EP4076402A1 - Darreichungsform mit einer amorphen festen lösung von empagliflozin mit polymer - Google Patents

Darreichungsform mit einer amorphen festen lösung von empagliflozin mit polymer

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Publication number
EP4076402A1
EP4076402A1 EP20835800.2A EP20835800A EP4076402A1 EP 4076402 A1 EP4076402 A1 EP 4076402A1 EP 20835800 A EP20835800 A EP 20835800A EP 4076402 A1 EP4076402 A1 EP 4076402A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
form according
total weight
relative
empagliflozin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20835800.2A
Other languages
English (en)
French (fr)
Inventor
Gregor RATEK
David ZUPANCIC
Klemen KORASA
Matej Smrkolj
Ivanka Kolenc
Sandi SVETIC
Ale POLOVIC
Rok AVSENIK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KRKA dd filed Critical KRKA dd
Publication of EP4076402A1 publication Critical patent/EP4076402A1/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to a pharmaceutical dosage form comprising Empagliflozin in the form of an amorphous solid solution with at least one polymer, as well as to a process for the preparation thereof.
  • the pharmaceutical dosage form exhibits excellent chemical and physical storage stability.
  • Empagliflozin is a white to yellowish non-hygroscopic crystalline solid, very slightly soluble in water (pH 1-7.4), slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol, and practically insoluble in toluene.
  • Empagliflozin is an orally administered selective sodium-dependent glucose co-transporter 2 (SGLT 2) inhibitor.
  • the sodium-dependent glucose co-transporter 2 (SGLT 2) is expressed in the renal proximal tubules and accounts for approximately 90% of renal glucose reabsorption. Inhibition of SGLT 2 decreases the renal reabsorption of glucose, thereby promoting glucose excretion in the urine with a consequent reduction in blood glucose levels. Due to their mainly insulin-independent mechanism of action, SGLT 2 inhibitors may have a low risk of hypoglycaemia. Further effects of SGLT 2 inhibition may include weight loss due to the calorie loss associated with increased glucose excretion and a reduction in blood pressure that is possibly due to a mild diuretic effect.
  • Empagliflozin is used for improvement of glycemic control in adults with type 2 diabetes mellitus and for reducing the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.
  • Empagliflozin is available on the market in the form of a free base and is sold under trade name Jardiance ® , as an oral tablet in 10 mg and 25 mg strengths. Further it is available on the market as a combination product with Metformin and a combination product with Linagliptin.
  • EP 1 730 131 discloses Empagliflozin, process for production thereof, its use and pharmaceutical composition thereof.
  • the composition of a tablet is disclosed that comprises active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, such as lactose, com starch, polyvinylpyrrolidone, magnesium stearate.
  • EP 1 888 551 and EP 1 888 552 disclose specific crystalline forms of Empagliflozin, methods for production thereof and synthesis of Empagliflozin.
  • EP 3 556 355 discloses a method of preparation of Empagliflozin in amorphous form by spray drying.
  • the thus prepared Empagliflozin is in the form of particles with pharmaceutically acceptable polymer, and can be used in the treatment or prevention of type 2 diabetes.
  • WO 2010/092126 discloses pharmaceutical dosage form of Empagliflozin wherein particle size distribution of Empagliflozin in the composition is D(90) >1 micron and D(90) ⁇ 200 micron and wherein Empagliflozin represents 25% or less of the weight of the composition.
  • Pharmaceutical compositions are disclosed that comprise lactose, microcrystalline cellulose, croscarmellose sodium as a disintegrant, hydroxypropyl cellulose as a binder, silicon dioxide as a glidant and magnesium stearate as a lubricant. These excipients are similar to those present in the marketed formulation of Empagliflozin.
  • the particle size of Empagliflozin in particular the particle size and the particle size distribution, influence the manufacturability, in particular that too small particles, especially too many small particles, negatively influence the manufacturability by sticking or filming during tableting.
  • too small particles especially too many small particles, negatively influence the manufacturability by sticking or filming during tableting.
  • too large particles negatively affect the dissolution properties of the pharmaceutical composition and dosage form and thus the bioavailability.
  • WO 2016/169534 discloses amorphous solid forms of Empagliflozin stabilized in the form of solid solutions with pharmaceutically acceptable excipient selected from the group consisting of polymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea.
  • a preferred excipient is such wherein the final composition achieves a glass transition temperature higher than 40 °C, even better higher than 70 °C.
  • Preferred excipients are especially hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, SoluplusTM, PEG 6000 or copovidone VA64.
  • stabilized amorphous substances can be prepared by solvent-free processes, wherein a mixture of Empagliflozin and a stabilizing polymer is heated and melted to obtain a melt, which is subsequently cooled down to produce amorphous solid substance.
  • processes can be hot melt extrusion, hot melt granulation, high shear mixer, solvent free fluid bed granulation.
  • CN 106 692 069 discloses an Empagliflozin solid dispersion preparation and a preparation method thereof.
  • the Empagliflozin solid dispersion preparation comprises Empagliflozin, povidone, a specific lubricant and a specific disintegrant and a diluent.
  • amorphous solid dispersions are disclosed which are prepared by dissolving Empagliflozin and polymer in methanol and spray drying the solution using spray drier.
  • compositions comprising active substance Empagliflozin in amorphous form.
  • Exemplified pharmaceutical compositions are prepared by dissolving Empagliflozin and povidone in a mixture of methylene chloride and ethanol, spraying of the prepared solution on pharmaceutically acceptable carrier to obtain granules, blending the granules with further excipients, lubricating the mixture and compressing into tablets.
  • the document discloses very broad range of possible ratios of Empagliflozin to polymer, which acts as a binder which varies form 1 :0.025 to 1 :4. Consequently Empagliflozin may be present in crystalline form or in amorphous form.
  • compositions comprising Empagliflozin.
  • the disclosed compositions comprise Empagliflozin in crystalline form wherein particle size must be carefully controlled, or in amorphous form wherein amorphous form is stabilized by preparing solid dispersions or solid solutions by processes such as evaporating the solvent by rotary evaporator or by lyophilization. These procedures are not convenient to be used on industrial scale. Furthermore, methylene chloride was used as a solvent which has several drawbacks when used in industrial scale.
  • amorphous solid dispersions as prepared by the prior art processes were intermediate products which have to be further processed into a pharmaceutical composition requiring processes such as milling, sieving, mixing with further inactive ingredients, granulating before compressing into the tablets. These processes are time consuming and are disadvantageous from economical point of view.
  • Methylene chloride and methanol are classified as Class 2 solvents; such solvents should be limited in pharmaceutical products because of their inherent toxicity.
  • the limit for residual solvent is 600 ppm for methylene chloride and 3000 ppm for methanol.
  • Halogenated solvents are carcinogenic or are suspected to be carcinogenic and such solvent should be used under strict conditions during technological process, requiring special conditions to prevent exposure of workers to the solvent. These solvent are not allowed to be released into environment and should be insinuated e.g. by pyrolysis, such measures increase the production cost.
  • pharmaceutical dosage forms comprising Empagliflozin in the form of an amorphous solid solution with at least one polymer can be prepared by simple technological process using fluid bed granulation process and using a specific ratio between Empagliflozin and the at least one polymer. It has been found that pharmaceutical dosage forms comprising Empagliflozin in the form of solid amorphous solution with at least one polymer prepared by a fluid bed granulation process results in excellent physical and chemical stability.
  • the term “stable” or “stability” means that the pharmaceutical dosage form is physically and chemically stable, whereas “chemically stable” means that the solid pharmaceutical dosage form when stored at 40 °C and 75 % relative humidity for 3 or 6 months, each of the degradation impurity is less than 0.2 % by weight of Empagliflozin and the total impurities, which is the sum of known and unknown impurities, is less than 2% by weight of Empagliflozin.
  • the term "physically stable” as used herein means that X-ray powder diffraction pattern (XRPD) of the solid pharmaceutical dosage form according to the invention when stored at 40 °C and 75 % relative humidity for 1 month in a closed vial does not exhibit detectable X-ray diffractions characteristic of the crystalline form of Empagliflozin.
  • XRPD X-ray powder diffraction pattern
  • the invention therefore provides a physically and chemically stable form of Empagliflozin, namely an amorphous solid solution with at least one polymer, which can be prepared by a simple technological process.
  • the invention provides pharmaceutical dosage forms that allow for accomplishing advantageous stabilization effects while maintaining excellent dissolution characteristics of Empagliflozin and suitability for industrial scale production.
  • the invention generally relates to a solid pharmaceutical dosage form, comprising
  • the pharmaceutical dosage form is prepared from granules that have been optionally compressed.
