Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K31/4245—Oxadiazoles
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4415—Pyridoxine, i.e. Vitamin B6
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • 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
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• compositions and pharmaceutical formulations comprising at least one active pharmaceutical ingredient chosen from nitrocatechol derivatives and salts thereof.
• L-DOPA Levodopa
• AADC peripheral amino acid decarboxylase
• catechol-O- methyltransferase This has led to an interest in the development of inhibitors of the enzyme catechol-O- methyltransferase (COMT) based on the hypothesis that inhibition of the enzyme may provide clinical improvements in patients afflicted with Parkinson's disease undergoing treatment with L-DOPA, since COMT catalyses the degradation of L-DOPA.
• CMT catechol-O- methyltransferase
• the compounds of formula I are sensitive to 10 certain excipients, which may cause decomposition of the compounds of formula I and/or lack of stability of the compositions and formulations containing these compounds.
• the compounds of formula 1 may also exhibit a low bulk density and/or poor flow characteristics, which may increase die difficulty in formulating and/or manufacturing a stable dosage formulation containing the active compound.
• compositions and formulations thereof comprising at least one active pharmaceutical ingredient (“API") chosen from nitrocatechol 0 derivatives of formula I as defined herein and salts, esters, hydrates, solvates and other derivatives thereof.
• API active pharmaceutical ingredient
• the at least one nitrocatechol derivative is preferably 2,5-dichloro-3-(5- (3 ,4-dihydroxy-5-nitrophenyl)- 1 ,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1 -oxide or S-fS-Cl.S-dichloro ⁇ .o-dimethylpyridin-S-yO-tl ⁇ Joxadiazol-S-ylJ-S-nitrobenzene-l ⁇ -diol.
• the at least one nitrocatechol derivative may also be a mixture of 2,5-dichloro-3-(5-(3,4- 5 dihydroxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1 -oxide and 5-[3-(2,5- dichloro-4,6-dimethylpyridin-3-yl)-[ 1 ,2,4]oxadiazol-5-yl]-3-nitrobenzene- 1 ,2-diol.
• the API is present in granular form.
• the compositions and/or formulations may comprise a further API, for example the compositions and/or formulations may comprise, in addition to the at least one API chosen from nitrocatechol derivatives of formula 1, further APIs such as L-DOPA, a peripheral amino acid decarboxylase (AADC) inhibitor, such as carbidopa or benserazide.
• the compositions and/or formulations may also comprise at least one filler and at least one binder.
• the filler is not a phosphate derivative.
• the binder is not a polyvinylpyrrolidone ("PVP") derivative compound.
• the at least one filler and at least one binder may, independently, be intragranular (i.e., granulated with the API and/or contained within the same granules as the API), extragranular (i.e., present outside the granules of API), or part intragranular and part extragranular.
• the compositions may exhibit a bulk density that is greater than that of the API alone, and that may, in certain embodiments, be a significantly increased.
• the compositions may also exhibit improvements in other characteristics such as compressibility.
• compositions and/or formulations are stable over time and under different conditions, and may, in certain embodiments exhibit enhanced stability.
• the present disclosure relates to stable compositions and formulations thereof comprising at least one API chosen from nitrocatechol derivatives of formula I as defined herein and salts, esters, hydrates, solvates and other derivatives thereof, at least one filler, and at least one binder.
• the at least one filler is not a phosphate derivative and/or the at least one binder is not a PVP derivative compound.
• the API may be present in granular form.
• granules As used herein, the term “granules,” “granular form,” “API granules” and variations thereof, refer to the particles produced by wet or dry granulation of the API chosen from nitrocatechol derivatives of formula I as defined herein and salts, esters, hydrates, solvates and other derivatives thereof.
• the API may comprise two or more nitrocatechol derivatives of formula I, for example the composition may comprise 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)- l,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)-[l,2,4]oxadiazoI-5-yl]-3-nitrobenzene-l,2-diol.
• the granules may further comprise at least one filler and/or at least one binder.
• composition is intended to mean a composite comprising at least one API chosen from nitrocatechol derivatives of formula I as defined herein and salts, esters, hydrates, solvates and other derivatives thereof, at least one filler, and at least one binder.
