Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

• the present invention relates to immediate release pharmaceutical compositions of empagliflozin and to a process for the manufacture of said pharmaceutical compositions.
• Empagliflozin is a drug used in the treatment of type 2 diabetes. It acts in the kidneys where it inhibits sodium glucose co-transporter-2 (SGLT2). Under normal conditions, SGLT2 is responsible for renal glucose reabsorption from the urine back into the blood, transporting approximately 180 g per day. Consequently, its inhibition allows some glucose to remain in the urine which is then excreted. In this way, empagliflozin lowers blood glucose levels.
• SGLT2 sodium glucose co-transporter-2
• XRPD X-ray powder diffraction
• W020061 17360 discloses two other forms of empagliflozin.
• Form I is a hydrated crystalline form which can be obtained by crystallisation from a solvent mixture comprising water.
• Form I has an XRPD with peaks at 17.86, 18.01 and 19.24 ( ⁇ 0.05) degrees 2Q.
• Form II is an alternative non-hydrated form having an XRPD with peaks at 15.88, 18.36, 18.87 and 19.20 ( ⁇ 0.05) degrees 2Q.
• empagliflozin Several pharmaceutical dosage forms of empagliflozin have been published.
• the main problem encountered when preparing formulations of empagliflozin is low solubility of empagliflozin, leading to difficulties with disintegration and dissolution times.
• US2017247356 relates to the problem of the low solubility of crystalline empagliflozin and discloses a co-crystal of empagliflozin and an amino acid.
• WO2010092126 discloses pharmaceutical compositions comprising empagliflozin as active ingredient, wherein empagliflozin represents 25% or less of the weight of the composition, and wherein the PSD of empagliflozin is D90 3 1 pm and D90 ⁇ 200 pm.
• WO2010092126 states that too large particles (i.e. larger than 200 pm) negatively affect the dissolution properties and the bioavailability of the pharmaceutical compositions of empagliflozin.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one active ingredient, wherein said active ingredient is the compound of the formula (1 ) or a co-crystal thereof
• composition comprises:
• composition is prepared preferably by dry methods
• composition is preferably a tablet.
• the present invention relates to a direct compression process for making the pharmaceutical composition according to the first aspect, the process comprising the steps of:
• step (1 ) Tableting the blend of step (1 ) by compressing it to produce tablet cores.
• the present invention relates to a dry granulation process for making the pharmaceutical composition according to any preceding claims, the process comprising the steps of:
• step (2) compaction of the mixture of step (1 ) to form granules, optionally using a roller compactor; (3) optionally mixing the granules of step (2) with one or more excipients.
• step (3) compressing the granules of step (2) or the final blend of step (3) to provide a tablet.
• a fourth aspect of the invention is the pharmaceutical composition according to the first aspect for use in the treatment of type 2 diabetes.
• a fifth aspect of the invention is a blister pack comprising the pharmaceutical composition of the first or fourth aspects wherein said blister pack is preferably an aluminum/PVC blister, an aluminum/aluminum blister, or a PVC/PE/PVDC/aluminum blister.
• a sixth aspect of the invention is a cardboard box with a patient information leaflet comprising at least one aluminum/aluminum or aluminum/PVC or PVC/PE/PVDC/aluminum blister pack of at least 4 units of the pharmaceutical composition of the first, fourth or fifth aspects.
• the present invention provides immediate release pharmaceutical compositions of compound of the formula (1 ), empagliflozin.
• Empagliflozin is also known by the IUPAC name (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4- [(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol.
• the empirical formula of Empagliflozin is C23H27CIO7 and the compound has a molecular weight of 450.9 g/mol.
• the structural formula of Empagliflozin is (1 ):
• empagliflozin and compound of formula (1 ) are used herein interchangeably.
• the aim of the present invention is to provide a pharmaceutical composition with a good dissolution profile that enables a high bioavailability of empagliflozin in a patient, while it avoids or reduces filming and sticking during the manufacturing process of the composition.
• empagliflozin API with a small particle size presents inadequate dissolution properties, and pharmaceutical compositions comprising it show manufacturability problems derived from the strong electrostatic interaction between particles.
• compositions comprising empagliflozin wherein the PSD is D90 higher than 25 pm up to 500 pm, preferably higher than 200 pm up to 400 pm may exhibit a good dissolution profile and thus a high bioavailability.
• Another aim of the present invention is to provide a pharmaceutical composition that presents a good stability, good friability, good uniformity and good solubility.
• Another aim of the present invention is to provide manufacturing methods for the manufacture of empagliflozin compositions which is easy, effective, competitive in terms of time and costs and environmentally friendly.
• Another aim of the present invention is to provide an acceptably sized tablet which can be swallowed easily.
• Tablets or capsules which are acceptable for patients are those with dimensions of between 5 mm and 15 mm along the longest axis, more preferably between 5 mm and 10 mm, more preferably between 9 to 6 mm. These dimensions allow the pharmaceutical composition of the first aspect to be swallowed easily.
• stable refers to a pharmaceutical composition
• a pharmaceutical composition comprising the compound of the formula (1 ) wherein the content of total impurities is below 5 % (w/w), preferably 3 % (w/w), more preferably 2 % (w/w), and most preferably 1 % (w/w), as determined by liquid chromatography (HPLC) at 225 nm if such a composition is stored for 1 month at 40°C and 75 % relative humidity (RH) or 1 month at 25 °C and 60 % relative humidity (RH).
• HPLC liquid chromatography
• uniform refers to the requirement that the content of the active agent in the tablets or capsules of a pharmaceutical batch has to be homogeneous. Content uniformity is ascertained according to the method specified in European Pharmacopoeia 9 th Edition 2.9.6. Uniformity of content of single-dose preparations.