  • the pharmaceutical dosage form according to the invention may comprise granules and an extragranular material, that preferably together have been compressed.
  • the pharmaceutical dosage form preferably comprises compressed granules or is a monolith of compressed granules preferably additionally comprising an extragranular material.
  • the granules are prepared by single pot fluid bed granulation process.
  • Figure 1 shows X-ray diffraction patterns of Example 1 (initial) and Example 1 (after 1 month 40 °C/75% RH PVC/Alu blister) in comparison with diffraction patterns of pure microcrystalline cellulose and pure crystalline Empagliflozin.
  • Figure 2 shows Raman spectrum of amorphous solid solution of Empagliflozin and PVP obtained by Raman mapping of cross-section of Example 1 in comparison with Raman spectrum of pure crystalline Empagliflozin and solid solution of Empagliflozin and PVP obtained in Reference Example 1.
  • Figure 3 shows a DSC curve of Example 1.
  • Figure 4 shows dissolution profile of Empagliflozin from the tablet according to Example 1 in comparison to reference product Jardiance ® .
  • Figure 5 shows dissolution profile of Empagliflozin from the tablet according to Example 9 in comparison to reference product Synjardy ® .
  • Figure 6 shows dissolution profile of metformin from the tablet according to Example 9 in comparison to reference product Synjardy ® .
  • a first aspect of the invention relates to a solid pharmaceutical dosage form comprising an amorphous solid solution of Empagliflozin with at least one polymer.
  • the pharmaceutical dosage form according to the invention is solid.
  • Preferred solid pharmaceutical dosage forms according to the invention include but are not limited to capsules, powders, tablets, minitablets, microtablets, coated tablets, coated minitablets, coated microtablets, pills, lozenges, and the like.
  • the pharmaceutical dosage form according to the invention is selected from capsules or tablets, preferably coated tablets.
  • tablette as used herein is intended to encompass compressed pharmaceutical dosage forms of all shapes and sizes. Coated tablets are particularly preferred.
  • capsule as used herein is intended to encompass pharmaceutical dosage forms wherein the active pharmaceutical ingredient (API) in a form of an amorphous solid solution with a polymer, optionally mixed with further excipients, is enclosed in a capsule shell of all shapes and sizes. Mixture can be optionally processed into granules which are later optionally mixed with additional excipient such as glidants and/or lubricants and filled into capsules.
  • API active pharmaceutical ingredient
  • the pharmaceutical dosage form according to the invention is preferably suitable and intended for oral administration, preferably for oral administration (i.e. by swallowing as a whole).
  • pharmaceutical dosage form according to present invention is an orally disintegrating dosage form or a dispersible solid dosage form.
  • the pharmaceutical dosage form according to the invention contains Empagliflozin or a physiologically acceptable salt thereof.
  • Empagliflozin refers to the non-salt, i.e. free base form of Empagliflozin and to any physiologically acceptable salt and/or to any solvate or polymorph thereof.
  • Empagliflozin and polymorphic forms of Empagliflozin are known e.g. from EP 1 888 552, WO 2006/117360, and CN 105481 843.
  • Empagliflozin is present in the non-salt form.
  • any reference to a weight or percentage or dose of Empagliflozin refers to the equivalent weight of the non-salt non-solvate (ansolvate) form of Empagliflozin.
  • amorphous solid solution means a homogeneous amorphous dispersion of Empagliflozin in a polymer matrix comprising at least one polymer without detectable individual solid particles of each component. It is a solid solution with the compound molecularly dissolved in a solid matrix.
  • the entire amount of the Empagliflozin is present in form of an amorphous solid solution with the at least one polymer, i.e. the pharmaceutical dosage form according to the invention preferably contains no crystalline Empagliflozin or physiologically acceptable salt thereof.
  • the amorphous solid dispersion of Empagliflozin is prepared in-situ during technological process of preparing the solid pharmaceutical dosage form by dissolving Empagliflozin and at least one polymer in an organic solvent which does not comprise halogenated organic solvents to obtain solution. The thus obtained solution is then subsequently used for granulation of at least one pharmaceutically acceptable excipient, preferably of a mixture of at least two pharmaceutically acceptable excipients.
  • Preferred organic solvents comprise or essentially consist of alcohols, such as ethanol, n-propanol, 2- propanol, butanol, ketones, such as acetone, methyl ethyl ketone, tert-butyl methyl ketone, or mixtures thereof.
  • the solvent comprises or essentially consists of alcohols, even more preferably ethanol.
  • the organic solvent comprises less than 5 wt.-% water, preferably less than 4 wt.-%, even more preferably less than 2 wt. -%.
  • anhydrous ethanol is used.
  • a mixture of ethanol an water can be used, which comprises up to 80 wt. -% of water, preferably up to 60 wt.-% of water, more preferably up to 50 wt.-% of water, most preferably up to 30 wt.-% of water.
  • the total weight of the pharmaceutical dosage form according to the invention is not particularly limited and inter alia depends upon the dose of Empagliflozin and whether further active pharmaceutical ingredients are contained or not.
  • the total weight of the pharmaceutical dosage form is within the range of 150 ⁇ 50 mg, 200 ⁇ 50 mg, 250 ⁇ 50 mg, 300 ⁇ 50 mg, 350 ⁇ 50 mg, 400 ⁇ 50 mg, 450 ⁇ 50 mg, 500 ⁇ 50 mg, 550 ⁇ 50 mg, 600 ⁇ 50 mg, 650 ⁇ 50 mg, 700 ⁇ 50 mg, 750 ⁇ 50 mg, 800 ⁇ 50 mg, 850 ⁇ 50 mg, 900 ⁇ 50 mg, 950 ⁇ 50 mg, 1050 ⁇ 50 mg, 1100 ⁇ 50 mg, 1150 ⁇ 50 mg, 1200 ⁇ 50 mg, or 1250 ⁇ 50 mg, or 1300 ⁇ 50 mg.
  • Empagliflozin is the sole active pharmaceutical ingredient that is contained in the pharmaceutical dosage form according to the invention, its dose is preferably
  • the preferred total weight of the pharmaceutical dosage form is then within the range of 200 ⁇ 100 mg;
  • the preferred total weight of the pharmaceutical dosage form is then within the range of 350 ⁇ 50 mg, preferably within the range 200 ⁇ 100.
  • the total weight of the pharmaceutical dosage form inter alia depends upon the dose and potency of the further active pharmaceutical ingredient(s).
  • the total weight content of the amorphous solid solution with at least one polymer, comprising Empagliflozin and of the at least one polymer is at least 2.5 wt.-%, more preferably at least 3.0 wt.-%, still more preferably at least 3.5 wt.-%, yet more preferably at least 4.0 wt.-%, even more preferably at least 4.5 wt.-%, most preferably at least 5.0 wt.-%, and in particular at least 5.5 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the amorphous solid solution with at least one polymer, comprising Empagliflozin and of the at least one polymer is at least 6.0 wt.-%, more preferably at least 6.5 wt. -%, still more preferably at least 7.0 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the amorphous solid solution with at least one polymer, comprising Empagliflozin and of the at least one polymer is at most 30 wt.-%, preferably at most 25 wt.-%, more preferably at most 22.5 wt.-%, still more preferably at most 20 wt.-%, yet more preferably at most 17.5 wt.-%, even more preferably at most 15 wt.-%, most preferably at most 12.5 wt.-%, and in particular at most 10 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the amorphous solid solution with at least one polymer, comprising Empagliflozin and of the at least one polymer is within the range of from 2.5 to 30 wt.-%, preferably within the range of from 2.5 to 25 wt.-%, 5.0 ⁇ 2.5 wt.-%, 7.5 ⁇ 5.0 wt.-%, 7.5 ⁇ 2.5 wt.-%, 10 ⁇ 5.0 wt.-%, 10 ⁇ 2.5 wt.-%, 12.5 ⁇ 5.0 wt.
  • the relative weight ratio of the Empagliflozin to the at least one polymer is within the range of from 10:1 to 1:25, preferably from 5:1 to 1:20.
  • the weight ratio of Empagliflozin to the at least one polymer is within the range from 1:1 to 1:20, preferably from 1:2 to 1:15, more preferably from 1:3 to 1:10, even more preferably from 1:4 to 1:7, most preferably 2:1 to 1:2, .
  • the relative weight ratio of the Empagliflozin to the at least one polymer is preferably within the range of from in the range of from 10:1 to 1:4, more preferably 3:1 to 1:3, even more preferably 2:1 to 1:2.
  • the relative weight ratio of the Empagliflozin to the at least one polymer is within the range of from 1:4 to 1:24, preferably within the range of from in the range of from 1:5 to 1:20.