• the composition may comprise two or more nitrocatechol derivatives of formula I (i.e.
• the composition may comprise 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine 1-oxide and 5-r3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[l,2,4]oxadiazol- 5-ylJ-3-nitrobenzene-l,2-diol, at least one phosphate derivative, and at least one PVP derivative compound.
• the composition may comprise granules of the at least one API, and the at least one filler and at least one binder may independently be intragranular (i.e., granulated with the API and/or contained within the same granules as the API), extragranular (i.e., present outside the granules of API, or part intragranular and part extragranular.
• the filler may be 10 wt% to 90 wt%, 20 wt% to 80 wt%, 30 wt% to 70 wt%, 40 wt% to 60 wt%, or about 50 wt% intragranular, with the remaining portion being extragra ⁇ ular.
• the binder may be 10 wt% to 90 wt%, 20 wt% to 80 Wt%, 30 wt% to 70 wt%, 40 wt% to 60 wt%, or about 50 wt% intragranular, with the remaining portion being extragranular.
• the composition may further comprise at least one excipient, which may be intragranular, extragranular, or part intra- and part extra-granular.
• the composition is preferably suitable for filling a capsule, making a tablet, and/or for directly administering to patients, for example packaged in sachets.
• the terms “formulation,” “pharmaceutical formulation,” and variations thereof, are intended to include compositions described herein that are further processed or formulated into a dosage form.
• the formulations may comprise a composition described herein, typically in the form of granules, in a dosage form suitable for administration to a subject, such as a capsule or compressed dosage form such as a tablet.
• the formulations may comprise a composition described herein, typically in the form of granules, mixed with at least one excipient in a dosage form suitable for administration to a subject, such as a capsule or compressed dosage form such as a tablet.
• nitrocatechol derivatives of formula I are defined as follows:
• Ri and Fb are independently selected from hydrogen or a group which is hydrolysable under physiological conditions, optionally substituted lower alkanoyl or aroyl;
• X is a methylene group;
• Y is an atom of oxygen, nitrogen, or sulphur, n is selected from 0, 1, 2, and 3;
• m is 0 or 1 ;
• Ri is a pyridine group chosen from the formulas A, B, C, D, E and F which is connected as indicated by the unmarked bond:
• RA, RS, R*. and R7 are independently chosen from hydrogen, Ci-C ⁇ -alkyl, CI-CO- thioalkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cu-aryloxy or a C ⁇ -Cn-thioaryl group, Ci-C ⁇ -alkanoyl or C7-Ci3-aroyl group, amino, C ⁇ -C ⁇ -alkylamino, Ci-C ⁇ -dialkylamino, C3-C12- cycloalkylamino, C3-Ci2-heterocycloalkylamino, Ci-C ⁇ -alkylsulphonyl, C «-Ci2- ary ⁇ sulphonyl, halogen, Ci-C ⁇ -haloalkyl, e.g., trifluoromethyl, cyano, nitro or a heteroaryl group; or two or more of residues R4, Rs, Re and R?
• P is a central unit, for example a planar unit, such as those selected from the regioisomers of l ,3,4-oxadiazol-2,5-diyl; l,2,4-oxadiazol-3,5-diyl; 4-methyl-4H- l,2,4-triazol-3,5-diyl; 1 ,3,5-triazin-2,4-diyl; l,2,4-triazin-3,5-diyl; 2H-tetrazol-2,5- diyl; 1 ,2,3-thiadiazol-4,5-diyl; l-alkyl-3-(alkoxycarbonyl)-lH-pyrrol-2,5 ⁇ yl wherein alkyl is represented by methyl, ethyl, n-propyl and n-bufyl and wherein alkoxy is represented by methoxy, eth
• P is chosen from l,3,4-oxadiazol-2,5-diyl and l,2,4-oxadiazol-3,5-diyl.
• the at least one nitrocatechol derivative of formula I is preferably 2,5-dichloro-3-(5- (3,4-dihydroxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide or 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[ 1 ,2,4]oxadiazol-5-yl]-3-nitrobenzene- 1 ,2-diol.