• active agent refers to a therapeutically active compound, as well as any prodrugs thereof and pharmaceutically acceptable salts, hydrates and solvates of the compound and the prodrugs.
• Dx means that x% of the particles in a composition (based on volume) have a diameter of or below a specified d value.
• a D90 of 100 pm means that 90% of the particles, by volume, have a diameter of or below 100 pm.
• D95 is occasionally used for such a purpose. Therefore, a D95 of 100 pm means that 95% of the particles, by volume, have a diameter of or below 100 pm.
• the volume mean particle size of the compound of the formula (1 ) is determined using Malvern Laser Diffraction Mastersizer 3000 with sample feeder Aero (S) and Mastersizer 3000 software, using a general purpose analysis model and enhanced sensitivity. Before measurement the sample was manually homogenized. The hopper was filled with 2-5 g of sample. The vibration rate was adjusted to 25% in order to have obscuration values between 0.5 and 8%.
• total composition means the total composition of components forming the pharmaceutical composition regardless of whether it contains a single phase or multiple phases (e.g. granules).
• the“total composition” will be the sum of the intragranular components and the extragranular components.
• the coating is an optional feature in some embodiments of the invention, the coating is not considered when referring to the“total composition” of a pharmaceutical composition.
• the present invention relates to a pharmaceutical composition comprising at least one active ingredient, wherein said active ingredient is the compound of the formula (1 ) or a co-crystal thereof
• composition comprises:
• composition is prepared preferably by dry methods
• the composition is preferably a tablet.
• the D90 of the compound of the formula (1 ) is preferably greater than 50 pm and less than 500 pm as measured by laser diffraction spectroscopy. More preferably, the D90 of the compound of the formula (1 ) is greater than 100 pm and less than 500 pm as measured by laser diffraction spectroscopy. Even more preferably, the D90 of the compound of the formula (1 ) is between 150 pm to 500 pm as measured by laser diffraction spectroscopy.
• the D90 of the compound of the formula (1 ) is between 200 pm and 500 pm, preferably between 200 pm and 400 pm, more preferably between 200 pm and 350 pm, even more preferably between 200 pm and 300 pm.
• This range has been found to improve the flowability of the mixture, and where the pharmaceutical composition of the first aspect is a tablet, to produce harder tablets with lower friability.
• working with this particle size range reduces the number of method steps as it avoids the need for micronisation, and avoids the exposure of workers to small airborne particles.
• this particle size range it is possible to manufacture pharmaceutical compositions by dry methods including direct compression and dry granulation which have a uniform distribution of API.
• the composition preferably comprises between 3.5 and 25 % by weight of the compound of the formula (1 ) in respect of the total amount of the pharmaceutical composition of the first aspect.
• it comprises between 5 and 20 % by weight of the compound of the formula (1 ) in respect of the total amount of the pharmaceutical composition of the first aspect.
• it comprises from about 10 to about 15 % by weight of the compound of the formula (1 ) in respect of the total amount of the pharmaceutical composition of the first aspect.
• the pharmaceutical composition of the first aspect as herein disclosed comprises excipients such as a diluent, an acid, a lubricant, a solubiliser or a disintegrant
• these excipients are pharmaceutically acceptable.
• pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
• diatomuent refers to pharmaceutically acceptable excipients which are added to the bulk volume of the active agent making up the solid composition. As a result, the size of the solid composition increases, which makes its size suitable for handling. Diluents are convenient when the dose of drug per solid composition is low and the solid composition would otherwise be too small.
• the terms“filler” and“diluent” are used interchangeably.
• the pharmaceutical composition of the first aspect as herein disclosed comprise a diluent.
• Diluents can be water soluble or water insoluble. Examples of water soluble diluents are lactose, sucrose, mannitol and sorbitol. Examples of water insoluble diluents are starch, powdered cellulose, microcrystalline cellulose and calcium phosphate.
• Suitable diluents according to the invention are for example, lactose, in particular lactose monohydrate or lactose anhydrous, cellulose and derivatives, such as powdered cellulose, microcrystalline or silicified microcrystalline cellulose, cellulose acetate, starches and derivatives such as pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, sterilizable maize, sodium chloride, calcium carbonate, calcium phosphate, particularly dibasic calcium phosphate, calcium sulphate, dicalcium or tricalcium phosphate, magnesium carbonate, magnesium oxide, sugars and derivatives such as confectioner's sugar, fructose, sucrose, dextrates, dextrin, sorbitol sulfobutylether 1 1 -cyclodextrin, dextrose, polydextrose, trehalose, maltose, maltitol, mannitol, maltodextrin, sorbitol, inulin
• Preferred diluents for use in the pharmaceutical composition of the first aspect are agglomerated isomalt, lactose monohydrate and microcrystalline cellulose and mixtures thereof.
• Compositions comprising isomalt or microcrystalline cellulose were found to have improved dissolution and disintegration times, and improved stability. Furthermore, isomalt does not stimulate an insulin response.
• the pharmaceutical composition of the first aspect comprises one or more water insoluble diluents.
• One embodiment of the pharmaceutical composition of the first aspect preferably comprises a total amount of diluent or mixture of diluents from about 50 to 95% w/w% of the total composition, preferably 60 to 90%, further preferably 70 to 90%, further preferably 75 to 85%.
• disintegrant means a pharmaceutically acceptable excipient or a mixture of pharmaceutically acceptable excipients added to a formulation to facilitate its breakup or disintegration after administration.
• the total amount of disintegrant or disintegrants present in the pharmaceutical composition of the first aspect usually ranges from 1 to 10 % w/w in respect of the total amount of the pharmaceutical composition of the first aspect.
• the total amount of disintegrant or disintegrants present in the pharmaceutical composition of the first aspect ranges from 1 to 8% or preferably 2 to 7 % w/w in respect of the total amount of the pharmaceutical composition of the first aspect.