  • the relative weight ratio refers to the total weight of all polymers that are contained in the amorphous solid solution (but not to any potentially present additional polymers that may be located elsewhere within the pharmaceutical dosage form).
  • the relative weight ratio of Empagliflozin to the at least one polymer is within the range of (6 ⁇ 4):1 (i.e. from 10:1 to 2:1), (5 ⁇ 4):1, (4 ⁇ 4):1, (3 ⁇ 4):1, 1:(3 ⁇ 4), 1:(4 ⁇ 4), 1:(5 ⁇ 4), 1:(6 ⁇ 4), 1:(7 ⁇ 4), 1:(8 ⁇ 4), 1:(9 ⁇ 4), 1:(10 ⁇ 4), 1:(11 ⁇ 4), 1:(12 ⁇ 4), 1:(13 ⁇ 4), 1:(14 ⁇ 4), 1:(15 ⁇ 4), 1:(16 ⁇ 4), 1:(17 ⁇ 4), 1:(18 ⁇ 4), 1:(19 ⁇ 4), 1:(20 ⁇ 4), or 1:(21 ⁇ 4).
  • the relative weight ratio of Empagliflozin to the at least one polymer is within the range of (7 ⁇ 3):1, (6 ⁇ 3):1, (5 ⁇ 3):1, (4 ⁇ 3):1, (3 ⁇ 3):1, 1:(3 ⁇ 3), 1:(4 ⁇ 3), 1:(5 ⁇ 3), 1:(6 ⁇ 3), 1:(7 ⁇ 3), 1:(8 ⁇ 3), 1:(9 ⁇ 3), 1:(10 ⁇ 3), 1:(11 ⁇ 3), 1:(12 ⁇ 3), 1:(13 ⁇ 3), 1:(14 ⁇ 3), 1:(15 ⁇ 3), 1:(16 ⁇ 3), 1:(17 ⁇ 3), 1:(18 ⁇ 3), 1:(19 ⁇ 3), 1:(20 ⁇ 3), 1:(21 ⁇ 3), or 1:(22 ⁇ 3).
  • the relative weight ratio of Empagliflozin to the at least one polymer is within the range of (8 ⁇ 2):1, (7 ⁇ 2):1, (6 ⁇ 2):1, (5 ⁇ 2):1, (4 ⁇ 2):1, (3 ⁇ 2):1, 1:(3 ⁇ 2), 1:(4 ⁇ 2), 1:(5 ⁇ 2), 1:(6 ⁇ 2), 1:(7 ⁇ 2), 1:(8 ⁇ 2), 1:(9 ⁇ 2), 1:(10 ⁇ 2), 1:(11 ⁇ 2), 1:(12 ⁇ 2), 1:(13 ⁇ 2), 1:(14 ⁇ 2), 1:(15 ⁇ 2), 1:(16 ⁇ 2), 1:(17 ⁇ 2), 1:(18 ⁇ 2), 1:(19 ⁇ 2), 1:(20 ⁇ 2), 1:(21 ⁇ 2), 1:(22 ⁇ 2), or 1:(23 ⁇ 2).
  • the weight content of the Empagliflozin is at least 0.1 wt.-%, more preferably at least 0.4 wt- %, still more preferably at least 1.0 wt.-%, yet more preferably at least 1.5 wt.-%, even more preferably at least 2.0 wt. -%, most preferably at least 2.5 wt.-%, and in particular at least 3.0 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the Empagliflozin is at most 15 wt.-%, preferably at most 10 wt.-%, more preferably at most 7.5 wt.-%, still more preferably at most 6.5 wt.-%, yet more preferably at most 6.0 wt.-%, even more preferably at most 5.5 wt.-%, most preferably at most 5.0 wt.-%, and in particular at most 4.5 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the Empagliflozin is less than 5.0 wt.-%.
  • the weight content of the Empagliflozin is within the range of from 0.1 to 15 wt.-%, 0.1 to 10 wt. -%, 1.0 ⁇ 0.5 wt. -%, 1.5 ⁇ 1.0 wt. -%, 1.5 ⁇ 0.5 wt.-%, 2.0 ⁇ 1.0 wt.-%, 2.0 ⁇ 0.5 wt.-%, 2.5 ⁇ 1.0 wt.-%, 2.5 ⁇ 0.5 wt- %, 3.0 ⁇ 1.0 wt.-%, 3.0 ⁇ 0.5 wt.
  • the weight content of Empagliflozin is within the range of from 1 to 80 wt- %, preferably 1 to 60 wt.-%, more preferably 1 to 50 wt.-%, even more preferably 1 to 30 wt.-%, in each case relative to the weight of the amorphous solid solution.
  • the weight content of the at least one polymer is within the range from 20 to 99 wt.-%, preferably 40 to 99 wt.%, even more preferably 50 to 99 wt.-%, relative to the weight of the amorphous solid solution.
  • the amorphous solid solution essentially consists of the Empagliflozin and the at least one polymer.
  • the pharmaceutical dosage form according to the invention is preferably formulated as a unit pharmaceutical dosage form, each pharmaceutical dosage form containing 1 to 50 mg of Empagliflozin, preferably 1 to 30 mg of Empagliflozin, more preferably about 5 mg, about 10 mg, about 12.5 mg or about 25 mg of Empagliflozin, still more preferably 5 mg, 10 mg, 12.5 mg or 25 mg of Empagliflozin.
  • the weight content of the at least one polymer is at least 0.1 wt.-%, preferably at least 0.3 wt- %, more preferably at least 0.5 wt.-%, still more preferably at least 1.0 wt.-%, yet more preferably at least 1.5 wt- %, even more preferably at least 2.0 wt.-%, most preferably at least 2.5 wt.-%, and in particular at least 3.0 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the at least one polymer is at most 20 wt.-%, preferably at most 18 wt- %, more preferably at most 16 wt.-%, still more preferably at most 14 wt.-%, yet more preferably at most 12 wt- %, even more preferably at most 10 wt.-%, most preferably at most 8.0 wt.-%, and in particular at most 3.0 wt- %, in each case relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the at least one polymer is within the range of from 0.1 to 20 wt.-%, 1.0 ⁇ 0.5 wt. -%, 2.0 ⁇ 1.5 wt. -%, 2.0 ⁇ 1.0 wt.-%, 2.0 ⁇ 0.5 wt.-%, 3.0 ⁇ 2.0 wt.-%, 3.0 ⁇ 1.5 wt.-%, 3.0 ⁇ 1.0 wt.-%,
  • the at least one polymer is selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, cellulose ether, dextrin, gum arabicum, pullulan, poly(meth)acrylate, and mixtures thereof.
  • the at least one polymer is a cellulose ether selected from the group consisting of hydro xymethylcellulose, hydro xyethylcellulose, hydroxypropylcellulose, low substituted hydro xypropylcellulose, hydro xypropylmethylcellulose, and mixtures thereof.
  • the at least one polymer is polyvinylpyrrolidone.
  • the pharmaceutical dosage form according to the invention comprises granules (granulate particles) comprising the amorphous solid solution.
  • the total weight content of the granules is at least 80 wt.-% wt.-%, more preferably at least 82 wt.-% wt.
  • the total weight content of the granules more than 90 wt.-% relative to the total weight of pharmaceutical dosage form.
  • the total weight content of the granules is at most 99 wt.-%, more preferably at most 98 wt- % wt.-%, still more preferably at most 97 wt.-% wt.-%, yet more preferably at most 96 wt.-% wt.-%, even more preferably at most 95 wt.-% wt.-%, most preferably at most 94 wt.-% wt.-%, and in particular at most 93 wt.-% wt. -%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the extragranular material is within the range of from 1.0 to 25 wt- %, preferably from 1.0 to 20 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • excipient refers to any physiologically acceptable substance that has no therapeutic activity as such but is present in the pharmaceutical dosage form for other reasons, e.g. to improve dissolution of the active pharmaceutical ingredient (API) itself.
  • Physiologically acceptable excipients may for instance be selected from diluents, lubricants, glidants, disintegrants and binders.
  • Individual excipients may have polyfunctional properties in the pharmaceutical dosage form according to the invention, e.g. may exert both disintegrating and binding properties, or both lubricating and gliding properties.
  • the pharmaceutical dosage form according to the invention may comprise one or more diluents (fillers).
  • Preferred diluents include but are not limited to polysaccharides (e.g. starches or celluloses), monosaccharides, disaccharides, oligosaccharides, sugar alcohols, inorganic salts of phosphoric acid, inorganic salts of carbonic acid, and inorganic salts of sulfuric acid.