• the at least one nitrocatechol derivative of formula I may also be a mixture of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-l,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-[l,2,4Joxadiazol-5-yl]-3- ni trobenzene- 1 , 2-diol .
• the at least one nitrocatechol derivative is a mixture of two nitrocatechol derivatives, such as 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyi)-l,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide and 5-[3-(2,5-dichloro-4,6-dimethylpyridin-3- yl)-[ l,2,4]oxadiazol-5-yl]-3-nitrobenzene-l, 2-diol, the ratio of the two components may be approximately 50:50 or any variation thereof, such as approximately 60:40, 70:30, 80: 20j 90: 10, 95:5, 97:3, or 99:1, or the proportion of one of the nitrocatechol derivatives may be present in an amount up to and including 5%, up to an including 3 % or up to and including 1 % of the amount of the other nitrocatechol, for example 5-[3-(2,5-CIiChIO
• the at least one API chosen from nitrocatechol derivatives of formula I as disclosed herein, and salts, esters, hydrates, solvates and other derivatives thereof, may exhibit low bulk density, thereby making it difficult to formulate and manufacture a dosage form.
• 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)- 1 ,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine 1 -oxide a nitrocatechol of formula I, exhibits a bulk density of less man 0.1 g/ml prior to granulation and/or formulation
• 5-[3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)-[l,2,4]oxadiazol-5-yl]-3-nitrobenzene-l,2-diol may exhibit a bulk density of around 0.2 g/ml prior to granulation and/or formulation, as determined by the method described hereinbelow.
• Formulating APIs of low bulk density can often give rise to many problems. For example poor content uniformity, particle segregation, little or no flowability, high average weight variability, capping and lamination of tablets and high friability of tablets.
• the amount (or dosage) of the at least one API present in the compositions and/or formulations is preferably a therapeutically effective amount.
• therapeutically effective amount means an amount of a therapeutic agent sufficient to treat, alleviate, and/or prevent any condition treatable and/or preventable by administration of a composition of the disclosure, in any degree. That amount can, for example, be an amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment, alleviation, and/or prevention of the conditions listed herein.
• the actual amount required e.g.
• a formulation i.e, a capsule or tablet dosage form
• the API content in the formulation can vary from 0.02 wt% to 90 wt%, for example from 0.1 wt% to 70 wt%, from 0.2 wt% to 50 wt%, or from 0.3 wt% to 45 wt%.
• the at least one filler of the present disclosure includes calcium carbonate, cellulose powder, silicified microcrystalline cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrane, dextrin, dextrose, fructose, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystalline cellulose, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starches, pregelatinized starch, sucrose, trehalose, and xylitol.
• the at least one filler is not a phosphate derivative.
• the te ⁇ n "phosphate derivative,” and variations thereof, is intended to mean substances comprising calcium phosphate, including, but not limited to: calcium phosphate, dibasic anhydrous (for example, A-TAB TM, Di-Cafos A-N TM, Emcompress TM Anhydrous, and Fujicalin TM); calcium phosphate, dibasic dihydrate (for example, Cafos TM, Calipharm TM, Calstar TM, Di-Cafos TM, Emcompress TM); and calcium phosphate tribasic (for example, Tri-Cafos TM, TRI-CAL TM WG, TRI-TAB TM).
• the at least one filler may be chosen from starches, lactose, and cellulose. In at least one embodiment, at least two fillers may be present, for example a combination of starch, lactose, and/or cellulose. In various embodiments, for example, the at least one filler may constitute 0.5 wt% to 99.5 wt % of the composition and/or formulation, for example, 20 wt% to 95 wt%, 40 wt % to 95 wt%, 40 wt % to 85 wt%, 40 wt % to 70 wt%, 60 wt% to 95 wt%, or 80 wt% to 95 wt % of the total weight of the composition and/or formulation.
• the filler may be intragranular, extragranular or part intragranular and part extragranular.
• a composition and/or formulation may comprise 85 wt% filler.
• the amount of the at least one filler will vary depending, in part, upon the desired dosage, bulk density, and stability of the composition and/or formulation.
