WO2018102526A1 - Forme posologique pharmaceutique - Google Patents

Forme posologique pharmaceutique Download PDF

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Publication number
WO2018102526A1
WO2018102526A1 PCT/US2017/063900 US2017063900W WO2018102526A1 WO 2018102526 A1 WO2018102526 A1 WO 2018102526A1 US 2017063900 W US2017063900 W US 2017063900W WO 2018102526 A1 WO2018102526 A1 WO 2018102526A1
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WO
WIPO (PCT)
Prior art keywords
dutasteride
dosage form
layer
tamsulosin
pharmaceutical composition
Prior art date
Application number
PCT/US2017/063900
Other languages
English (en)
Inventor
Matthew D. Burke
Daniel GOODWIN
Ramprakash GOVINDARAJAN
Adam HARRIDANCE
Sandeep KEDIA
Quynh LE
Paul Mcaleese
Julian Westrup
Original Assignee
Glaxosmithkline Llc
Smithkline Beecham (Cork) Limited
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.)
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Publication date
Application filed by Glaxosmithkline Llc, Smithkline Beecham (Cork) Limited filed Critical Glaxosmithkline Llc
Publication of WO2018102526A1 publication Critical patent/WO2018102526A1/fr

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present invention relates to a pharmaceutical dosage form comprising a steroid 5-alpha reductase inhibitor such as dutasteride, or an alpha adrenergic blocker such as tamsulosin, or both.
  • a steroid 5-alpha reductase inhibitor such as dutasteride
  • an alpha adrenergic blocker such as tamsulosin, or both.
  • Aza steroids are an important class of pharmaceutically active compounds.
  • 4- aza steroids and 6-aza steroids known to be inhibitors of the enzyme testosterone 5-alpha-reductase (hereinafter “5-AR inhibitors” or “5-ARIs”).
  • 5-alpha-reductase hereinafter “5-AR inhibitors” or “5-ARIs”
  • Such compounds are useful in the treatment and/or prevention of benign prostatic hyperplasia (“BPH”), prostate cancer, and other androgen responsive or mediated diseases and conditions.
  • dutasteride is commercially available from GlaxoSmithKline, and is marketed under the brand names AVODART® and AVOLVE®.
  • Dutasteride is approved, currently, for the treatment of patients with moderate to severe symptoms of BPH and for alopecia.
  • Dutasteride binds both the type 1 and type 2 enzymes of 5-cx-reductase to inhibit the conversion of testosterone to dihydrotestosterone (DHT), and reduces circulating DHT concentrations by more than 90%.
  • DHT dihydrotestosterone
  • dutasteride may also be referred to as GI198745.
  • dutasteride such as in the treatment of prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), hormone related diseases, e.g., polycystic ovary disease, are disclosed in international patent application published as WO95/07927.
  • Another active compound which is useful in the treatment of BPH is tamsulosin. Its generic name is 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy-benzenesulfonamide and is described in U.S. Pat. No. 4,703,063 and U.S. Pat. No.
  • Tamsulosin hydrochloride is marketed under various tradenames, including FLOMAXTM, HARNAL-DTM, and OMNICTM, for the treatment of symptoms of BPH, such as urinary volume and frequency problems.
  • U.S. Pat. No. 4,772,475 (the "'475 patent") describes a controlled-release pharmaceutical dosage form containing tamsulosin.
  • Harnal DTM is an orally disintegrating tablet containing modified release pellets of tamsulosin hydrochloride.
  • dutasteride and tamsulosin are also commercially available from
  • GlaxoSmithKline under the brand name COMBODART®, DUODART® or JALYN® for the treatment of BPH, containing 0.5mg dutasteride and 0.4mg tamsulosin.
  • Certain fixed dose combinations of dutasteride and tamsulosin are disclosed in the international patent application published as WO2006/055659.
  • the choice of excipients in a pharmaceutical composition is important in order to ensure good solubility of the drug and good bioavailability, stability, robustness, and elegance. See, for example, A. Matso, Excipients Commonly Used in Soft Gelatin Capsules: Their Analysis and
  • Dutasteride as an active ingredient in a pharmaceutical composition, is not readily soluble or easy to dissolve. The poor solubility of dutasteride can result in reduced or unpredictable bioavailability.
  • the only currently marketed pharmaceutical formulation of AVODART® and AVOLVE® is a soft gelatin capsule.
  • the fill includes a mixture of glyceride esters. Esters of glycerol and/or propylene glycol have been used in a variety of formulations. See, for example, U.S. Pat. Nos. 4,316,917 (Antoshkiw et. al.) and 4,343,823 (Todd et. al.).