  • Preferred polysaccharides comprise from 200 to 10,000 monosaccharide residues, preferably 500 to 10,000 monosaccharide residues, preferably glucose residues.
  • Preferred celluloses are selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose.
  • Preferred starches are selected from starches from any suitable vegetal source, for example com starch, wheat starch, rice starch, tapioca starch, potato starch; and from modified starches, such as pregelatinized starch, which is a type of modified starch that has been processed to render the starch more flowable and directly compressible. Partially or wholly pregelatinized starches can be used.
  • Preferred monosaccharides, disaccharides, oligosaccharides and sugar alcohols are selected from glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugars, and mixtures thereof.
  • Preferred inorganic salts of phosphoric acid, carbonic acid, or sulfuric acid are selected from calcium hydrogen phosphate (anhydrous or hydrate) and calcium carbonate.
  • the diluent is selected from cellulose powder (Ph. Eur.), microcrystalline cellulose and sugar alcohols. More preferably, the diluent is selected from microcrystalline cellulose and mannitol.
  • Microcrystalline cellulose is preferably selected from microcrystalline cellulose with average particle size from 10 to 200 pm, preferably from 20 to 150 pm and/or moisture content ⁇ 5%.
  • microcrystalline cellulose is selected from
  • microcrystalline cellulose with an average particle size 20 pm and a moisture content ⁇ 5%, such as Avicel ® PH-105;
  • microcrystalline cellulose with average particle size 50 pm and a moisture content ⁇ 5%, such as Avicel ® PH- 101 or Vivapur ® 101;
  • microcrystalline cellulose with average particle size 50 pm and a moisture content ⁇ 2%, such as Avicel ® PH- 113;
  • microcrystalline cellulose with average particle size 90 to 120 pm and a moisture content ⁇ 5%, such as Avicel ® PH-102 or Vivapur ® 102; and
  • microcrystalline cellulose with average particle size 90 to 120 pm and a moisture content ⁇ 1.5%, such as Avicel ® PH-112.
  • mannitol has an average particle size within the range of from 50 to 300 pm, more preferably from 100 to 250 pm.
  • the pharmaceutical dosage form according to the invention may comprise one or more disintegrants.
  • Preferred disintegrants include but are not limited to crospovidone, starch, maize starch, pregelatinized starch, sodium starch glycollate, hydroxypropyl starch, microcrystalline cellulose, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potassium, low substituted hydroxypropylcellulose (L-HPC), sodium and/or calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan, alginic acid and mixtures thereof.
  • crospovidone starch
  • maize starch pregelatinized starch
  • sodium starch glycollate sodium starch glycollate
  • hydroxypropyl starch hydroxypropyl starch
  • microcrystalline cellulose sodium and/or calcium salts of carboxymethyl cellulose
  • cross-linked carboxymethylcellulose e.g. croscarmellose sodium
  • Preferred disintegrants are selected from sodium and/or calcium salts of carboxymethyl cellulose, cross- linked carboxymethylcellulose and salts thereof (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potassium, low substituted hydroxypropylcellulose (L-HPC), sodium and/or calcium alginate, and crospovidone. Most preferred disintegrants are croscarmellose sodium, crospovidone and mixtures thereof.
  • the pharmaceutical dosage form according to the invention may comprise one or more binders.
  • Preferred binders include but are not limited to povidone (polyvinylpyrrolidone), copovidone (vinylpyrrolidone-vinyl acetate copolymer), powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose derivatives such as cellulose esters or cellulose ethers (preferably selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose and hydro xypropylmethylcellulose), starch (e.g. com starch, potato starch, or rice starch), a-starch, pregelatinized starch, dextrin, gum arabic, pullulan, poly(meth)acrylates and mixture thereof.
  • povidone polyvinylpyrrolidone
  • copovidone vinylpyrrolidone-vinyl acetate copolymer
  • powdered cellulose crystalline cellulose
  • microcrystalline cellulose microcrystalline
  • the pharmaceutical dosage form according to the invention may comprise one or more lubricants.
  • Preferred lubricants include but are not limited to
  • fatty acids i.e. carboxylic acids with 12 to 20 carbon atoms
  • glyceride esters such as glyceryl monostearate, glyceryl tribehenate, or glyceryl dibehenate (e.g. Compritol ® 888);
  • - metal salts of fatty acids including magnesium, calcium, aluminum or zinc salts of fatty acids (e.g. magnesium, calcium, aluminum or zinc stearate, magnesium palmitate, or magnesium oleate);
  • waxes e.g. Sterotex ® NF, Lubriwax ® [hydrogenated vegetable oil type], meads wax or spermaceti);
  • - polymers e.g., PEG, macrogols
  • sugar esters such as sorbitan monostearate and sucrose monopalmitate; and mixtures thereof.
  • Preferred lubricants are magnesium stearate, sodium stearyl fumarate, and mixtures thereof.
  • the pharmaceutical dosage form according to the invention may comprise one or more glidants.
  • Preferred glidants include but are not limited to colloidal silicon dioxide (colloidal silica), talc, magnesium trisilicate, and mixtures thereof.
  • Preferred glidants are colloidal silica, talc, and mixtures thereof.
  • the pharmaceutical dosage form according to the invention comprises a first excipient selected from diluents, binders and disintegrants.
  • the first excipient typically differs from the at least one polymer according to the invention which is preferably polyvinylpyrrolidone.
  • the first excipient is selected from starch, pregelatinized starch, powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, sugar alcohols, cross-linked carboxymethylcellulose and salts thereof; preferably microcrystalline cellulose.
  • the first excipient is contained in the granules.
  • the first excipient is preferably contained in the extragranular phase.
  • the weight content of the first excipient is at least 5.0 wt.-%, preferably at least 15 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the first excipient is at most 70 wt.-%, preferably at most 66 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the first excipient is within the range of from 5.0 to 70 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention comprises a second excipient selected from diluents, binders and disintegrants.
  • the second excipient can be a mixture of two or more individual excipients with same or different functionality in the pharmaceutical dosage form.
  • the second excipient is selected from starch, pregelatinized starch, powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, sugar alcohols, cross-linked carboxymethylcellulose and salts thereof; preferably from croscarmellose and physiologically acceptable salts thereof; more preferably croscarmellose sodium.
  • the second excipient differs from the first excipient.
  • the second excipient typically differs from the at least one polymer according to the invention which is preferably polyvinylpyrrolidone.
  • the second excipient is contained in the granules.
  • the second excipient is preferably contained in the extragranular phase.
  • the weight content of the second excipient is at least 1.0 wt.-%, preferably at least 1.5 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the second excipient is at most 10 wt.-%, preferably at most 7.5 wt.-%, more preferably at most 5.5 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the second excipient is within the range of from 1.0 to 10 wt.-%, preferably 1.0 to 7.5 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention comprises a third excipient selected from diluents, binders and disintegrants.
  • the third excipient is selected from starch, pregelatinized starch, powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, sugar alcohols, cross-linked carboxymethylcellulose and salts thereof; preferably from starch, pregelatinized starch, and mannitol.
  • the third excipient differs from the first excipient and the second excipient.
  • the third excipient typically differs from the at least one polymer according to the invention which is preferably polyvinylpyrrolidone.
  • the third excipient is contained in the granules.
  • the third excipient is preferably contained in the extragranular phase.
  • the weight content of the third excipient is at least 5.0 wt.-%, preferably at least 7.5 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the third excipient is at most 65 wt.-%, preferably at most 60 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the third excipient is within the range of from 5.0 to 65 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form contains the first excipient, preferably in the granules, and the third excipient, preferably also in the granules, whereas the first excipient is microcrystalline cellulose and the third excipient is mannitol.
  • the granules preferably contain a mixture of microcrystalline cellulose with mannitol.
  • the relative weight ratio of mannitol to microcrystalline cellulose in the pharmaceutical dosage form is within the range of 5:1 to 1:5, more preferably of 4:1 to 1 :4, still more preferably of 3 : 1 to 1:3.
  • the total weight content of the first excipient, preferably microcrystalline cellulose, and of the third excipient, preferably mannitol, in the pharmaceutical dosage form is within the range of from 50 to 99 wt.-%, more preferably 60 to 95 wt.-%, still more preferably 70 to 90 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the first excipient, preferably microcrystalline cellulose, and of the third excipient, preferably mannitol, in the pharmaceutical dosage form is within the range of from is at most 25 wt.%, more preferably at most 15 wt.-%, still more preferably at most 10 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form contains the first excipient, preferably in the granules, the second excipient, preferably also in the granules, and the third excipient, preferably also in the granules, whereas the first excipient is microcrystalline cellulose, the second excipient is croscarmellose sodium, and the third excipient is mannitol.
