity in a suspension. In nanoscale systems Pdl is always lower than 1. An index of 0.2 or lower indicates a mono dispersed suspension while a Pdl higher than 0.7 is an indication of a broad particle size distribution or particle aggregation.
  • the Pdl index of the formulated systems is in the range of 0.6 ⁇ 0.1 which shows a certain degree of particle size variation increasing the tendency of particle aggregate formation (see table 4).
  • Capsules were obtained from CapsulCN International Co., Ltd.
  • non-milled compound of formula I the compound of formula I was made using the process described in WO 201 1/004162.
  • the non-coated or enteric coated gelatin capsules were individually filled with 180 mg of non-milled compound of formula I, or a mixture containing said compound and accompanying excipients as indicated. Both capsule types were filled with either compound of formula I alone or compound of formula I together with 1.8 mg of sodium docusate, 0.18 mg of PVP K30 and 9 mg of mannitol.
  • non-coated or enteric coated gelatin capsules were individually filled with 180 mg of dry-milled compound of formula I (as obtained in Example 1 c).
  • Each capsule type was filled with either compound of formula I alone or compound of formula I together with 1.8 mg of sodium docusate, 0.18 mg of PVP K30 and 9 mg of mannitol.
  • each gelatin capsule was individually filled with 55.9 mg of the wet-milled compound together with accompanying excipients (using the product obtained in Example 2c). Once prepared, the capsules were stored in a desiccator at between 19 and 25 °C prior to administration to the animals.
  • Rabbits (New Zealand white; male) were housed under standard laboratory conditions, in environmentally monitored air-conditioned room with adequate fresh air supply (10-15 air changes per hour), room temperature (22 ⁇ 3°C) and relative humidity 30 to 70 %, with 12- hour light and 12-hour dark cycle. The temperature and relative humidity were recorded once daily.
  • Each animal was housed in a standard stainless steel rabbit cage SS-304 (Size: L 24” x B 18” x H 18”) with stainless steel mesh and removable bottom tray for refuse disposal, food hopper for holding pelleted food, holder for drinking water bottle and siphon tube and label holder. Clean, sterilized corncob was provided as bedding material.
  • the animals were fed ad libitum throughout the acclimatization and experimental periods, with Krishna Valley Agrotech rabbit feed.
  • Water was provided ad libitum throughout the acclimatization and experimental periods. Water from an Aqua guard water filter cum purifier was autoclaved and provided in polypropylene water bottles with stainless steel sipper tubes.
  • the animals were acclimatized for a minimum period of 1 weeks (7 days) to facility room conditions and observed for clinical signs daily. Veterinary examination of all the animals were performed on the day of receipt, daily and on the day of randomization. Grouping
  • Animal grouping was done by the method of body weight stratification and randomization. The animals selected for the study were weighed and grouped in to body weight ranges. These body weight stratified rabbits were distributed to all the study groups in equal numbers if possible, such that body weight variation of animals used does not exceed ⁇ 20% of the mean body weight. The grouping was done one day prior to the initiation of treatment.
  • a soft plastic dosing tube was used to dose the filled capsules.
  • the filled capsule was inserted into the dosing tube so that the short end of the capsule protrudes slightly from the tip of the tube.
  • the tip of the capsule was dipped in mineral oil to aid swallowing.
  • the head was grasped firmly with one hand about the maxilla.
  • the dosing tube containing the capsule was inserted behind the incisors.
  • the dosing tube was slid straight into the back of the mouth.
  • the capsule was ejected by pushing the plunger on the dosing tube.
  • the dosing tube was removed, and the rabbit's mouth was closed. The neck was stroked gently to facilitate swallowing.
  • an infant feeding tube was used to dose the suspension.
  • the feeding tube was inserted through the mouth of the rabbit to the oesophagus and the stomach, and ascertained that it has not been placed in the trachea before dosing to the animals.
  • the suspension of the compound of formula I was administered through the feeding tube.
  • drinking water of approximately 2.0-2.5 ml_ was administered to flush out the contents in the feeding tube.
  • the animals were restrained in a rabbit restrainer and blood samples (400-500 pl_ /time point) were collected via the central ear artery at 0.16, 0.25, 0.50, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0, 48.0 and 72 hours post-dosing. Collected blood specimens were centrifuged at 4000 rpm, 4°C for 10 minutes and plasma samples were separated and stored at -80°C until analysis.
  • Concentrations of the analyte of the compound of formula I in New Zealand white rabbits was determined using an API 3200 Q-trap LC-MS/MS system.
  • Chromatographic separation was achieved on Zorbax C18, 50 x 4.6 mm, 5pm column with methanol-0.1 % formic acid as mobile phase with gradient elution.
  • the flow rate was set at 1.0 ml_ min 1 .
  • Detection was accomplished by a triple- quadrupole tandem mass spectrometer in multiple-reaction monitoring (MRM) scanning via electrospray ionization source, applied in the positive mode.
  • MRM multiple-reaction monitoring
  • the optimised mass transition ion-pairs for quantitation were m/z 379.999 125.000 for the compound of formula I and m/z 376.165 165.00 for the ISD (Haloperidol).
  • Calibration plots were linear over the range of 11.073 to 50620.625 ng/ml_.
  • Haloperidol Sigma-Aldrich
  • Calibration curve standards were prepared in a range between 11.073 - 50620.63 ng/mL (Prepared concentrations: 11.073, 13.842, 27.683, 55.366, 110.733, 221.465, 442.930, 885.861 , 1771.722, 3543.444, 7086.887, 14173.78, 28347.55, 40496.50 and
  • NCA non-compartmental analysis
  • wet-milled compound of formula I generated a similar increase in bioavailability compared to a dry milled formulation in a non-coated capsule (Examples 5 and 12; Figures 7 to 10).
  • the variation in the bioavailability between subjects who have been administered wet milled compound of formula I in an enteric coated capsule is much less compared to the variation in the bioavailability between subjects who have been administered wet milled compound of formula I in a non-coated capsule ( Figure 11).
  • the variation in the bioavailability between subjects who have been administered wet milled compound of formula I in an enteric coated capsule is much less compared to the variation in the bioavailability between subjects who have been administered dry milled compound of formula I in an enteric-coated capsule ( Figure 13)