  • the composition includes dutasteride dissolved in a fatty acid ester of glycerol or propylene glycol.
  • the fatty acids are preferably carboxylic acids containing from 6 to 12 carbon atoms.
  • the ester is a monoester.
  • the compositions are particularly suitable for use as fill formulations for soft gelatin capsules.
  • dutasteride may interact unfavourably with actives and excipients, which may affect dissolution. Therefore other dosage forms of dutasteride would be useful, particularly for fixed dose combinations of dutasteride with other actives such as tamsulosin. However, to date, no oral solid dosage forms of dutasteride with enhanced bioavailability is available.
  • tamsulosin exhibits very low release in pH 1.2 but significant release in pH 3. Achieving such a large difference in release within the narrow pH range of 1.2 to 3.0 is challenging.
  • early prototype test formulations of tamsulosin modified release beads failed dissolution test criteria under the pH 3 condition and did not meet generally accepted in vivo bioequivalence criteria in the fed state, although some formulations met bioequivalence criteria in the fasted state (Clin Drug Investig 2014; 34(5): 335- 49).
  • the present invention provides an oral solid dosage form of dutasteride, comprising a solid dispersion of dutasteride in a thermoplastic, matrix-forming polymer, optionally with a
  • the present invention provides a solid dispersion of dutasteride comprising a thermoplastic, matrix-forming polymer and one or more pharmaceutically acceptable excipient(s).
  • the present invention provides a process for manufacturing solid dispersion particles of dutasteride, comprising:
  • dutasteride and a thermoplastic, matrix-forming polymer to a hot melt extrusion (HME) process; then
  • the present invention provides a pharmaceutical composition in a fixed dosage form comprising:
  • sustained release beads of tamsulosin comprise:
  • a layer B comprising a pH independent polymer and a pore former; wherein the layer B is coated with
  • a layer C comprising a pH dependent polymer, a pH independent polymer and a pore former.
  • the present invention also provides an oral solid dosage form, a solid dispersion of dutasteride or a fixed dose combination of the present invention for the treatment or prophylaxis of an androgen mediated disease or condition.
  • the androgen mediated disease or condition may be, for example, BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, or a hormone related disease.
  • Dutasteride refers to 17-beta-N-(2,5,-bis(trifluoromethyl) )-phenylcarbamoyl-4-aza- 5-alpha-androst-l-en-3-one as well as salts, solvates, or physiologically functional derivatives thereof.
  • dutasteride is 17-beta-N-(2,5,-bis(trifluoromethyl) )-phenylcarbamoyl-4-aza-5- alpha-androst-l-en-3-one.
  • Dutasteride can be prepared by well-known methods, for example as described in international patent applications published as WO95/07927 or WO02/046207.
  • AVODART® and AVOLVE® are interchangeable, and refer to the same product which is the commercially available form of dutasteride from GlaxoSmithKline.
  • This product is a soft capsule containing dutasteride and mono- and diglycerides of caprylic/capric acid.
  • Tamsulosin refers to 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2
  • Tamsulosin can be prepared by well-known methods such as disclosed in JP 56-110665 and JP 62-114952. Tamsulosin can form pharmaceutically acceptable salts with various inorganic and organic acids. These pharmaceutically acceptable salts may be used in the present invention.
  • salts examples include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; salts with organic acids such as fumaric acid, malic acid, citric acid, and succinic acid; salts with alkali metals such as sodium and potassium; and salts with alkali earth metals such as calcium and magnesium.
  • inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid
  • organic acids such as fumaric acid, malic acid, citric acid, and succinic acid
  • salts with alkali metals such as sodium and potassium
  • salts with alkali earth metals such as calcium and magnesium.
  • tamsulosin hydrochloride is used.
  • bearing as used herein has the standard art meaning of an approximately spherical shape, and is interchangeable with “pellet” and “granule”.
  • particles as used herein means granules, powder or pellets, obtained by eg milling or peptization.
  • a solid dispersion of dutasteride as used herein is where dutasteride is dissolved or dispersed molecularly in a polymeric matrix.
  • pH independent polymer as used herein means a polymer which is pH-insensitive, ie has a solubility independent of pH conditions.
  • pH dependent polymer as used herein means a polymer which is pH-sensitive, ie has a solubility which is dependent on pH conditions.
  • Bioequivalent if the 90% confidence interval of the difference in the average values of AUC and Cmax between the two products are within log(0.80) - log(1.25).
  • Bioequivalence may be tested in fasted state, or fed state, or both.
  • bioequivalence is achieved in at least the fed state.
  • a fixed dose combination means a pharmaceutical composition in a fixed dosage form.