• Suitable disintegrants according to the first aspect of the invention are for example powdered cellulose, crospovidone, croscarmellose sodium, docusate sodium, low- substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, silicon dioxide, sodium starch glycolate, starch, particularly pregelatinized starch and cornstarch.
• Preferred disintegrants according to the first aspect of the invention are colloidal silicon dioxide, croscarmellose sodium and crospovidone.
• composition of the first aspect of the invention preferably comprises intragranular disintegrant, more preferably it comprises both intragranular and extragranular disintegrant.
• Suitable intragranular disintegrants are for example powdered cellulose, colloidal silicon dioxide, crospovidone, croscarmellose sodium, low -substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, particularly pregelatinized starch and cornstarch or a mixture thereof, and is preferably, crospovidone, microcrystalline cellulose, sodium starch glycolate or a mixture thereof.
• Suitable extragranular disintegrants are for example powdered cellulose, colloidal silicon dioxide, crospovidone, croscarmellose sodium, low -substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, particularly pregelatinized starch and cornstarch or a mixture thereof, and is preferably sodium starch glycolate, crospovidone, colloidal silicon dioxide or a mixture thereof.
• the disintegrant comprises less than 10% w/w% of the total composition.
• the disintegrant comprises from about 1 to 10% w/w% of the total composition, more preferably from about 1 to 8% w/w%, even more preferably from about 2 to 7% w/w%.
• the intragranular disintegrant comprises less than 6% w/w% of the total composition.
• the intragranular disintegrant comprises from about 0.5 to 6% w/w% of the total composition, more preferably from about 1 to 5% w/w%, even more preferably from about 2 to 4.5% w/w%.
• the extragranular disintegrant comprises less than 6% w/w% of the total composition.
• the extragranular disintegrant comprises from about 0.5 to 6% w/w% of the total composition, more preferably from about 1 to 5% w/w%, even more preferably from about 2 to 4.5% w/w%.
• binder as used herein is defined as an agent able to bind particles which cannot be bound only by a simple compression force.
• the binder may be present in the pharmaceutical composition of the first aspect of the invention in the form of a single compound or in the form of a mixture of compounds.
• the pharmaceutical composition of the first aspect comprises at least a binder, generally the total amount of binder or mixture of binders is from about 0.5 to 10%, preferably 1 -5% and further preferably 2-3% w/w% of the total composition.
• binders which may be used are for example naturally occurring or partially or totally synthetic polymers selected from acacia, agar, alginic acid, carbomers, carmellose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioner's sugar, copovidone, povidone, cottonseed oil, dextrate, dextrin, dextrose, polydextrose, maltodextrin, maltose, cellulose and derivatives thereof such as microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl celluloses, carboxymethylcelluloses, hypromelloses (cellulose hydroxypropyl methyl ether), starch and derivatives thereof, such as pregelatinized starch, hydroxypropylstarch, corn starch, gelatin, glyceryl behen
• the pharmaceutical composition of the first aspect is free from polyethylene glycol.
• Preferred binders include cellulose derivatives such as microcrystalline cellulose, copovidone, crospovidone, lactose anhydrous, or silicified microcrystalline cellulose, pregelatinized starch, low density starch, dibasic calcium phosphate dihydrate, or hydroxypropyl cellulose, hydroxypropylmethyl cellulose or polyvinylpyrrolidone.
• the pharmaceutical composition of the first aspect of the invention comprises a binder selected from povidone, copovidone or crospovidone, preferably copovidone.
• lubricant means a substance that reduces friction between the composition of the present invention and the surfaces of the apparatus used to compact the composition into a compressed form.
• the pharmaceutical composition of the first aspect comprises at least a lubricant.
• the total amount of lubricant or lubricants present in the pharmaceutical composition of the first aspect ranges from 0.5 to 4% w/w in respect of the total amount of the pharmaceutical composition of the first aspect. More preferably, the total amount of lubricant or lubricants present in the pharmaceutical composition of the first aspect ranges from 1 to 3% w/w in respect of the total amount of the pharmaceutical composition of the first aspect. More preferably, the total amount of lubricant or lubricants present in the pharmaceutical composition of the first aspect ranges from 1 to 2% w/w in respect of the total amount of the pharmaceutical composition of the first aspect.
• the lubricant of the pharmaceutical composition of the first aspect is selected from magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, talc, sodium lauryl sulfate, polyoxyl 40 stearate, polysorbate, polyoxyethylene lauryl ether, sorbitan monooleate, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate.
• lubricants are magnesium stearate and sodium stearyl fumarate, particularly preferred is sodium stearyl fumarate.
• Pharmaceutical compositions comprising magnesium stearate were found to have improved stability.
• Pharmaceutical compositions comprising sodium stearyl fumarate have been found to have shorter disintegration times and fewer problems such as sticking to the apparatus during manufacture.
• antiadherent means any substance that prevents the tablet formulation from sticking to the metal punches and dies used during the manufacturing process.
• any commonly used antiadherent may be used in the pharmaceutical composition of the first aspect, preferably the antiadherent is selected from magnesium stearate, colloidal silicon dioxide, talc and starch.
• the preferred antiadherents is colloidal silicon dioxide.
• the antiadherent may be intragranular or extragranular in granulated formulations.
• the total amount of antiadherent present in the pharmaceutical composition of the first aspect ranges from 0.5 to 2% w/w in respect of the total amount of the pharmaceutical composition of the first aspect.
• the term“solubiliser” means agents which increase the bioavailability of the API, particularly where poor solubility of the API is a problem.
• the pharmaceutical composition of the first aspect may also comprise a solubiliser.