• the at least one binder of the present disclosure may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose sodium, ceratonia, cottonseed oil, dextrin, dextrose, gelatin, guar gum, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, maltose, methylcellulose, ethylcellulose, microcrystalline cellulose, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, starch, pregelatinised starch, stearic acid, sucrose and zein.
• the at least one binder is not a PVP derivative compound.
• PVP derivative compound and variations thereof, is intended to mean substances comprising polyvinyl pyrrolidone (PVP) and substituted versions thereof, including, but not limited to: povidone (for example, plasdone and kollidon); copovidone (for example, plasdone S-630 TM and kollidon VA-64 TM); and cross-linked PVP (for example crospovidone).
• the at least one binder may be chosen from starches, and in at least one embodiment, it may be starch
• the at least one binder may constitute 0.5 wt% to 40 wt% of the composition and/or formulation, for example, 1 wt% to 25 wt%, 5 wt% to 20 wt%, 8 wt % to 15 wt%, or 10 wt% to 15 wt% of the total weight of the composition and/or formulation.
• the binder may be intragranular, extragranular or part intragramilar and part extragranular.
• a composition and/or formulation may comprise between 6 wt% and 8 wt% binder, such as 7 wt% or 6.3 wt% binder.
• the amount of the at least one binder will vary depending, in part, upon the desired dosage, bulk density, and stability of the resulting composition and/or formulation.
• the composition and/or formulation comprises 0.2 to 50 wt% API, 5 to 10 wt% binder, and 33 to 85 wt% filler, such as the following compositions and/or formulations:
• Lubricants 1.0-10.0 wt%
• Lubricants 1.0 - 10.0 wt%
• Disintegrant 3.040.0 wt% The invention also relates to formulations comprising a composition of the invention.
• Such formulations may be in the form of a dosage form such as a capsule or a compressed form such as a tablet.
• the invention also includes a method of making a composition or formulation of the invention comprising the steps of:
• the filler is not a phosphate derivative.
• the binder is not a polyvinylpyrrolidone (“PVP”) derivative compound.
• the at least one API, at least one filler, and at least one binder may be combined by mixing (also referred to herein as blending).
• the appropriate apparatus and mixing time and rate may easily be determined by those of skill in me art based on, for example, the amount of material present, the type of mixing process used, and other parameters known to those of skill in the art.
• the components may be mixed manually, using a V-blender, a high shear mixer, or any other mixing apparatus and/or process known to those of skill in the art.
• the components may be mixed for any appropriate period of time, such as 1 to 20 minutes or 2 to 10 minutes.
• the mixture may be dry or wet granulated.
• the granules are wet-granulated using at least one granulation liquid.
• the at least one granulation liquid may be chosen from water, ethanol, isopropanol, and/or acetone.
• the granulation liquid is preferably water.
• the appropriate apparatus and mixing time and rate for granulation may be determined by those of skill in the art based on, for example, the amount of material and the amount of granulation liquid, if present.
• die components may be granulated manually, using a high shear mixer, planetary mixer or any other granulator apparatus and/or process known to those of skill in the an.
• the components may be granulated for any appropriate period of time, such as 1 to 60 minutes or 2 to 30 minutes. Determination of the endpoint of granulation is within the capability of the skilled person but can be determined by observance of stabilization of granule size and particle cohesion resulting in a decrease in air trapped inside the granule, or by attainment of steady state of rheological or correlated determination of voltage, conductivity torque, power consumption or near IR techniques. Granulation speeds may vary from 5% to 100% of the granulator mixing speed, such as from 25% to 100%.
• the granules may men be dried.
• Granules may be dried to loss on drying (LX)D) values below 6%, preferably below 5% and even more preferably between 1-3%.
• LX loss on drying
• the appropriate drying apparatus and drying time and temperature may be determined by those of skill in the art based on, for example, the amount of material present, moisture content of the material, and the granulation liquid.
• a fluid bed dryer or tray dryer may be used, for example at a temperature of 25 0 C or higher, 4O 0 C or higher, or 70 0 C or higher, to dry the granules.
• the granules may be dried at a temperature of 66°C.