  • the present invention provides an oral solid dosage form of dutasteride, comprising a solid dispersion of dutasteride in a thermoplastic, matrix-forming polymer, optionally with a pharmaceutically acceptable excipient(s).
  • the solid dispersion of dutasteride in the thermoplastic, matrix-forming polymer is obtained by a hot melt extrusion process.
  • Hot melt extrusion is a well known method of pharmaceutical formulation and involves subjecting a mixture of one or more active ingredient(s) and a
  • thermoplastic, matrix-forming polymer to a controlled elevated temperature, and extruding through an orifice. See for example US4,880,585; and "Hot Melt Extrusion: Pharmaceutical Applications” Dennis Douroumis, Wiley 2012 (ISBN 978-0-470-71118-7).
  • Polymeric excipients for dutasteride solid dispersions and its physicochemical characterization has been looked at, for example by Kim et al, Arch. Pharm. Res (2014) 37:214-224.
  • the present invention provides a novel oral solid dosage form of dutasteride using HME.
  • Dutasteride is thermally stable and the HME process does not cause degradation of the molecule.
  • HME provides the advantage of reducing the amount of free particles in the atmosphere compared to a traditional milling step, which is important in a dutasteride processing plant given its high potency and hence low occupational exposure limit.
  • thermoplastic, matrix-forming polymers with a high solubilization capacity are preferable.
  • suitable polymers include povidone and copovidone. A mixture of these may be used, for example a mixture of copovidone and povidone.
  • the polymer is copovidone.
  • the solid dispersion of dutasteride of the present invention comprises a thermoplastic, matrix-forming polymer, such as copovidone or povidone, in the amount of about 80.0 to about 95.0% w/w, preferably about 85.0% to about 90%, more preferably 85%, 86%, 87%, 88%, 89% or 90%, of the total weight of the solid dispersion.
  • the solid dispersion of dutasteride of the present invention comprises about 85.0% to about 90% of copovidone, of the total weight of the solid dispersion.
  • the present invention provides a solid dispersion of dutasteride comprising a thermoplastic, matrix-forming polymer and one or more pharmaceutically acceptable excipient(s).
  • the solid dispersion of the first or second aspects of the present invention comprises a thermoplastic, matrix-forming polymer and a surfactant.
  • the surfactant is sorbitan monolaurate.
  • the surfactant comprises about 2.0 to about 9.4% of the total weight of the solid dispersion.
  • the surfactant comprises 5.0-9.0%, more preferably 6.0 to 9.0%, more preferably 7.0 to 9.0%, more preferably 8.0 to 9.0% of the total weight of the solid dispersion.
  • the solid dispersion of dutasteride of the present invention comprises sorbitan monolaurate in the amount of 5.0-9.0%, more preferably 6.0 to 9.0%, more preferably 7.0 to 9.0%, more preferably 8.0 to 9.0% of the total weight of the solid dispersion.
  • the solid dispersion comprises one or more further excipients, such as a glidant.
  • the glidant may be, for example, colloidal silicon dioxide.
  • the solid dispersion of the present invention comprises copovidone, sorbitan monolaurate (surfactant) and colloidal silicon dioxide (glidant).
  • the amount of glidant in the solid dispersion of dutasteride of the present invention is 0 to about 1.5% w/w, more preferably 0.8 to 0.9% w/w, of the total weight of the solid dispersion.
  • the solid dispersion of dutasteride of the present invention comprises colloidal silicon dioxide in the amount of 0 to about 1.5% w/w, more preferably 0.8 to 0.9% w/w, of the total weight of the solid dispersion.
  • the solid dispersion comprises about 0.1 to about 0.5% w/w dutasteride, about 85.0 to about 95.0% w/w copovidone, about 2.0 to about 9.4% w/w sorbitan monolaurate and 0 to about 1.5% w/w colloidal silicon dioxide.
  • the solid dispersion comprises about 0.44% dutasteride, about 90% copovidone, about 8.7% sorbitan monolaurate and about 0.87% silicon dioxide.
  • the solid dispersion comprises about 0.44% dutasteride, about 90% copovidone, about 8.7% sorbitan monolaurate and about 0.87% silicon dioxide.
  • the solid dispersion of dutasteride is processed (for example pelleted, milled or hot-face pelleted) to particles of about 550 to about 780 microns.
  • the solid dispersion of dutasteride is processed (for example pelleted, milled or hot-face pelleted) to particles of less than about 300 microns, for example about 100 to about 300 microns, or about 200 to about 300 microns.
  • the solid dispersion of dutasteride is processed (for example pelleted, milled or hot-face pelleted) to particles of around 100 to 150 microns.
  • the oral solid dosage form of the present invention is in the form of a tablet or a capsule.