• the solubiliser of the pharmaceutical composition of the first aspect is selected from commonly used solubilisers, for example pH modifiers such as citric acid, benzoic acid and tartaric acid; water soluble organic solvents such as polyethylene glycol 300 and 400, ethanol, propylene glycol, glycerin, N-methyl 2-pyrrolidone, dimethyl acetamide; water insoluble organic solvents such as beeswax, D-alpha tocopherol, oleic acid, mono- and di- glycerides; nonionic surfactants such as cremphor, tween 20, sorbitan monooleate, peppermint oil, polysorbate, polysorbate 20 and 80; water insoluble lipids such as peanut oil, corn oil, soybean oil, sesame oil, olive oil, cottonseed oil; cyclodextrins such as alpha, beta and gamma cyclodextrins,
• Preferred solubilisers are polyvinyl alcohol, microcrystalline cellulose, copovidone, sodium lauryl sulfate and those manufactured under the SEPITRAPTM 80 brand or SEPITRAPTM 4000 brand.
• SEPITRAPTM 80 comprises between 45 and 65 wt% polysorbate-80 and between 35 and 55 wt% of magnesium aluminometasilicate with respect of the total amount of SEPITRAPTM 80.
• SEPITRAPTM 4000 comprises between 55 and 75 wt% of polyoxyl 40 hydrogenated castor oil and between 25 and 45 wt% magnesium aluminometasilicate with respect to the total amount of SEPITRAPTM 4000. Surprisingly low quantities of solubiliser were required.
• the pharmaceutical composition of the first aspect comprises at least a solubiliser, generally the total amount of solubiliser or mixture of solubilisers is from about 0 to 10%, preferably 1 -5% and further preferably 2-3% w/w% of the total composition.
• the pharmaceutical composition of the first aspect is preferably free from polyethylene glycol (PEG).
• PEG polyethylene glycol
• the preferred pharmaceutical composition of the invention is a tablet composition.
• Suitable methods of manufacturing the pharmaceutical composition of the first aspect include compression of the pharmaceutical composition of the first aspect in the form of a powder, i.e. direct compression, or compression of the pharmaceutical composition of the first aspect in the form of granules, and if needed with additional excipients, i.e. dry or wet granulation.
• Dry methods include direct compression, direct mix and dry granulation.
• dry methods which do not include the addition of any solvent during manufacture of a pharmaceutical composition are employed in the present invention.
• Dry methods include direct mix, dry granulation and direct compression. Dry methods are preferred for the manufacture of the pharmaceutical composition of the first aspect, preferably a tablet composition, as they were found to produce more stable compositions with better dissolution times. Direct compression and dry granulation are particularly preferred.
• the present invention relates to a direct compression process for making the pharmaceutical composition according to the first aspect, the process comprising the steps of:
• step (1 ) Tableting the blend of step (1 ) by compressing it to produce tablet cores.
• a preferred embodiment of the invention is the direct compression process according to the second aspect, wherein the process comprises the steps of:
• step (3) Adding the lubricant to the second blend of step (2) and mixing to obtain a final blend
• step (3) Tableting the final blend of step (3) by compressing it on a suitable tablet press to produce tablet cores;
• step (5) film-coating of the tablet cores of step (5) with a film coat.
• the present invention relates to a dry granulation process for making the pharmaceutical composition according to any preceding claims, the process comprising the steps of:
• step (1 ) compaction of the mixture of step (1 ) to form granules, optionally using a roller compactor
• step (3) optionally mixing the granules of step (2) with one or more excipients.
• step (3) compressing the granules of step (2) or the final blend of step (3) to provide a tablet.
• a preferred embodiment of the invention is a dry granulation process according to the third aspect of the invention, wherein the process comprises the steps of: (1 ) mixing the compound of the formula (1 ) or a co-crystal thereof, with the diluent, disintegrant, optionally antiadherent, optionally binder, optionally solubiliser and optionally a first lubricant in a mixer;
• step (1 ) compaction of the mixture of step (1 ) to form granules, optionally using a roller compactor
• step (3) optionally mixing the granules of step (2) with a second lubricant in a mixer to obtain the final blend;
• step (4) compressing the granules of step (3) or the final blend of step (4) to provide a tablet
• step (5) optionally film-coating of the product of step (5) with a film coat.
• the manufacturing of the pharmaceutical composition of the first aspect by dry methods is more efficient as it demands less steps than a wet method.
• dry methods are more environmentally friendly because the use of organic solvents is avoided. Using organic solvents might be needed if manufacturing by wet methods is intended, due to the low solubility of empagliflozin API.
• the dissolution profile of empagliflozin formulations according to the present invention prepared by dry methods has been found to be faster than for wet methods.
• the composition is free of organic solvents, preferably free of any solvent other than water, most preferably essentially free of any solvent.
• wet granulation may be used for pharmaceutical compositions of the first aspect.
• the composition comprises granules.
• the excipients of the composition are then divided in intragranular excipients, extragranular excipients, and optionally a coating.
• the granules usually comprise the active ingredient (i.e. compound of formula (1 )), one or more diluents or binders, one or more disintegrants and optionally a lubricant.
• the extragranular excipients usually comprise one or more diluents or binders, one or more disintegrants and optionally a lubricant.
• the coating usually comprises a polymer, an oxide and another excipient, e.g. talc.
• a preferred embodiment of the first aspect of the invention is a pharmaceutical composition comprising at least one active ingredient, wherein said active ingredient is the compound of the formula (1 ) or a co-crystal thereof
• composition comprises:
• composition is prepared preferably by dry methods
• composition is preferably a tablet
• the compound of formula (1 ) or a co-crystal thereof have a particle size distribution D90 higher than 200 pm up to 400 pm, preferably higher than 200 pm up to 300 pm, and the composition is prepared by dry methods, preferably dry granulation.