• the granules may be sieved. Sieving the granules separates out granules of a particular particle size, and may be used to select particles of an advantageous size for formulating a dosage form or manufacturing a dosage form. In various embodiments, the granules may be sieved over a screen or sieve of 0.5 mm or larger, for example a 0.6 mm, 0.8 mm, 1.0 mm and 1.6 mm screen.
• the composition may further include at least one additional excipient which may be blended with the at least one API, at least one filler and at least one binder before, during or after granulation.
• the at least one additional excipient may be chosen from excipients such as disintegrants, glidants, and lubricants.
• Suitable disintegrants of the present disclosure include agar, calcium carbonate, alginic acid, calcium phosphate (tribasic), carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, polacrilin potassium, silicified microcrystalline cellulose, starch and pre- gelatinized starch, and mixtures thereof.
• the disintegrant may be a combination of disintegrants and/or at least two disintegrants are present, for example a combination of sodium starch glycolate and sodium carboxymethyl starch, such as that sold under the trade name ExplotabTM.
• the disintegrant may constitute 0.5 wt% to 40 wt% of the composition and/or formulation, for example, 1 wt% to 25 wt%, 5 wt% to 20 wt%, 10 wt % to 15 wt%, or 5 wt% to 15 wt%.
• a composition and/or formulation may comprise between 6 wt% and 9 wt% disintegrant, such as 6.8 wt% disintegrant.
• the amount of the at least one disintegrant will vary depending, in part, upon the desired dosage, bulk density, and stability of the resulting composition and/or formulation.
• Suitable glidants of the present disclosure include calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch, and talc, and mixtures thereof.
• the glidant may constitute 0.1 wt% to 15 wt% of the composition and/or formulation, for example, 0.5 wt% to 15 wt%, 1 wt % to 10 wt%, or 2 wt% to 6 wt%.
• the amount of glidant will vary depending, in part, upon the desired dosage, bulk density, and stability of the resulting composition and/or formulation.
• Lubricants of the present disclosure include calcium stearate, glycerine monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, magnesium lauryl sulphate, magnesium stearate, medium- chain triglycerides, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, sucrose stearate, and zinc stearate, and mixtures thereof.
• Lubricants may constitute 0.1 wt% to 15 wt% of the composition and/or formulation, for example, 0.5 wt% to 15 wt%, I wt % to 10 wt%, 1 wt % to 2 wt%, or 2 wt% to 8 wt%.
• the amount of lubricant will vary depending, in part, upon the desired dosage, bulk density, and stability of the resulting composition and/or formulation.
• the at least one excipient may be added before, during or after mixing of the at least one API and before (prior to) or during granulation and, thus may be an intragranular excipient.
• the at least one excipient may be added to the composition after granulation, for example by blending with the granules, and thus may be present as an extragranular excipient.
• at least one first excipient may be added prior to or during granulation and at least one second excipient and/or more of the at least one first excipient may be added to the composition after granulation.
• disintegrants may be added prior to or during granulation
• lubricants and glidants may be added after granulation.
• the composition comprising at least one API, at least one filler, and at least one binder may be used to make a formulation, such as, for example, to fill capsules or to form tablets.
• Capsules for use in the present disclosure include, but are not limited to, gelatin capsules and hydroxypropylmethyl cellulose (hypromellose) capsules. Suitable methods for filling such capsules with a composition according to an embodiment of the disclosure are well-known to those of skill in the art.
• Tablets of the present disclosure may be formed by any method known to those of skill in the art such as compression.
• the tablets may be coated, for example with aqueous based film-coatings, solvent based film- coatings and/or sugar coatings.
• the formulations of the invention may also be coloured, for example by inclusion of a colouring in the composition of the invention and/or by coating the composition and/or formulation.
• the formulation is a capsule comprising at least one API, at least one filler, and at least one binder, optionally in granular form, and may further comprise at least one glidant and/or at least one disintegrant.
• the formulation is a tablet comprising at least one API, at least one filler, and at least one binder, optionally in granular form, and may further comprise at least one glidant, at least one lubricant, and/or at least one disintegrant.
• compositions may exhibit improved bulk density and/or flow properties relative to those of the API alone.