  • the oral solid dosage form is a capsule as follows: Table 1 Component of Formulation 1 Formulation 2 Formulation 3 Formulation 4 dutasteride solid Mg/cap Mg/cap Mg/cap Mg/cap dispersion
  • the oral solid dosage form of the present invention may be co-formulated with one or more pharmaceutically acceptable excipient(s), such as a filler, disintegrant, glidant and/or lubricant.
  • the tablet of the present invention comprises a filler such as microcrystalline cellulose (for example Avicel PH102) or a sugar alcohol (for example mannitol) or a mixture of microcrystalline cellulose and a sugar alcohol.
  • the filler is Avicel PH102 or Mannitol 100SD or a mixture of both.
  • the disintegrant is croscarmellose sodium or crospovidone.
  • the lubricant is magnesium stearate.
  • the glidant is colloidal silicon dioxide.
  • the oral solid dosage form of the present invention is in the form of a tablet, and the tablet comprises any combination of the following (% w/w to the tablet core): ⁇ Dutasteride solid dispersion: about 30.0% to about 48.5%, preferably about 31.0% to about 46.0%
  • Avicel PH102 about 31.7% to about 59.2%, preferably about 40.0% to about 59.2%
  • Mannitol 100SD 0% to about 15.5% to about 31.7%, preferably either 0%, or about 15.5% to about 31.7%
  • Croscarmellose sodium about 5.4% to about 10%; preferably either 0%, or about 5.3% to about 10%
  • Crospovidone about 5% to about 15%; preferably either 0%, or about 5.0% to about 15.0%
  • the oral solid dosage form of the present invention is in the form of a tablet, and the tablet comprises any combination of the following (% w/w to the tablet core):
  • Dutasteride solid dispersion about 18.0% to about 20.0%, more preferably about 19.0%, preferably 19.17%;
  • ⁇ Avicel PH102 about 65.0% to about 70.0%, preferably about 70.00%, more preferably about 69.83%;
  • Mannitol 100SD 0% to about 15.5% to about 31.7%, preferably either 0%, or about 15.5% to about 31.7%
  • Croscarmellose sodium from 0% to about 5.4% or to about 10%; preferably either 0%, or about 5.3% to about 10%
  • Crospovidone about 5% to about 15%; preferably either 0%, or about 5.0% to about 15.0%, such as about 10.0% •
  • Magnesium Stearate about 0.5% to about 1%, or about 1.% to about 1.5%; preferably about 1.1% or about 0.75%
  • Colloidal silicon dioxide from 0% to about 0.25%, preferably either 0%, or about about 0.1% to about 0.30%, preferably about 0.25%.
  • the oral solid dosage form of the present invention is in the form of a tablet providing O.lmg of dutasteride and comprising (% w/w to the tablet core):
  • crospovidone such as Kollidon CL or polyplasdone XL
  • ⁇ about 0.5% to about 1.5%; more preferably about 0.75% of a lubricant such as magnesium stearate; and
  • a glidant such as colloidal silicon dioxide.
  • the oral solid dosage form of the present invention is in the form of a tablet, providing 0.5mg of dutasteride and comprising (% w/w to the tablet core):
  • a disintegrant such as crospovidone (such as Kollidon CL or polyplasdone XL);
  • a glidant such as colloidal silicon dioxide.
  • the oral solid dosage form of the present invention is in the form of a tablet and has a tensile strength (MPa) greater or equal to 1.7.
  • MPa tensile strength
  • the tablet has a disintegration time less than 10 minutes as measured by the standard United States Pharmacopia test in water for immediate release tablets.
  • the oral solid dosage form of the present invention is in the form of a tablet
  • the tablet is coated appropriately, using techniques that would be apparent to the skilled person.
  • Coating may be done, for example, using an aqueous film coating process using a perforated coating pan. Coating may be performed via a step wise control with a "dry" start-up conditions until tablet coat weight gain of approximately 1% is achieved. Thereafter the coating conditions may be controlled at the product standard conditions. Preferably, coating is performed using Opadry using a step wise process as described above. In one embodiment, the present invention provides a coated tablet.
  • the tablet is about 300mg total weight or less, for ease of ingestion.
  • the tablet contains 0.5mg of dutasteride, or O.lmg of dutasteride.
  • the oral dosage form is any of the tablets shown below: Table 2
  • the solid oral dosage form of the present invention is a tablet as follows: Table 3
  • the oral solid dosage form of the present invention is bioequivalent to Avolve® in either fed or fasted state.
  • it is bioequivalent to Avolve® in fed state. More preferably, it is bioequivalent to Avolve® in both fed and fasted state.
  • mean plasma dutasteride concentrations of the oral solid dosage form of the present invention are at or above 650 pg/mL for a mean duration of at least 18.8 hours for a single dose pharmacokinetic profile.