• Another preferred embodiment of the first aspect of the invention is a pharmaceutical composition comprising at least one active ingredient, wherein said active ingredient is the compound of the formula (1 ) or a co-crystal thereof
• composition comprises:
• At least one lubricant wherein the compound of formula (1 ) or a co-crystal thereof have a particle size distribution D90 higher than 200 pm,
• composition is prepared preferably by dry methods
• composition is preferably a tablet
• the composition comprises granules, and the composition comprises at least one intragranular disintegrant, preferably at least one intragranular disintegrant and one extragranular disintegrant.
• the pharmaceutical composition of the first aspect of the present invention is an immediate release composition, preferably a tablet composition.
• immediate release refers to the rapid release of the majority of the therapeutic compounds contained in a pharmaceutical composition, allowing said therapeutic compounds to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the therapeutic compounds.
• Preferred conditions for immediate release are the release of at least 80% of the therapeutic compounds within a specified time, typically 45 min or less after oral ingestion, further preferably within 30 minutes and still further preferably within 20 minutes.
• the pharmaceutical composition in use remains intact in saliva and subsequently disintegrates in the stomach.
• the pharmaceutical composition of the first aspect is preferably in the form of tablets.
• the tablets preferably have a mass of between 50 mg and 300 mg, even more preferably between 75 mg and 250 mg as this range is acceptable to most patients. Preferably they are no longer than 2.5 cm. This ensures patient acceptability.
• the pharmaceutical composition of the first aspect is preferably swallowed whole and is preferably not in the form of orally disintegrating tablets. To aid swallowing and prevent dissolution in the mouth, the pharmaceutical composition of the first aspect is preferably coated tablets.
• the tablets may be coated with any conventional coating agent to form a film coat.
• the coating agent may be a polymer based coating agent and preferably comprises a cellulose base polymer such as hypromellose (HPMC) or a polyvinyl alcohol based polymer, such as polyvinyl alcohol (PVA).
• HPMC hypromellose
• PVA polyvinyl alcohol
• the coating agent comprises titanium dioxide and talc.
• Such coating agents have been found to improve friability and surprisingly, improve stability of the composition.
• the coating agent comprises PVA based polymer or a HPMC based polymer. Examples of suitable coating agents are those made under the trade name Opadry®, VIVACOAT® and Methocel®.
• the coating comprises no more than 5% of the total mass of the pharmaceutical composition of the first aspect.
• the coating agent comprises from 1 % to 3% of the total mass of the pharmaceutical composition of the first aspect.
• the coating agent may further comprise colouring or flavouring compounds.
• the composition is film coated and the film coat is a polymer based coating, most preferably a HPMC based coating, for example those produced under the trade name Opadry®, VIVACOAT® and Methocel®.
• a polymer based coating most preferably a HPMC based coating, for example those produced under the trade name Opadry®, VIVACOAT® and Methocel®.
• the final water content of the pharmaceutical composition of the first aspect is below 7 wt%, preferably from 0 wt% to 5 wt% by weight in respect of the total amount of the pharmaceutical composition of the first aspect. More preferably, the final water content of the pharmaceutical composition of the first aspect is from 0.1 wt% to 2 wt% by weight in respect of the total amount of the pharmaceutical composition of the first aspect. This range has been found to provide improved solubility of the active ingredient, the compound of the formula (1 ).
• the compound of the formula (1 ) is in crystalline form, preferably anhydrous crystalline form (II).
• the compound of the formula (1 ) comprises the crystalline form having an X-ray powder diffraction pattern that comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Q ( ⁇ 0.05 5 2Q).
• the crystal form is further characterised by a melting point of about 149°C ⁇ 3°C (determined via Differential Scanning Calorimetry using a DSC 821 (Mettler Toledo), as described in W020061 17359 (A1 ).
• the compound of the formula (1 ) is amorphous. Surprisingly stable formulations have been achieved using amorphous compound of the formula (1 ) in the compositions of the invention.
• the compound of the formula (1 ) may be present as a co-crystal with an acceptable pharmaceutical excipient.
• co-crystal refers to a crystal composed of at least two molecules bound by non-covalent interactions in a crystal.
• the pharmaceutical composition of the first aspect may comprise anhydrous compound of the formula (1 ).
• Compositions comprising amorphous compound of the formula (1 ) were found to be surprisingly stable.
• the compound of the formula (1 ) is not agglomerated.
• agglomerated refers to the active ingredient, the compound of the formula (1 ), having an appearance of a crystalline powder with macroscopic agglomerates.
• the pharmaceutical composition of the first aspect comprises between 5 and 50 mg of the compound of the formula (1 ) per tablet or capsule.
• the pharmaceutical composition of the first aspect comprises 10 mg or 25 mg of the compound of the formula (1 ) by tablet or capsule.
• composition of the first aspect are manufactured by dry granulation techniques or dry mix techniques.
• pharmaceutical composition of the first aspect are manufactured by direct compression or dry granulation.
• An embodiment of the present invention relates to a process for the manufacture of a pharmaceutical batch of a tablet of the first or second aspect, wherein the process comprises the following steps:
• step (i) process used to prepare the test tablet in step (i) provided that the test tablet is stable and has an immediate release dissolution profile
• step (iv) optionally, packaging the pharmaceutical batch manufactured in step (iii) preferably in blister packs or in bottles.
• a fourth aspect of the invention is the pharmaceutical composition according to the first aspect for use in the treatment of type 2 diabetes.
• a fifth aspect of the invention is a blister pack comprising the pharmaceutical composition of the first or fourth aspects wherein said blister pack is preferably an aluminum/PVC blister, an aluminum/aluminum blister, or a PVC/PE/PVDC/aluminum blister.