• improved bulk density means that the bulk density of the composition is approximately at least double, least three times, at least four times, or at least five times that of the API alone. It is within the ability of one of skill in the art to determine the bulk density of a compound or composition using methods generally accepted in the art.
• suitable methods include, for example, the European Pharmacopeia edition 6, Test 2.9.15 "apparent volume,” pages 285-286, EDQM, 2007, and USP 31, vol. 1, test ⁇ 616> page 231-232, The United States Pharmacopeia Convention, 2008. A suitable method is described below:
• the support for the graduated cylinder with its holder has a mass of 450 _+ 5 g
• Vsoo Vi25o, to the nearest milliliter. If the difference between Vsoo and V 1250 is greater than 2 ml, carry out another 1250 taps.
• 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)- l ,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide exhibits a bulk density of less than 0.1 g/ml prior to granulating.
• compositions according to the present disclosure comprising 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-l,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide exhibit bulk densities of 0.2 g/ml or greater, for example 0.4 g/ml or greater, or 0.5 g/ml or greater.
• Compositions of the present disclosure for use as final blends for capsule filling or tabletting comprising 2,5-dichloro-3-
• (5-(3,4-dihydroxy-5-nitrophenyl)-l ,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide may also exhibit bulk densities of 0.2 g/ml or greater, for example 0.4 g/ml or greater, 0.5 g/ml or greater, and 0.6 /ml or greater.
• compressed formulations of the disclosure exhibit apparent density of 0.5 g/mL to 1.5 g/mL, such as 0.6 g/mL to 1.4 g/mL, 0.7 g/mL to 1.3 g/mL, or 0.8 g/mL to 1.2 g/mL.
• the apparent density of a compressed formulation is measured in terms of mass and volume of the formulation and is well within the capabilities of the skilled person.
• the compressibility index and Hausner ratio are also suitable methods to assess the compound or compositions.
• the compressibility index and Hausner ratio may be assessed using USP 31, vol. 1, test ⁇ 1174 > , The United States Pharmacopeia Convention, 2008, and measuring both the bulk volume (Vo) and the tapped volume (Vr) of the granules.
• the compressibility index (CI) may then be calculated using the following formula:
• the Hausner ratio (HR) can be calculated by using the following formula:
• a compressibility index is considered good when a value of less than 15% is calculated.
• a Hausner ratio value (a measure of flowability) is considered good when a value of less than 1.25 is calculated.
• compositions and/or formulations are stable and/or exhibit enhanced stability over other compositions and/or formulations.
• stability is intended to mean that less than 15 wt% of the at least one API in the composition and/or formulation decomposes over 6 months at test conditions of 40 0 C and 75% relative humidity, or over 3 years at test conditions of 25°C or 30 0 C and 60% relative humidity or over 15-30 days at test conditions of 7O 0 C and uncontrolled humidity.
• the at least one API may decompose under these conditions. It is within Ae ability of one of skill in the art to determine the stability of a compound, composition, or formulation using methods generally accepted in the art.
• the amount of me at least one API may be measured by any suitable method, e.g., HPLC.
• the assay (i.e. the amount of API) of a stable composition or formulation may indicate 85-115% of API after testing conditions, such as 95-105% of API.
• Decomposition is a chemical process made up of at least one reaction, such as oxidation, reduction or hydrolysis, that results in a chemical change in the decomposing substance resulting in the generation of one or more new chemical compounds.
• These new compounds may result in reduced and/or variable amount of the API in a given composition and/or formulation, reducing its efficacy, and may have unwanted and/or harmful side effects on the patients.
• impurity means any such new compound that is present in the composition and/or formulation in an amount less than
• the change in total impurities in the composition and/or formulation under the conditions and time periods set forth herein may also be indicative of a stable composition or formulation and may be measures by a suitable method, e.g., HPLC.
• the total impurities relative to the API in a stable composition and/or formulation after testing conditions may increase by less than 5 wt%, less than 2 wt%, less than 1 wt% or less than 0.5 wt%,
• Stability may also be tested under the influence of a variety of other test conditions, including, for example:
• the terin "visual stability,” and variations thereof, is intended to mean insubstantial changes in the color, integrity of a compressed formulation (for example, not breaking up), shape, and/or size of the granules, composition and/or formulation.