  • the granules preferably contain a mixture of microcrystalline cellulose with croscarmellose sodium and with mannitol.
  • the pharmaceutical dosage form when the pharmaceutical dosage form contains Empagliflozin in combination with further pharmaceutical active ingredient(s) (e.g. with a biguanide such as Metformin hydrochloride) the pharmaceutical dosage form contains at least one of the first excipient, optionally the second excipient and optionally the third excipient in the extragranular phase.
  • a biguanide such as Metformin hydrochloride
  • the pharmaceutical dosage form contains the first excipient, preferably in the extragranular phase, optionally the second excipient, preferably also in the extragranular phase, and optionally the third excipient, preferably also in the extragranular phase, whereas the first excipient is microcrystalline cellulose, the second excipient is croscarmellose sodium, and the third excipient is mannitol.
  • the pharmaceutical dosage form according to the invention comprises an extragranular material.
  • the granules obtained according to the present invention are preferably mixed with one or more extragranular excipients or their processed or non-processed mixtures.
  • the amount of the extragranular material is preferably comparatively low so that the granules do not form a discontinuous phase within the matrix of the extragranular material but come into intimate contact with one another.
  • the total weight content of the extragranular material is at least 0.1 wt.-%, preferably at least 1.0 wt. -%, relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the extragranular material is at most 25 wt.-%, preferably at most 20 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the extragranular material is within the range of from 0.1 to 20 wt.-%, relative to the total weight of the pharmaceutical dosage form, more preferably in the range of from 0.1 to 15 wt.% relative to total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention comprises a fourth excipient selected from diluents, binders and disintegrants.
  • the fourth excipient is selected from starch, pregelatinized starch, powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, sugar alcohols, cross-linked carboxymethylcellulose and salts thereof; preferably microcrystalline cellulose.
  • the fourth excipient typically differs from the first excipient, the second excipient and/or the third excipient.
  • the fourth excipient is contained in the extragranular material.
  • the weight content of the fourth excipient is at least 2.5 wt.-%, preferably at least 4.0 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the fourth excipient is at most 10 wt.-%, preferably at most 7.5 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the fourth excipient is within the range of from 2.5 to 10 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the first excipient is microcrystalline cellulose that is contained in the granules and the fourth excipient is also microcrystalline cellulose that is contained in the extragranular material.
  • the two microcrystalline celluloses differ from one another.
  • the first excipient is a microcrystalline celluloses with average particle size 50 pm and a moisture content ⁇ 5% (such as Avicel ® PH- 101 or Vivapur ® 101)
  • the fourth excipient is a microcrystalline cellulose with average particle size 90 to 120 pm and a moisture content ⁇ 5% (such as Avicel ® PH-102 or Vivapur ® 102).
  • the two microcrystalline celluloses do not differ from one another, i.e. that the same type of microcrystalline cellulose is present extragranular and intragranular. Further, it is also contemplated that mixtures of different types of microcrystalline cellulose are present intragranular and/or extragranular, e.g.. MCC 101 and MCC 102
  • the pharmaceutical dosage form according to the invention comprises a lubricant.
  • the lubricant is selected from the group consisting of fatty acids, fatty acid esters, metal salts of fatty acids, hydrogenated vegetable oil, hydrogenated castor oil, waxes, boric acid, sodium stearyl fumarate, macrogol, sugar esters and mixtures thereof; preferably magnesium stearate.
  • the lubricant is contained in the extragranular material.
  • the weight content of the lubricant is at least 0.1 wt.-%, preferably at least 0.4 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the lubricant is at most 5.0 wt. -%, preferably at most 3.0 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the lubricant is within the range of from 0.1 to 5.0 wt.-%, more preferably in the range of from 0.4 to 3.0 wt.-% relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention comprises a glidant.
  • the glidant is selected from the group consisting of colloidal silicon dioxide, talc, magnesium trisilicate, and mixtures thereof; preferably colloidal silicon dioxide, talc, and mixtures thereof; preferably colloidal silicon dioxide, talc, and mixtures thereof.
  • the glidant is contained in the extragranular material.
  • the weight content of the glidant is at least 0.1 wt.-%, preferably at least 0.4, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the glidant is at most 5.0 wt.-%, preferably at most 3.5 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the weight content of the glidant is within the range of from 0.1 to 5.0 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • Empagliflozin is the only active pharmaceutical ingredient that is contained in the pharmaceutical dosage form.
  • the relative weight ratio of the Empagliflozin to the at least one polymer is within the range offrom 4:l to 1:4, preferably from 4:1 to 1:1, more preferably 1:1.5 to 1:2, most preferably 2:1 to 1:2.
  • the weight content of the at least one polymer is within the range of from 1 to 10 wt.-%, preferably from 4.0 to 7.0 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the amorphous solid dispersion comprising Empagliflozin and the at least one polymer is within the range of from 7 to 18 wt.-%, preferably from 10 to 15 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention comprises a further active pharmaceutical ingredient, preferably an antihyperglycemic active pharmaceutical ingredient.
  • the further active ingredient such as antihyperglycemic API is useful for the management of type 2 diabetes.
  • the further active pharmaceutical ingredient is selected from
  • DPP-4 dipeptidyl peptidase-4 (DPP-4) inhibitors; preferably selected from the group consisting of Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Gemigliptin, Dutogliptin, and the physiologically acceptable salts thereof; preferably Sitagliptin and the physiologically acceptable salts thereof;
  • sulfonylureas preferably selected from the group consisting of Glyburide, Glipizide, Gliclazide, Glibenclamide, Glimepiride, Tolazamide, Tolbutamide, and the physiologically acceptable salts thereof; and
  • - alpha-glucosidase inhibitors preferably selected from the group consisting of Acarbose, Voglibose, Miglitol, and the physiologically acceptable salts thereof.
  • the further active pharmaceutical ingredient is contained in the granules, preferably outside the amorphous solid solution.
  • the further active pharmaceutical ingredient is contained in the granules, preferably inside the amorphous solid solution.
  • the further active pharmaceutical ingredient is contained outside the granules, preferably inside the extragranular material.
  • the pharmaceutical dosage form according to the invention comprises the Empagliflozin and as further pharmaceutical active ingredient Metformin or a physiologically acceptable salt thereof.
  • the relative weight ratio of the Empagliflozin to the at least one polymer is within the range of from 1:6 to 1:19.
  • the weight content of the at least one polymer is within the range of from 3.0 to 12.0 wt.-%, preferably from 6.0 to 9.0 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the amorphous solid solution comprising Empagliflozin and the at least one polymer is within the range of from 4.0 to 13 wt.-%, preferably from 7.0 to 10 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • An effective amount of Metformin hydrochloride can be, for example, 100 mg to about 2000 mg, or 100 mg to 1500 mg, or 250 mg to 1500 mg, or 250 mg to 1000 mg, or 500 mg to 1000 mg. In particular, an effective amount can be about 500 mg or about 1000 mg.
  • Examples of pharmaceutical dosage forms e.g., tablets) contain
  • the pharmaceutical dosage form according to the invention comprises Empagliflozin and as further pharmaceutical active ingredient Linagliptin or a physiologically acceptable salt thereof.
  • the relative weight ratio of the Empagliflozin to the at least one polymer is within the range of from 5:1 to 1:1.5.
  • the weight content of the at least one polymer is within the range of from 3.0 to 9.0 wt.-%, preferably from 6.0 to 12 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the total weight content of the amorphous solid solution comprising Empagliflozin and the at least one polymer is within the range of from 5.0 to 28 wt.-%, preferably from 8.0 to 25 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • An effective amount of Linagliptin can be, for example, 1 mg to 20 mg; or 1 mg to about 10 mg; or 2.5 mg to 10 mg; or 2.5 mg to 5 mg.
  • Examples of pharmaceutical dosage forms e.g., tablets) include 10 mg of Empagliflozin and 5 mg or Linagliptin ("10/5"); or - 25 mg of Empagliflozin and 5 mg or Linagliptin ("25/5").
  • the pharmaceutical dosage form according to the invention contains Empagliflozin in combination with two further active pharmaceutical ingredients, preferably Metformin of a physiologically acceptable salt thereof as well as Linagliptin or a physiologically acceptable salt thereof.
  • the pharmaceutical dosage form according to the invention is a tablet, more preferably a coated tablet.
  • Suitable coating materials are known to the skilled person and include but are not limited to water soluble polymers such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethylene glycol. Commercially available ready to use coating materials can be used such as those commercially available under the tradename Opadry ® .