  • single dose administration in human patients provides >23.0% of mean dutasteride Cmax in vivo at 60 minutes post dose of the oral solid dosage form of the present invention.
  • the present invention also provides an oral solid dosage form of dutasteride which is bioequivalent to the oral solid dosage form of the present invention.
  • the present invention provides a process for manufacturing solid dispersion particles of dutasteride, comprising:
  • dutasteride and a thermoplastic, matrix-forming polymer to a hot melt extrusion (HME) process; then
  • the thermoplastic, matrix-forming polymer is preferably copovidone or povidone, in the amount of about 80.0 to about 95.0% w/w, preferably about 85.0% to about 90%, more preferably 85%, 86%, 87%, 88%, 89% or 90%, of the total weight of the solid dispersion.
  • the thermoplastic, matrix-forming polymer is copovidone, and the copovidone comprises about 85.0% to about 90% of the total weight of the solid dispersion particles.
  • a surfactant and a glidant are also included in the HME process.
  • the surfactant may be, for example, sorbitan monolaurate and the glidant may be colloidal silicon dioxide.
  • a surfactant such as sorbitan monolaurate is also added.
  • the surfactant comprises about 2.0 to about 9.4% of the total weight of the solid dispersion.
  • the surfactant comprises 5.0 to 9.0%, more preferably 6.0 to 9.0%, more preferably 7.0 to 9.0%, more preferably 8.0 to 9.0% of the total weight of the solid dispersion.
  • sorbitan monolaurate is added in the amount of 5.0 to 9.0%, more preferably 6.0 to 9.0%, more preferably 7.0 to 9.0%, more preferably 8.0 to 9.0% of the total weight of the solid dispersion.
  • a glidant such as colloidal silicon dioxide is also added, with or without a surfactant such as sorbitan monolaurate.
  • the amount of glidant in the solid dispersion of dutasteride of the present invention is 0 to about 1.5% w/w, more preferably 0.8 to 0.9% w/w, of the total weight of the solid dispersion.
  • colloidal silicon dioxide is added in the amount of 0 to about 1.5% w/w, more preferably 0.8 to 0.9% w/w, of the total weight of the solid dispersion.
  • both a glidant such as colloidal silicon dioxide and a surfactant such as sorbitan monolaurate are added, preferably in the amounts as described above.
  • the dutasteride is subjected to the HME process together with copovidone, sorbitan monolaurate and colloidal silicon dioxide.
  • the product obtained from the process of the present invention is a solid dispersion comprising about 0.1 to about 0.5% w/w dutasteride, about 85.0 to about 95.0% w/w copovidone, about 2.0 to about 9.4% w/w sorbitan monolaurate and 0 to about 1.5% w/w colloidal silicon dioxide.
  • the solid dispersion comprises about 0.43% dutasteride, about 90.0% copovidone, about 8.69% sorbitan monolaurate and about 0.87% silicon dioxide.
  • the dutasteride is subjected to the HME process together with copovidone, sorbitan monolaurate and colloidal silicon dioxide, in the amounts of about 0.44% dutasteride, about 90% copovidone, about 8.7% sorbitan monolaurate and about 0.87% colloidal silicon dioxide.
  • the dutasteride is subjected to the HME process together with copovidone, sorbitan monolaurate and colloidal silicon dioxide, in the amounts of about 0.44% dutasteride, about 90% copovidone, about 8.7% sorbitan monolaurate and about 0.87% colloidal silicon dioxide.
  • the skilled person would be able to judge the appropriate extrusion temperature for the polymer used.
  • the extrusion is at about 80 to 190 degrees C, preferably 130-190 degrees C, more preferably 148-182 degrees C.
  • particles are formed from the cooled extrudate.
  • the particles may be a powder, pellets or granules.
  • pellets are formed by hot-face peptization (also known as micropelletization).
  • powder is formed by milling.
  • the skilled person would be able to select the appropriate method for processing the cooled extrudate in order to obtain the desired shape; for example, milling may be performed in a cone mill.
  • the final size of the particles may be chosen appropriately, for example for manufacturability reasons such as ease of manufacturing tablets, or ease of filling capsules.
  • the size of the particles is about 550 to about 780 microns.
  • the extrudate particles formed after step c) may optionally be sifted and desired particle sizes selected for further processing. After the desired particle sizes are selected, the remaining particles may be returned to step a) and undergo the process of the present invention again, to increase yield.