• the term “enhanced stability,” “improved stability * and variations thereof, means that the amount of decomposition of the at least one API in a given composition and/or formulation, and/or the increase in impurities in a given composition and/or formulation is less than that of a comparative composition and/or formulation that has been subject to the test conditions.
• the use of “the,” “a,” or “an” means “at least one,” and should not be limited to “only one” unless explicitly indicated to the contrary.
• the use of “the formulation” or “a formulation” is intended to mean at least one formulation.
• the granules were then dried using a fluid bed dryer until a loss on drying value of the granule was below 6%.
• the dried granules were sieved and then blended with the remaining ingredients set forth in Table 1.
• Gelatin capsules were filled with the formulation using an InCAP HS capsule filling machine.
• the granules and final compositions were evaluated for bulk and tapped density using the methods described above. Flowability/flow rate was also assessed by testing the flow rate through an orifice described in USP 31, vol. 1, test ⁇ 1174 > , The United States Pharmacopeia Convention, 2008. The flowability was measured as the mass per time flowing through the 10 mm diameter opening of a glass funnel. A flow rate of value greater than 10 g/second is considered good whereas a value of less than 10 g/second is considered poor.
• the compressibility index and Hausner ratio were assessed using USP 31, vol. 1, test ⁇ 1174> , The United States Pharmacopeia Convention, 2008, and measuring both the bulk volume (Vo) and the tapped volume (Vr) of the granules.
• the Hausner ratio (HR) can be calculated by using the following formula:
• a compressibility index is considered good when a value of less than 15% is calculated.
• a Hausner ratio value (a measure of flowability) is considered good when a value of less than 1.25 is calculated.
• Moisture or dryness was determined by loss on drying as described in USP 31, vol. I, test ⁇ 731 > , The United States Pharmacopeia Convention, 2008.
• the test involves accurately weighing the substance to be tested (mo), (e.g. using a sample amount of 1 to 2 g).
• the test specimen is then dried at 105 0 C until a constant weight (mr) is achieved.
• the moisture can be calculated by using the following expression:
• Capsules were evaluated for uniformity of mass and impurities. Uniformity of mass was assessed by the individual weight of 20 capsules; average mass and standard deviation were then calculated. Amount of total impurities was obtained using HPLC method with a limit of quantification of below 0.05%.
• the granules were then dried in a tray dryer until a loss on drying of the granule was below 6% .
• the dried granules were sieved.
• the granules were men blended with the remaining ingredients set forth in Table 1 in a V- blender.
• Gelatin capsules were filled with the formulation using an InCAP HS capsule filling machine.
• AU batches from Examples 1 and 2 were put on stress studies to determine their stability. Each of the eight batches was stored for 15 days at room temperature as well as under stress conditions (7O 0 C without relative humidity control). AU batches were tested for impurities content for both storage conditions, the results of which are set forth in Tables 4 and 5. Impurities values were obtained using HPLC method with a limit of quantification of below 0.05%.
• API used in these batches contained around 3% of impurities prior to formulation (composed of impurity 8).
• Batch E from Example 2 was put on long term stability studies to determine its stability. In one study, the batch was stored for 6 months at 25 0 C and 60% relative humidity, and in a second study, the batch was stored for 6 months at 40 0 C and 75% relative humidity. After each test, the batch was tested for assay and impurities content, the results of which are set forth in Table 6. Assay and impurities values were obtained using HPLC method with a limit of quantification of below 0.05% . Table 6: Stability Data for Batch E
• Three intermediate dosage capsules were made by first mixing the API, the filler(s) the binder and the disintegrant (smaller portion in comparative example and the total amount in batches I and J) in the amounts set forth in Table 7 below for 3 minutes in a high shear mixer.
• the API used in these examples was 2,5-dichloro-3-(5-(3,4-dihydroxy-5- nitrophenyl)-l,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide. Purified water was added to each mixture over a 3 minute period, and the mixtures were granulated by mixing for an additional 3 minutes.

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