  • the coating may additionally contain pigments, such as iron oxide, plasticizers, such as low molecular weight polyethylene glycol, antitacking agents, such as talc, metal salts of fatty acids, colloidal silicone dioxide.
  • the weight content of the coating material is not particularly limited. Typically, the weight of the coating material is within the range of 1.0 to 5.0 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form is made from a blend of granules comprising an amorphous solid solution of Empagliflozin and a polymer ("Solid Solution”) as well as excipients ("Intragranular”), and an extragranular material ("Extragranular”) which may comprise excipients such as diluent, binder, disintegrant, lubricant and/or glidant. All weight percentages are relative to the total weight of the pharmaceutical dosage form:
  • PVP polyvinylpyrrolidone
  • MCC microcrystalline cellulose
  • CRC croscarmellose or salt thereof
  • MAN mannitol
  • ST A starch
  • the pharmaceutical dosage form is a film coated tablet made from a blend of granules comprising an amorphous solid solution of Empagliflozin and a polymer ("Solid Solution”) as well as excipients ("Intragranular”), and an extragranular material ("Extragranular”). After compressing the blend of granules and extragranular material, the compacts are film coated with a coating composition ("Film Coating"). All weight percentages are relative to the total weight of the pharmaceutical dosage form:
  • PVP polyvinylpyrrolidone
  • MCC microcrystalline cellulose
  • CRC croscarmellose or salt thereof
  • MAN mannitol
  • STA starch
  • MGS magnesium stearate
  • CSD colloidal silicon dioxide
  • TAL talc
  • 2 expressed as total content of all optionally present lubricant(s) and all optionally present glidant(s)
  • the pharmaceutical dosage form is made from a blend of granules comprising an amorphous solid solution of Empagliflozin and a polymer ("Solid Solution”) as well as excipients ("Intragranular”), and an extragranular material ("Extragranular”) which may comprise excipients such as diluent, binder, disintegrant, lubricant and/or glidant. All weight percentages are relative to the total weight of the pharmaceutical dosage form:
  • PVP polyvinylpyrrolidone
  • MCC microcrystalline cellulose
  • STA starch and/or pregelatinized starch
  • MAN mannitol
  • the invention also relates to a packaged pharmaceutical dosage form comprising the pharmaceutical dosage form according to the invention as described above, which is present in a low gas and moisture permeable primary packaging.
  • the low gas and moisture permeable primary packaging may comprise materials such as aluminum or polychloro-3-fluoroethylene homopolymer/P VC laminate.
  • the thickness of the packaging will be in the range of 10 to 40 pm for Al/Al blisters and 10 to 110 pm for Al-polychloro-3-fluoroethylene homopolymer/PVC laminate blisters.
  • the packaged pharmaceutical dosage form may further comprise a desiccant.
  • the desiccant may be placed inside the packaging unit together with a pharmaceutical dosage form such as a tablet and or in the closure system and/or can be incorporated into the walls of the primary packaging unit.
  • the pharmaceutical dosage form can be packaged in containers made of glass or polymers, with or without desiccant.
  • the pharmaceutical dosage form according to the invention does not contain residual amounts of solvents according to ICH Q3C Class 2 ⁇ European Medicines Agency, ICH guideline Q3C (R6) on impurities: guideline for residual solvents, preferably in the edition of 9 August 2019).
  • Solvents of Class 2 include e.g. acetonitrile, chloroform, 1,2-dichloroethane, dichloromethane, methanol, hexane, cyclohexane, and others.
  • compositions according to the invention may be manufactured using wet methods or in another embodiment melt methods.
  • the invention provides, as a further embodiment, processes for preparing the pharmaceutical dosage forms according to the invention.
  • the processes described below are suitable for the preparation of all pharmaceutical dosage forms according to the invention (to the extent that the components of the individual pharmaceutical dosage forms are compatible with the components mentioned in connection with the processes described below).
  • Another aspect of the invention relates to a process for the preparation of a solid pharmaceutical dosage form according to any of the preceding claims comprising the steps of
  • composition comprising at least one excipient selected from the group consisting of a first excipient selected from diluents, binders and disintegrants; a second excipient selected from diluents, binders and disintegrants; and a third excipient selected from diluents, binders and disintegrants;
  • step (c) granulating the composition provided in step (b) with the solution obtained in step (a) thereby obtaining granules comprising an amorphous solid solution of the Empagliflozin in the at least one polymer;
  • Another aspect of the invention relates to a process for the preparation of a solid pharmaceutical dosage form that contains Empagliflozin in combination with further pharmaceutical active ingredient(s) (e.g. with a biguanide such as Metformin hydrochloride) comprising the steps of
  • composition comprising at least one further pharmaceutical ingredient and optionally at least one excipient selected from the group consisting of a first excipient selected from diluents, binders and disintegrants; a second excipient selected from diluents, binders and disintegrants; and a third excipient selected from diluents, binders and disintegrants;
  • step (c) granulating the composition provided in step (b) with the solution obtained in step (a) thereby obtaining granules comprising an amorphous solid solution of the Empagliflozin in the at least one polymer;
  • the solvent comprises or essentially consists of ethanol, n-propanol, 2-propanol, butanol, acetone, methyl ethyl ketone, tert-butyl methyl ketone, water, or a mixture thereof; preferably ethanol, water, or a mixture thereof.
  • the mixture of ethanol and water can comprise up to 80 wt. -% of water, preferably up to 60 wt. -% of water, more preferably up to 50 wt. -% of water, most preferably up to 30 wt. -% of water.
  • the Empagliflozin that is employed in step (a) has an average particle size in the range of from 1 to 1000 pm, preferably from 5 to 500 pm, more preferably from 1 to 250 pm and most preferably from 5 to 150 pm.
  • Empagliflozin that is employed in step (a) can be milled or non-milled. There is no specific requirement for using specific particle size of Empagliflozin, in contrast to prior art processes that require specific control of particle size.
  • the solution obtained in step (a) is close to saturation, i.e. it is not a highly diluted solution.
  • the relative weight ratio of the “dry ingredients”, i.e. Empagliflozin and at least one polymer, to the solvent is within the range of from 1:2 to 1:25, preferably within the range from 1:3 to 1:20.
  • the solution obtained in step (a) is filtered before it is further used, e.g. to make sure that the solution does not contain any suspended solid material such as residual, undissolved crystalline Empagliflozin.
  • the solution obtained in step (a) may also contain further pharmaceutical active ingredient(s) other than Empagliflozin, e.g. Linagliptin.
  • a composition that comprises at least one excipient, preferably at least two excipients independently selected from the group consisting of a first excipient selected from diluents, binders and disintegrants; a second excipient selected from diluents, binders and disintegrants; and a third excipient selected from diluents, binders and disintegrants.
  • the composition provided in step b) comprises additionally a second active pharmaceutical ingredient such as Metformin or a physiologically acceptable salt thereof or/and a DDP-4 inhibitor such as Linagliptin or a physiologically acceptable salt thereof.
  • the composition provided in step b) comprises a second active ingredient as the sole excipient, at least one excipient, preferably at least two excipients independently selected from the group consisting of a first excipient selected from diluents, binders and disintegrants; a second excipient selected from diluents, binders and disintegrants; and a third excipient selected from diluents, binders and disintegrants are added extragranularly in step f).
  • Particularly preferred combinations include but are not limited to (i) microcrystalline cellulose and croscarmellose sodium, (ii) microcrystalline cellulose and mannitol, (iii) croscarmellose sodium and mannitol, and (iv) microcrystalline cellulose and croscarmellose sodium and mannitol.
  • composition provided in step (b) may also contain further pharmaceutical active ingredient(s) other than Empagliflozin, e.g. Metformin hydrochloride or Linagliptin.
  • step (c) involves fluid bed granulation in a single pot.
  • Suitable devices for fluid bed granulation are known to the skilled person and are commercially available.
  • step (c) the composition is granulated with the solution obtained in step (a) having a temperature of more than 35 °C, preferably more than 40 °C, even more preferably more than 45 °C.
  • step (c) the composition is granulated with the solution obtained in step (a) having a temperature of not more than 70 °C, preferably not more than 60 °C.
  • the temperature of the solution is within the range of from 50 to 60 °C.
  • the solvent used in step a) is a mixture of ethanol and water the solution is having a temperature in the range of 10 °C to 40 °C, preferably in the range of 20 °C to 30 °C.
  • the temperature of the composition provided in step (b), which is granulated in step (c), is preferably in the range of from 20 to 35 °C.
  • the temperature of the granules which are provided in step (c), which are dried in optional step (d) is in the range from 35° to 45°C.
  • Step (c) is a wet granulation process wherein at least the majority of the solvent used in step (a) is evaporated.