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Abstract

L'invention concerne une formulation pharmaceutique du composé de formule (I), la formulation pharmaceutique étant obtenue par un procédé qui implique un broyage humide pour produire des particules comprenant ledit composé ou un mélange contenant ledit composé ; et la formulation comprenant un enrobage gastro-résistant sur ladite formulation ou sur lesdites particules. Ladite formulation trouve une utilité particulière dans le traitement ou la prévention d'un trouble ou d'un état soulagé par l'activation de l'AMPK.
PCT/GB2020/051692 2019-07-15 2020-07-14 Nouvelles formulations WO2021009504A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011004162A2 (fr) 2009-07-08 2011-01-13 Betagenon Ab Composés utilisés en tant que médicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011004162A2 (fr) 2009-07-08 2011-01-13 Betagenon Ab Composés utilisés en tant que médicaments

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Remington The Science and Practice of Pharmacy", 1995, MACK PRINTING COMPANY
LANGER, SCIENCE, vol. 249, 1990, pages 1527
LOH ET AL., ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 10, 2015, pages 255 - 274
MD. SAIFUL ISLAM ET AL., IJPPR. HUMAN, vol. 6, no. 3, 2016, pages 141 - 159
NEKKANTI ET AL., DRUG NANOPARTICLES - AN OVERVIEW, THE DELIVERY OF NANOPARTICLES, vol. 4, pages 67 - 87
ZHI HUI LOH ET AL: "Overview of milling techniques for improving the solubility of poorly water-soluble drugs", ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 10, no. 4, 17 February 2015 (2015-02-17), NL, pages 255 - 274, XP055293546, ISSN: 1818-0876, DOI: 10.1016/j.ajps.2014.12.006 *

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