• a sixth aspect of the invention is a cardboard box with a patient information leaflet comprising at least one aluminum/aluminum or aluminum/PVC or PVC/PE/PVDC/aluminum blister pack of at least 4 units of the pharmaceutical composition of the first, fourth or fifth aspects.
• the pharmaceutical composition of the first aspect is packaged in a blister pack of aluminium/PVC or aluminium/aluminium.
• the pharmaceutical composition of the first aspect as herein disclosed are packaged in aluminium/PVC blisters.
• a blister aluminium/PVC is less protective than the aluminium/aluminium blister, the pharmaceutical composition of the first aspect as herein disclosed shows good stability in aluminum/PVC blisters.
• the pharmaceutical composition of the first aspect preferably contains no lactose. Surprisingly, it has been found that compositions prepared by dry methods without lactose have acceptable dissolution profiles.
• Figure 1 depicts a graph showing the dissolution profiles of formulations of Example 4.
• Figure 2 depicts a mixer with rests of a mixture comprising Empagliflozin with D90 17 pm (left capture) and the same mixer with rests of a mixture comprising Empagliflozin with D90 207 pm (right capture).
• Figure 3 depicts a graph showing the dissolution profiles of formulations of Example 6.
• Example 1 Tablet comprising empagliflozin manufactured by dry granulation.
• step 2 Blend the screened components of step 1 in the high shear mixer.
• step 4 Add the screened magnesium stearate of step 3 to the high shear mixer and blend all components.
• step 4 Compact the mix of step 4 using a roller compactor and screen through a mesh.
• step 7 Blend the screened components of step 6 with the granules obtained in step 5 in the high shear mixer.
• Example 2 Tablet comprising empagliflozin manufactured by direct compression.
• step 2 Blend the screened components of step 1 in a high shear mixer.
• Example 3 Tablet comprising empagliflozin manufactured by wet granulation.
• hydroxypropyl cellulose and purified water are mixed in a blender.
• step 3 Blend the screened components of step 2 in a high shear mixer.
• step 5 Screen the granulate obtained in step 4 through a mesh.
• Formulation 4a comprises empagliflozin with a D90 of 17 pm
• formulation 4b comprises empagliflozin with a D90 of 207 pm
• formulation 4c comprises empagliflozin with a D90 of 260 pm.
• compositions comprising empaaliflozin with D90 of 17 um:
• Example 6 Empagliflozin formulations comprising different amounts of excipients
• Example 7 Dissolution profiles of Tablets of Example 6
• the higher amount of intragranular binder in formulation 6b did not produce any dissolution enhancement in comparison with formulation 6a, but rather a slight decrease from 10 minutes onwards.
• the higher amount of intragranular and extragranular disintegrant did not lead to a higher degree of dissolution after 15, 30 or 60 minutes, but only to a faster start compared to that of 6a that than led to a lower dissolution rate at 15 minutes and onwards.
• Particle Size Distribution is performed for example via light scattering or laser diffraction technique.
• the powder is fed into a laser diffraction spectrometer for example by means of a dispersing unit. The test method is described below in detail:
• Dispersant Medium Water with 0.1% Tween80
• Dissolution Test The standard dissolution test is described in USP31 -NF26 S2, chapter 71 1 (dissolution).
• the paddle method with an agitation speed of 50 rpm was used.
• the medium consisted of phosphate buffer with a pH of 6.8 and at a temperature of 37 5 C.
• the volume of medium per vessel was 900 ml.
• the tests are usually run for as long as 60 minutes.
• the samples are analysed by HPLC.
• a pharmaceutical composition comprising at least one active ingredient, wherein said active ingredient is the compound of the formula (1 ) or a co-crystal thereof wherein said composition comprises:
• composition is prepared preferably by dry methods
• composition is preferably a tablet.
• composition according to clause 1 wherein the dry methods comprise direct mix, direct compression or dry granulation, more preferably, dry granulation. 3. The composition according to any preceding clause wherein the compound of formula
• (1 ) in the composition is in amorphous form or in crystalline form.
• composition according to any preceding clauses wherein the diluent is selected from a carbohydrate or a carbohydrate derivative, lactose, preferably lactose monohydrate, cellulose and derivatives, such as powdered cellulose, microcrystalline or silicified microcrystalline cellulose, cellulose acetate, starches and derivatives such as pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, sterilizable maize, sodium chloride, calcium carbonate, calcium phosphate, particularly dibasic calcium phosphate, calcium sulphate, dicalcium or tricalcium phosphate, magnesium carbonate, magnesium oxide, sugars and derivatives such as confectioner's sugar, fructose, sucrose, dextrates, dextrin, sorbitol sulfobutylether 1 1 -cyclodextrin, dextrose, polydextrose, trehalose, maltose, maltitol, mannitol, maltodextrin,
• composition according to any preceding clause wherein the disintegrant is selected from powdered cellulose, crospovidone, croscarmellose sodium, low- substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, particularly pregelatinized starch and cornstarch, and is preferably croscarmellose sodium, crospovidone, colloidal silicon dioxide or a mixture thereof.
• composition according to any of the preceding clauses, wherein the intragranular disintegrant is selected from powdered cellulose, colloidal silicon dioxide, crospovidone, croscarmellose sodium, low -substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, particularly pregelatinized starch and cornstarch or a mixture thereof, and is preferably, crospovidone, microcrystalline cellulose, sodium starch glycolate or a mixture thereof.
• the extragranular disintegrant is selected from powdered cellulose, colloidal silicon dioxide, crospovidone, croscarmellose sodium, low -substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, particularly pregelatinized starch and cornstarch or a mixture thereof, and is preferably sodium starch glycolate, crospovidone, colloidal silicon dioxide or a mixture thereof.