  • the solid dispersion of dutasteride according to the present invention may be made by any suitable method which would be apparent to the skilled person, for example as described in US4,880,585. .Examples are as follows:
  • An excipient pre-blend is performed by mixing the polymer and a glidant (such as colloidal silicon dioxide) in a high shear mixer (such as a GEA Aeromatic Fielder PMA 65). If used, the surfactant (such as sorbitan monolaurate) is then gradually added to the blend with continued mixing.
  • the excipient pre-blend is added to dutasteride drug substance and blended in a tumble-blender.
  • the active blend is fed into a twin-screw extruder (such as a Leistritz 18mm) with an aperture die fitted. Cooling of the extruded strand is performed using a cooling conveyor prior to being fed into a pelletizer, the pelletized material is collected and then milled using a rotor mill before being screened to achieve the required size distribution.
  • the polymer, dutasteride and any glidant are blended in a tumble blender.
  • the blend together with a surfactant such as sorbitan monolaurate
  • a twin- screw extruder such as Leistritz 27mm Micro
  • the extrudate is cooled and crushed into flakes using a chill roller before being fed into a cone mill followed by a centrifugal sifter to achieve the required particle size distribution.
  • the flakes from the chill roller may be collected and then further milled using a beater mill to achieve the required size distribution.
  • a tablet is formed with the milled cooled extrudate, and is then coated with an aqueous film coat such as Opadry.
  • the tablet may be formed by any standard technique such as dry compression. Coating may be done, for example, using an aqueous film coating process using a perforated coating pan. Coating may be performed via a step wise control with a "dry" start-up conditions until tablet coat weight gain of approximately 1% is achieved. Thereafter the coating conditions may be controlled at the product standard conditions. Preferably, coating is performed using Opadry using a step wise process as described above.
  • the present invention provides a solid oral dosage form of dutasteride, obtained by any process as described above.
  • the invention provides a dutasteride tablet obtained by any process as described above.
  • the invention provides a dutasteride capsule obtained by any process as described above.
  • the present invention provides aa process for manufacturing a coated tablet comprising solid dispersion particles of dutasteride, comprising:
  • dutasteride and a thermoplastic, matrix-forming polymer to a hot melt extrusion (HME) process; then
  • the present invention overcomes a challenge and provides a formulation of tamsulosin in a fixed dose combination with dutasteride, wherein the dissolution profile of the tamsulosin is similar or equivalent to the dissolution profile of Harnal DTM.
  • a pharmaceutical composition in a fixed dosage form comprising any of the solid dosage forms of dutasteride described above and a plurality of sustained release beads of tamsulosin which is bioequivalent and has a similar or equivalent dissolution profile to Harnal DTM, comprising:
  • a layer B comprising a pH independent polymer and a pore former; wherein the layer B is coated with
  • a layer C comprising a pH dependent polymer, a pH independent polymer and a pore former.
  • the tamsulosin portion of the pharmaceutical composition in a fixed dosage form is bioequivalent to Harnal D ® under fed conditions (fed state).
  • the dutasteride portion of the pharmaceutical composition in a fixed dosage form is bioequivalent to Avolve® under fed conditions (fed state).
  • the dutasteride portion and the tamsulosin portion of the pharmameutical composition in a fixed dosage form are bioequivalent to coadministered Avolve® and Harnal D ® respectively under fed conditions, or both fed and fasted conditions (fed and fasted states).
  • the fixed dose combination of the present invention provides a mean AUCO-24 or mean AUCO-infinity of 80% to 125% of the mean AUCO-24 or AUCO-infinity provided by coadministration of dutasteride and tamsulosin.
  • the sustained release beads of tamsulosin in the pharmaceutical composition in a fixed dosage form of the present invention is bioequivalent to Harnal D ® under fed conditions. More preferably, the sustained release beads of tamsulosin according to the present invention is bioequivalent to Harnal D ® under fasted and fed conditions (fasted and fed states).
  • the sustained release beads of tamsulosin in the pharmaceutical composition in a fixed dosage form of the present invention is bioequivalent to Harnal D ® coadministered with Avolve® under fed conditions.
  • the sustained release beads of tamsulosin according to the present invention is bioequivalent to Harnal D ® coadministered with Avolve® under fasted and fed conditions (fasted and fed states).
  • mean plasma tamsulosin concentrations are at or above 1450 pg/mL for a mean duration of at least 21.2 hours for a single dose pharmacokinetic profile of the sustained release beads of tamsulosin in the pharmaceutical composition in a fixed dosage form of the present invention.
  • sustained release beads of tamsulosin in the pharmaceutical composition in a fixed dosage form of the present invention provides >16.7% of mean tamsulosin Cmax in vivo at 60 minutes post dose.
  • the pharmaceutical composition in a fixed dosage form is in the form of a capsule, wherein the capsule is filled with dutasteride particles as described herein and sustained release tamsulosin beads as described herein.