  • the granules that are formed are composed of the ingredients dissolved in the solution obtained in step (a) and the ingredients of the composition provided in step (b).
  • the Empagliflozin and the at least one polymer contained in the solution obtained in step (a) solidify thereby in-situ forming an amorphous solid solution of Empagliflozin with the at least one polymer.
  • said amorphous solid solution is present in admixture with the ingredients of the composition provided in step (b), i.e.
  • Step (d) of the process according to the invention is optional.
  • the wet granules obtained in step (c) may subsequently be further dried in step (d).
  • Suitable devices for drying granules are known to the skilled person and are commercially available, preferably optional drying step d) is performed in same equipment as the granulation step c).
  • the process steps c) and d) are performed continuously.
  • the content of residual solvent used in preparation of granulate in the dry granules is less than 3 wt.%, more preferably less than 2 wt.%, and even more preferably less than 1.5 wt.%.
  • Step (e) of the process according to the invention is optional.
  • the granulation step (c) will typically provide granules of different size, it can be desirable to reduce the particle size and to narrow the particle size distribution by sieving in step (e).
  • the granules obtained in step (c), optional step (d) and/or optional step (e) have an average particle size (CED - circular equivalent diameter) in the range of from 20 pm to 1000 pm, preferably from 50 pm to 600 pm, and most preferably from 80 pm to 350 pm.
  • the particle size distribution is given in terms of volume and is determined by means of well-known image analysis algorithms.
  • Step (f) of the process according to the invention is optional.
  • these further excipients are preferably provided as extragranular material in substep (i) of step (f) of the process according to the invention.
  • the extragranular material comprises at least one excipient, preferably at least two excipients independently selected from the group consisting of a fourth excipient selected from diluents, binders and disintegrants; lubricants; and glidants, or mixtures thereof as described above in connection with the pharmaceutical dosage form according to the invention.
  • the extragranular material provided in substep (i) of step (f) may also contain further pharmaceutical active ingredient(s) other than Empagliflozin, e.g. Metformin hydrochloride or Linagliptin.
  • step (ii) of step (f) the granules are blended with the extragranular material.
  • Suitable devices for blending granules with excipients are known to the skilled person and are commercially available. Typically, blending is performed under conditions of very little mechanical impact just to make sure that the granules remain intact, i.e. are not significantly comminuted in the course of blending.
  • step (g) of the process according to the invention the granules or the blend of the granules with the extragranular material, respectively, are compressed. Suitable devices for compressing are known to the skilled person and are commercially available. Depending upon the size of the compacts to be prepared, a large variety of punches can be selected. [0186] Typical compression forces are within the range of from 1 kN to 100 kN, preferably within the range of from 1 to 50kN.
  • Step (h) of the process according to the invention is optional. Suitable devices for coating compacts are known to the skilled person and are commercially available. Preferably, coating step (h) is performed using an aqueous solution of film forming excipients such as Opadry.
  • compact or tablet cores obtained in step g) can be optionally coated with a coating dispersion containing a further active ingredient and at least one additional excipient selected from binders, diluents, antitacking agents dispersed in a solvent such as purified water or its mixtures with volatile organic solvents.
  • Such coated tablet cores can be further film coated with water soluble film coating comprising a water soluble polymer, and optional additional excipients selected from plasticizers, antitacking agents and/or pigmets and colouring agents.
  • the weight content of the coating material is not particularly limited. Typically, the weight of the coating material is preferably within the range of 1.0 to 5.0 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • a second pharmaceutical active ingredient is contained in the solution obtained in step (a), in the composition provided in step (b), and or in the extragranular material provided in step (f).
  • Another aspect of the invention relates to a pharmaceutical dosage form obtainable by the process according to the invention as described above.
  • Another aspect of the invention relates to a granulate obtainable by the process according to the invention as described above, particularly obtainable by a process comprising steps (a), (b), and (c), optionally (d) and/or optionally (e), as described above.
  • the granules preferably have an average particle size (CED - circular equivalent diameter) in the range of from 20 pm to 1000 pm, preferably from 50 pm to 600 pm, and most preferably from 80 pm to 350 pm.
  • the particle size distribution is given in terms of volume and is determined by means of well-known image analysis algorithms.
  • Granule size can be of particular importance, since the content uniformity, dissolution behavior and thus the bioavailability depend on the granule size distribution.
  • Another aspect of the invention relates to the pharmaceutical dosage form according to the invention as described above for use in the treatment of diabetes, preferably type 2. Another aspect of the invention relates to the use of Empagliflozin for the manufacture of a pharmaceutical dosage form according to the invention as described above for the treatment of diabetes, preferably type 2. Another aspect of the invention relates to a method for treating diabetes, preferably type 2, comprising the step of administering to a subject in need thereof a pharmaceutical dosage form according to the invention as described above. [0195] Preferably, the pharmaceutical dosage form for use according to the invention is administered orally.
  • the pharmaceutical dosage form for use according to the invention is administered once daily or twice daily.
  • Stability testing The pharmaceutical compositions were stored in vials at 40 °C/75%RH for 1 month. Stability of amorphous phase was monitored by X-ray powder diffraction pattern. XPRD data was obtained in order to determine if a sample remains in the starting form, indicating that it is stable under these conditions or transformed partially or completely into a crystalline material, indicating that it is not stable under these conditions.
  • Particle size distributions of granules Measurements were carried out using a Camsizer® XT device (Retsch Technology GmbH, Germany) equipped with the X-Jet plug-in cartridge and its related software.
  • the Camsizer® set-up employs a dynamic imaging technique, rather than physical sieving of the particles. Samples are dispersed by pressurized air and passed through a gap illuminated by two pulsed light sources. The images of the dispersed particles (more specifically of their projections) are recorded by two digital cameras at a take-up rate of 60 images per second.
  • the mean particle size as used herein is a weighted arithmetic mean value as measured by dynamic image analysis, such as according to ISO 13322-2.
  • the particle size distribution is given in terms of volume and is determined by means of well-known Image analysis algorithms.
  • Raman spectra Measurements were carried out using an alpha500 AR commercial confocal reflectance Raman microscope (WITec) with a 532 nm Nd:YAG laser source, 30 mW output. Imaging technique was performed in case of formulation analysis. Cross-sections with total imaging area of 600 pm c 600 pm were recorded, and relevant Raman spectrum characteristic for regions of amorphous solid solution was exported. Raman spectrum of amorphous solid solution obtained by evaporation and Raman spectrum of powder sample of crystalline API were also recorded (as shown in figure 2).
  • DSC Differential scanning calorimetry
  • Measurements were carried out using DSC 1 Mettler Toledo scanning calorimeter. Samples of approx. 3 mg were scanned at a heating rate of 1 °C/min using temperature modulation with amplitude of +- 0,4 K and period of 30 s between -20 °C and 200 °C. Nitrogen atmosphere was used (40ml/min) and samples were scanned in aluminum pans, covered with pierced lid.
  • Dissolution Profile The dissolution testing illustrated in Figure 4 was carried out in 900 ml of dissolution medium (0.1 M hydrochloric acid). The dissolution testing was performed during 15 minutes at a rotation speed of 100 rpm. The dissolution testing was carried out at a temperature of the dissolution medium of 37°C ⁇ 0.5°C (especially 37°C).
  • the apparatus used for dissolution testing was USP apparatus I (Basket).
  • the dissolution testing illustrated in Figures 5 and 6 were carried out in 900 ml of dissolution medium (50 luM Phosphate buffer having pH 6.8). The dissolution testing was performed during 20 minutes at a rotation speed of 100 rpm. The dissolution testing was carried out at a temperature of the dissolution medium of 37°C ⁇ 0.5°C (especially 37°C).
  • the apparatus used for dissolution testing was USP apparatus I (Basket).
  • Example 1 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1:2):
  • Ethanol was heated to 60 °C.
  • Povidone was added to ethanol and mixed until a solution was obtained.
  • Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution (“Spray Solution”) was sprayed onto the mixture of com starch, microcrystalline cellulose type PH 101 and croscarmellose sodium (“Intragranular”) by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with microcrystalline cellulose type PH 102 and colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate (“Extragranular”) to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and yellow iron oxide (“Film Coating”) by conventional coating process.
  • Figure 1 shows X-ray powder diffraction patterns of Example 1 (initial before storage) and Example 1 (after 1 month storage at 40 °C/75% RH PVC/aluminum blister) in comparison to X-ray powder diffraction patterns of pure microcrystalline cellulose and pure crystalline Empagliflozin as disclosed inEP 1 888552 Bl).