• composition according to any preceding clauses wherein the lubricant is selected from magnesium stearate, stearic acid, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, talc, sodium lauryl sulfate, polyoxyl 40 stearate, polysorbate, polyoxyethylene lauryl ether, sorbitan monooleate, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate or a mixture thereof and is preferably sodium stearyl fumarate.
• the lubricant is selected from magnesium stearate, stearic acid, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, talc, sodium lauryl sulfate, polyoxyl 40 ste
• composition further comprises at least a binder and optionally wherein the binder is selected from microcrystalline cellulose, copovidone, crospovidone, lactose anhydrous, or silicified microcrystalline cellulose, pregelatinised starch, low density starch, dibasic calcium phosphate dihydrate, or hydroxypropyl cellulose, hydroxypropylmethyl cellulose or polyvinylpyrrolidone, preferably hydroxypropyl cellulose.
• binder is selected from microcrystalline cellulose, copovidone, crospovidone, lactose anhydrous, or silicified microcrystalline cellulose, pregelatinised starch, low density starch, dibasic calcium phosphate dihydrate, or hydroxypropyl cellulose, hydroxypropylmethyl cellulose or polyvinylpyrrolidone, preferably hydroxypropyl cellulose.
• composition according to any preceding clauses further comprising at least an antiadherent, optionally wherein the antiadherent is selected from magnesium stearate, colloidal silicon dioxide, talc and starch, and preferably wherein the antiadherent is colloidal silicon dioxide.
• composition according to any preceding clause further comprising at least a solubiliser, optionally wherein the solubiliser is a polymer based on vinyl- pyrrolidone such as a copolymer of vinyl- pyrrolidone and vinyl acetate, preferably copovidone, or sodium lauryl sulfate or a mixture of polysorbate-80 and magnesium aluminometasilicate or polyoxyl 40 hydrogenated castor oil and magnesium aluminometasilicate, or alternatively the solubilizer is microcrystalline cellulose or a mixture of solubilisers.
• the solubiliser is a polymer based on vinyl- pyrrolidone such as a copolymer of vinyl- pyrrolidone and vinyl acetate, preferably copovidone, or sodium lauryl sulfate or a mixture of polysorbate-80 and magnesium aluminometasilicate or polyoxyl 40 hydrogenated castor oil and magnesium alumin
• composition according to any preceding clause wherein the composition comprises the compound of formula (1 ) in an amount from about 3.5 to 25% w/w% of the total composition, preferably from about 5 to 20% w/w%, preferably from about 10 to 15% w/w% .
• composition according to any preceding clause wherein the lubricant comprises from 0.5 to 4 w/w% of the total composition, preferably from about 1 to 3% w/w% , further preferably 1 to 2% w/w% .
• composition according to any preceding clause wherein the disintegrant comprises from about 1 to 10% w/w% of the total composition, preferably from about 1 to 8% w/w%, further preferably from about 2 to 7% w/w%.
• the total amount of diluent or mixture of diluents is from about 45 to 75% w/w% of the total composition, preferably 50 to 70%, further preferably 60 to 70%.
• composition according to any preceding clause wherein the total amount of lubricant is from about 0 to 2% w/w%, preferably 0.5 to 2% w/w%, further preferably from about 0.5 to 1 % w/w% of the total composition.
• the total amount of solubiliser is from about 0 to 10% w/w%, preferably about 3 to 8 w/w% of the total composition.
• composition according to any preceding clause which is free of polyethylene glycol.
• composition according to any preceding clause which is free of hydroxypropyl cellulose.
• composition according to any preceding clause further comprising a coating.
• composition according to clause 28 wherein the coating comprises a cellulose based polymer, preferably hypromellose, or a polyvinyl alcohol based polymer, preferably polyvinyl alcohol, titanium dioxide and talc.
• composition according to clauses 28 or 29, wherein the coating comprises no more than 5% of the total mass of the pharmaceutical composition, preferably from 1 % to 3% of the total mass of the pharmaceutical composition.
• composition according to any preceding clause wherein the composition comprises microcrystalline cellulose and compound of formula (1 ) or a co-crystal thereof and have a D90 higher than 200 pm.
• composition according to any preceding clause further comprising metformin or metformin hydrochloride.
• composition according to any preceding clause further comprising a DPP-IV inhibitor, preferably linagliptin.
• a direct compression process for making the pharmaceutical composition according to any preceding clause comprising the steps of: (1 ) Sieving the compound of formula (1 ) or a co-crystal thereof and at least one excipient and mixing them to obtain a blend;
• step (1 ) Tableting the blend of step (1 ) by compressing it to produce tablet cores.
• step (3) Adding the lubricant to the second blend of step (2) and mixing to obtain a final blend
• step (3) Tableting the final blend of step (3) by compressing it on a suitable tablet press to produce tablet cores;
• step (5) film-coating of the tablet cores of step (5) with a film coat.
• step (1 ) compaction of the mixture of step (1 ) to form granules, optionally using a roller compactor
• step (3) optionally mixing the granules of step (2) with one or more excipients.
• step (3) compressing the granules of step (2) or the final blend of step (3) to provide a tablet.
• step (1 ) compaction of the mixture of step (1 ) to form granules, optionally using a roller compactor
• step (3) optionally mixing the granules of step (2) with a second lubricant in a mixer to obtain the final blend;
• step (4) compressing the granules of step (3) or the final blend of step (4) to provide a tablet
• step (5) optionally film-coating of the product of step (5) with a film coat.
• a blister pack comprising the pharmaceutical composition of any of clauses 1 -33 and 38-39 wherein said blister pack is preferably an aluminum/PVC blister, an aluminum/aluminum blister, or a PVC/PE/PVDC/aluminum blister.
• a cardboard box with a patient information leaflet comprising at least one aluminum/aluminum or aluminum/PVC or PVC/PE/PVDC/aluminum blister pack of at least 4 units of the pharmaceutical composition of any of clauses 1 -33 or 38-39.