  • the capsule may be any suitable capsule, such as a hydroxypropylmethylcellulose capsule.
  • the capsule contains 0.5mg dutasteride and 0.2mg tamsulosin.
  • the pharmaceutical composition in a fixed dosage form is a capsule which consists of 115mg of a solid dosage form of dutasteride according to the present invention and 90mg of tamsulosin sustained release beads according to the present invention.
  • the present invention also provides a pharmaceutical composition in a fixed dosage form of dutasteride and tamsulosin which is bioequivalent to the of the fixed dose combination of the present invention.
  • Number of vessels 12 vessels or more under each testing condition.
  • the testing time is normally 24 hours, but at pH 1.2, the test may be concluded after two hours. The test can be stopped at the time when the average dissolution of reference product reaches 85%.
  • Test solutions The 1st and 2nd fluids for the dissolution test (JP16) are used as pH 1.2 and 6.8 test solutions, respectively. Diluted Mcllvaine buffers (pH is adjusted by 0.05mol/L disodium hydrogen phosphate and 0.025mol/L citric acid) are used for other pH solutions. If the average dissolution rate of the reference product does not reach 85% by six hours under any of the above-mentioned dissolution test conditions but does reach 85% in another suitable dissolution media, a test using the other dissolution media may be added.
  • test solution where the dissolution is the slowest should be selected.
  • the test solution where the dissolution is the fastest should be selected.
  • the dissolution profile of the test product is judged to be similar to that of the reference product. If the average dissolution of the reference product reaches 80% within the testing time point specified in at least one test condition, and the results meet one of the following criteria shown in 2) under all testing conditions, the dissolution profile of the test product is judged to be equivalent to that of the reference product.
  • the average dissolution of the test product reaches 80% within the testing time specified: the average dissolution of the test product are within that of the reference product ⁇ 15% at three appropriate time points when the average dissolution of the reference product are around 30%, 50% and 80%.
  • Or f2 value is not less than 42.
  • the average dissolution of the test product reaches 80% within the testing time specified: the average dissolution of the test product are within that of the reference product ⁇ 10% at three appropriate time points when the average dissolution of the reference product are around 30%, 50% and 80%.
  • Or f2 value is not less than 50.
  • the average dissolution of the test product are within that of the reference product ⁇ 8% at the testing time specified and at an appropriate time point when the average dissolution of the reference product reaches about a half of the average dissolution at the testing time specified.
  • f2 value is not less than 55.
  • the average dissolution of the test product are within that of the reference product ⁇ 6% at the testing time specified and at an appropriate time point when the average dissolution of the reference product is about a half of the average dissolution at the testing time specified. Or f2 value is not less than 61. However, when the average dissolution of the reference product is not more than 10% within the testing time specified, the average dissolution of the test product is within that of the reference product ⁇ 6% at the testing time specified only.
  • time points for f2 should be employed.
  • F2 is defined as follows. Ti and Ri show the average dissolutions of the test and reference products at the time point (i), respectively, and n is the number of time points at which the average dissolution are compared.
  • Ta is the time point at which average dissolution of the reference product reaches approximately 85% (80% for extended release products).
  • the dissolution tests used are:
  • the dissolution of the tamsulosin sustained release beads of the present invention are similar or equivalent to the dissolution of Harnal DTM if the above criteria for similarity or equivalence are met in at least one of the 9 tests listed above.
  • the sustained release beads of the present invention meets the criteria for similarity or equivalence in at least 2, 3, 4, 5, 6, 7 or 8 of the 9 tests listed above.
  • the sustained release beads of the present invention meets the criteria for similarity or equivalence in all 9 of the tests listed above.
  • the tamsulosin sustained release bead of the present invention includes a bead core, such as a commercially available microcrystalline cellulose bead (e.g., Celphere 25 or Celphere CP-507) or a sugar bead, which may be referred to as non-pareils.
  • the bead core is preferably approximately spherical, but may be various other shapes as will be understood by those skilled in the art.
  • the weight of the bead is about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80% of the final bead weight.
  • the tamsulosin in layer A can be any of the various forms (e.g, free base, pharmaceutically acceptable salts or solvates) of tamsulosin or can be a mixture of these forms.
  • the tamsulosin is preferably tamsulosin hydrochloride.
  • the total amount of tamsulosin hydrochloride present in the fixed dose combination of the present invention is 0.2 mg.
  • tamsulosin other than tamsulosin hydrochloride can be used in the present invention, and in such cases the foregoing dosage ranges can be adjusted such that the same quantity of the active tamsulosin is administered in the final dosage form (eg fixed dose
  • the tamsulosin in layer A may be various weight percentages with respect to the final bead weight as will be understood by those skilled in the art.