  • Figure 2 shows the Raman spectmm of the amorphous solid solution of Empagliflozin and PVP obtained by Raman mapping of tablet cross-section of Example 1 in comparison to the Raman spectmm of pure crystalline Empagliflozin and in comparison to the Raman spectrum of the solid solution of Empagliflozin and PVP obtained in Reference Example 1.
  • Figure 3 shows a DSC curve of Reference Example 1.
  • Figure 4 shows dissolution profile of Empagliflozin from the tablet according to Example 1 in comparison to reference product Jardiance ® .
  • Example 2 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1:2):
  • Ethanol was heated to 60 °C. Povidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution (“Spray Solution”) was sprayed onto the mixture of mannitol, microcrystalline cellulose type PH 101 and croscarmellose sodium (“Intragranular”) by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with microcrystalline cellulose type PH 102 and colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate (“Extragranular”) to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and yellow iron oxide (“Film Coating”) by conventional coating process.
  • Example 3 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1:4):
  • Example 4 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1:2):
  • Example 2 The same process as disclosed in Example 2 was used to prepare the tablet with the difference that water was used instead of ethanol. This process does not result in formation of a solid amorphous dispersion. As evident from the results of stability testing the active ingredient remains in the form of crystalline particles.
  • Example 4.1 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1:1):
  • Ethanol was heated to 60 °C.
  • Povidone was added to mixture of ethanol and water and mixed until a solution was observed.
  • Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution (“Spray Solution”) was sprayed onto the mixture of mannitol, microcrystalline cellulose type PH 101 and croscarmellose sodium (“Intragranular”) by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with microcrystalline cellulose type PH 102, croscarmellose sodium and colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate (“Extragranular”) to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and yellow iron oxide (“Film Coating”) by conventional coating process.
  • Example 4.1 was further characterized by the absence of the diffraction peaks characteristic of the crystalline forms of Empagliflozin using X-ray powder diffraction analysis.
  • Example 5 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1:1):
  • Example 5.1 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1 :0.75):
  • Ethanol was heated to 60 °C. Povidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution (“Spray Solution”) was sprayed onto the mixture of mannitol, microcrystalline cellulose type PH 101 and croscarmellose sodium (“Intragranular”) by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with microcrystalline cellulose type PH 102, croscarmellose Sodium and colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate (“Extragranular”) to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and yellow iron oxide (“Film Coating”) by conventional coating process.
  • Example 6 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 2:1):
  • Example 7 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 4:1):
  • Example 8 Empagliflozin film coated tablets (Empagliflozin : PVP weight ratio 1:1):
  • formulations obtained according to Examples 1 to 3 and 5 to 6 are stable for 1 month during accelerated stability testing (1 months heated at 40 °C, 75% relative humidity in a closed vial).
  • the formulation obtained according to Example 4, wherein water was used as a solvent for granulation comprises crystalline Empagliflozin. This example shows that use of water as the granulation solvent does not result in amorphous solid solution of Empagliflozin.
  • compositions comprising a combination of active ingredients
  • Example 9 Film coated tablets comprising Empagliflozin and Metformin:
  • Ethanol was heated to 60 °C. Povidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto the mixture of Metformin and microcrystalline cellulose type PH 101 by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules. The granules were blended with colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate to obtain compression mixture which was compressed into tablets. The tablets were coated with Opadry and red iron oxide by conventional coating process.
  • Figure 5 shows dissolution profile of Empagliflozin from the tablet according to Example 9 in comparison to reference product Synjardy ® .
  • Figure 6 shows dissolution profile of metformin from the tablet according to Example 9 in comparison to reference product Synjardy ® .
  • Example 10 Film coated tablets comprising Empagliflozin and Metformin:
  • Ethanol was heated to 60 °C.
  • Povidone was added to ethanol and mixed until a solution was observed.
  • Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto Metformin by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with microcrystalline cellulose type PH 102 and colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and red iron oxide by conventional coating process.
  • Example 10.1 - Film coated tablets comprising Empagliflozin and Metformin:
  • Ethanol was heated to 60 °C. Povidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto Metformin by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with microcrystalline cellulose type PH 102, croscarmellose sodium and colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and red iron oxide by conventional coating process.
  • Example 10.1. was further characterized by the absence of the diffraction peaks characteristic of the crystalline forms of Empagliflozin using X-ray powder diffraction analysis.
  • Example 10.2 Film coated tablets comprising Empagliflozin and Metformin:
  • Ethanol and water were mixed at 25 ⁇ 5 °C. Povidone was added and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto Metformin by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 450 to obtain uniform granules. The granules were blended with microcrystalline cellulose type PH 102, croscarmellose sodium and colloidal silicon dioxide to obtain a mixture which was further lubricated with magnesium stearate to obtain compression mixture which was compressed into tablets. The tablets were coated with Opadry and red iron oxide by conventional coating process.
  • Example 10.2 was further characterized by the absence of the diffraction peaks characteristic of the crystalline forms of Empagliflozin using X-ray powder diffraction analysis.
  • Example 11 Film coated tablets comprising Empagliflozin and Linagliptin:
  • Ethanol was heated to 60 °C. Povidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto the mixture of Linagliptin, pregelatinized com starch, com starch and microcrystalline cellulose type PH 101 by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with microcrystalline cellulose type PH 102 and croscarmellose sodium to obtain a mixture which was further lubricated with talc and magnesium stearate to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and yellow iron oxide by conventional coating process.
  • Example 12 Film coated tablets comprising Empagliflozin and Linagliptin:
  • Ethanol was heated to 60 °C.
  • Povidone was added to ethanol and mixed until a solution was observed.
  • Empagliflozin and linagliptin were added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto the mixture of mannitol, microcrystalline cellulose type PH 101 and croscarmellose sodium by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with mannitol and colloidal silicon dioxide to obtain a mixture, which was further lubricated with magnesium stearate to obtain compression mixture, which was compressed into tablets.
  • the tablets were coated with Opadry and red iron oxide by conventional coating process.
  • Example 12 This process results in formation of a solid amorphous dispersion confirmed by the results of Raman spectroscopic imaging.
  • Example 12 was further characterized by the absence of the diffraction peaks characteristic of the crystalline forms of Empagliflozin using X-ray powder diffraction analysis.
  • Example 13 Film coated tablets comprising Empagliflozin and Linagliptin:
  • Ethanol was heated to 60 °C. Povidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto the mixture of linagliptin, mannitol, microcrystalline cellulose type PH 101 and croscarmellose sodium by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with mannitol and colloidal silicon dioxide to obtain a mixture, which was further lubricated with magnesium stearate to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and red iron oxide by conventional coating process.
  • Example 14 Film coated tablets comprising Empagliflozin and Linagliptin:
  • Ethanol was heated to 60 °C. Povidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto the mixture of mannitol, microcrystalline cellulose type PH 101 and croscarmellose sodium by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with linagliptin, mannitol and colloidal silicon dioxide to obtain a mixture, which was further lubricated with magnesium stearate to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and red iron oxide by conventional coating process.
  • Example 15 Film coated tablets comprising Empagliflozin and Linagliptin:
  • Ethanol was heated to 60 °C. Copovidone was added to ethanol and mixed until a solution was observed. Empagliflozin was added to the obtained solution and mixed until completely dissolved.
  • the API solution was sprayed onto the mixture of linagliptin, mannitol, microcrystalline cellulose type PH 101 and crospovidone by top spraying process to obtain dry granulate, which was sieved through sieve with mesh 800 to obtain uniform granules.
  • the granules were blended with mannitol and colloidal silicon dioxide to obtain a mixture, which was further lubricated with magnesium stearate to obtain compression mixture which was compressed into tablets.
  • the tablets were coated with Opadry and red iron oxide by conventional coating process.

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EP20835800.2A 2019-12-19 2020-12-18 Darreichungsform mit einer amorphen festen lösung von empagliflozin mit polymer Pending EP4076402A1 (de)

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EP4285894A1 (de) * 2022-05-31 2023-12-06 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulierung von empagliflozin und metforminhydrochlorid
EP4285893A1 (de) * 2022-05-31 2023-12-06 Sanovel Ilac Sanayi Ve Ticaret A.S. Kombination mit empagliflozin und metforminhydrochlorid
CN114848604A (zh) * 2022-06-13 2022-08-05 河北戴桥医药科技有限公司 一种恩格列净和盐酸二甲双胍复方制剂及其制备方法
WO2024095137A1 (en) * 2022-11-05 2024-05-10 Morepen Laboratories Limited Pharmaceutical composition of empagliflozin and process thereof
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US7723309B2 (en) 2005-05-03 2010-05-25 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
UA91546C2 (uk) 2005-05-03 2010-08-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ
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