• a pharmaceutical composition comprising at least one active ingredient, wherein said active ingredient is the compound of the formula (1 ) or a co-crystal thereof
• composition comprises:
• composition is preferably prepared by dry methods. 43. The composition according to any preceding clause wherein the compound of formula (1 ) or a co-crystal thereof have a particle size distribution D90 higher than 200 pm. 44. The composition according to any preceding clause wherein when the composition is manufactured by dry granulation, the granules have a D90 of less than 800 pm.
• composition according to any preceding clause wherein the composition comprises the compound of formula (1 ) in an amount from about 3.5 to 25% w/w% of the total composition, preferably from about 5 to 20% w/w%, preferably from about 10 to 15% w/w% .
• composition according to any preceding clause wherein the lubricant comprises from 0.5 to 4 w/w% of the total composition, preferably from about 1 to 3% w/w% , further preferably 1 to 2% w/w% .
• composition according to any preceding clause wherein the disintegrant comprises from about 1 to 10% w/w% of the total composition, preferably from about 1 to 8% w/w%, further preferably from about 2 to 7% w/w%.
• composition according to any preceding clause wherein when the composition comprises the compound of formula (1 ) in an amount from about 3.5 to 25% w/w%, the total amount of diluent or mixture of diluents is from about 50 to 95% w/w% of the total composition, preferably 60 to 90% w/w%, further preferably 70 to 90% w/w%, further preferably 75 to 85% w/w%;
• the total amount of diluent or mixture of diluents is from about 45 to 75% w/w% of the total composition, preferably 50 to 70%, further preferably 60 to 70%. 50.
• the composition according to any preceding clause wherein the total amount of antiadherent is from about 0 to 2% w/w%, preferably 0.5 to 2% w/w%, further preferably from about 0.5 to 1 % w/w% of the total composition.
• composition according to any preceding clause wherein the total amount of solubiliser is from about 0 to 10% w/w%, preferably about 3 to 8 w/w% of the total composition.
• composition according to any preceding clause which is free of hydroxypropyl cellulose.
• composition according to any preceding clause comprising polyvinyl alcohol, preferably in an amount from about 0.5 to 10% w/w with respect to the weight of the total composition.
• composition according to any preceding clause which in use remains intact in saliva and subsequently disintegrates in the stomach.
• composition according to any of the preceding clause wherein when the compound of formula (1 ) is amorphous, the amorphous form has a glass transition temperature of above 60 °C, optionally wherein the compound of formula (1 ) is an amorphous solid dispersion.
• composition according to any preceding clause which is not an orally disintegrating tablet.
• composition according to clause 1 wherein the composition is prepared by dry methods and wherein the compound of formula (1 ) or co-crystal thereof has a particle size distribution D90 higher than 200 pm and up to 500, preferably higher than 200 pm and up to 300 pm, preferably higher than 200 pm and up to 250 pm, further preferably higher than 200 pm and up to 220 pm; and wherein the compound of formula (1 ) is in amorphous form.
• composition according to clause 1 wherein the composition is prepared by dry methods and wherein the compound of formula (1 ) is in amorphous form.
• composition according to any preceding clause wherein the compound of formula (1 ) or co-crystal thereof has a particle size distribution D90 higher than 200 pm and up to 500, preferably higher than 200 pm and up to 300 pm, preferably higher than 200 pm and up to 250 pm, further preferably higher than 200 pm and up to 220 pm.
• composition according to any preceding clause further comprising a solubiliser, optionally wherein the solubiliser is a polymer based on vinyl- pyrrolidone such as a copolymer of vinyl- pyrrolidone and vinyl acetate, preferably copovidone, or sodium lauryl sulfate or a mixture of polysorbate-80 and magnesium aluminometasilicate or polyoxyl 40 hydrogenated castor oil and magnesium aluminometasilicate, or a mixture of solubilisers.
• a solubiliser is a polymer based on vinyl- pyrrolidone such as a copolymer of vinyl- pyrrolidone and vinyl acetate, preferably copovidone, or sodium lauryl sulfate or a mixture of polysorbate-80 and magnesium aluminometasilicate or polyoxyl 40 hydrogenated castor oil and magnesium aluminometasilicate, or a mixture of solub
• composition according to clauses any preceding clause comprising compound of formula (1 ) having a D90 higher than 200 pm and microcrystalline cellulose, preferably wherein the compound of formula (1 ) is amorphous.
• composition according to according to any preceding clause comprising compound of formula (1 ) having a D90 above 200 pm, microcrystalline cellulose and sodium stearyl fumarate as a lubricant.
• composition according to any any preceding clause wherein the composition comprises above 25% by weight of the compound of the formula (1 ) with respect to the total weight of the composition, preferably between about 28% and 40%, preferably between 28% and 35%.
• composition according to any preceding clause wherein the composition comprises above 25% to 35% by weight of the compound of the formula (1) with respect to the total weight of the composition and microcrystalline cellulose and sodium stearyl fumarate.
• step (3) Tableting the final blend of step (3) by compressing it on a suitable tablet press to produce the tablet cores;
• step (5) film-coating of the tablet cores of step (5) with a film coat.
• step (1 ) compacting of the mixture of step (1 ) on a suitable roller compactor to form granules
• step (3) optionally mixing the granules of step (2) with an additional lubricant in a mixer to obtain a blend;
• step (4) optionally film-coating of the products of step (4) with a film coating composition.
• Tablets produced according to the above clauses have acceptable disintegration times and friability.
• the target disintegration time is 20 minutes and the target friability of ⁇ 1 %. Unless otherwise indicated, all the analysis methods are carried out according to the European Pharmacopoeia 7 th edition.

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