  • the tamsulosin in layer A is preferably about about 0.80% to about 1.00% w/w of the final bead weight, more preferably about 0.80, 0.81, 0.82, 0.83, 0.84, 0.95, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99% w/w of the final bead weight.
  • any suitable binders could be used in layer A.
  • the binder in layer A is povidone (Plasdone K29/32).
  • the ratio of tamsulosin: povidone in layer A is about 0.3:1.
  • the total weight of the bead core and layer A is about 70 to about 80% of the final bead weight.
  • it is about 73, 74, 75, 76, or 77% of the final bead weight.
  • it is about 75% of the final bead weight.
  • the pH independent polymer in layer B may be any suitable pH independent polymer, such as disclosed in WO 2006/055659.
  • it may be a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, a mixture of ethyl cellulose and water soluble polymers, or the aqueous dispersions thereof.
  • the pH independent polymer is ethyl cellulose, Eudragit NE 400, a mixture of Eudragit RS and Eudragit RL 300 in a ratio of about 0-50% w/w RL 300.
  • the pH independent polymer in layer B is ethyl cellulose.
  • the ethyl cellulose may be various ethyl celluloses, such as Surelease®, which is commercially available from Colorcon of West Point, Pennsylvania, or Aquacoat, which is commercially available from FMC BioPolymer of Philadelphia, Pennsylvania.
  • Surelease® which is commercially available from Colorcon of West Point, Pennsylvania
  • Aquacoat which is commercially available from FMC BioPolymer of Philadelphia, Pennsylvania.
  • a plasticizer such as medium chain triglycerides, dibutyl sebacate or triethyl citrate is optionally included in the layer.
  • the pore former (pore-forming material) in layer B may be any suitable disclosed in for example WO 2006/055659, such as a PVA-PEG graft copolymer, hydroxypropyl methyl cellulose, povodone or lactose.
  • a PVA-PEG graft copolymer Preferably it is a PVA-PEG graft copolymer.
  • it is Kollicoat IR.
  • layer B comprises ethyl cellulose as the pH independent polymer and a PVA-PEG graft copolymer as the pore former, in a ratio of about 8:1 to about 10:1 (ethyl cellulose: PVA-PEG graft copolymer) w/w total weight of layer B.
  • the ratio is from about 9:1 to about 11:1, more preferably about 10:1 to about 11:1.
  • layer B comprises Aquacoat ECD-30 and Kollicoat IR, preferably in the ratio of about 8:1 to about 10:1 w/w total weight of layer B.
  • the weight of layer B is about 10.5%-11.5% of the total weight of the bead. Preferably it is 11.0, 11.1, 11.2, 11.3, 11.4 or 11.5% of the total weight of the bead. More preferably it is about 11.2 to about 11.5% of the total weight of the bead.
  • the pH dependent polymer in layer C may be any suitable such polymer, such as described in WO 2006/055659. Examples include methacrylic acid copolymers with methyl methacrylate, or ethyl acrylate (Eudragit®).
  • the pH dependent polymer in layer C is a polymethacrylic acid derivative or a derivative of cellulose.
  • the pH dependent polymer in layer C is Eudragit L 30 D-55 or cellulose acetate phthalate. Preferably it is Eudragit L 30 D-55.
  • the pH independent polymer in layer C is a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, a mixture of ethyl cellulose and water soluble polymers, or the aqueous dispersions thereof.
  • the pH independent polymer is ethyl cellulose, Eudragit NE 400, a mixture of Eudragit RS and Eudragit RL 300 in a ratio of about 0-50% w/w RL 300.
  • the ethyl cellulose may be various ethyl celluloses, such as Surelease®, which is commercially available from Colorcon of West Point, Pennsylvania, or Aquacoat, which is commercially available from FMC BioPolymer of Philadelphia, Pennsylvania.
  • a plasticizer such as medium chain triglycerides, dibutyl sebacate or triethyl citrate may optionally be included in the layer.
  • the pH independent polymer in layer C also comprises ethyl acrylate-methyl acrylate copolymer (eg Eudragit NE30 D).
  • it is a mixture of ethyl cellulose (such as Aquacoat ECD-30) and an ethyl acrylate-methyl acrylate copolymer (such as Eudragit NE30D), in a ratio of about 1:1.
  • the ratio of the pH dependent polymer: pH independent polymer(s) in layer C is about 1.5:1.
  • the pore former in layer C is a PVA-PEG graft copolymer such as Kollicoat IR.
  • layer C comprises Eudragit L30D-55, Eudragit NE30D, Aquacoat ECD-30 and Kollicoat IR.
  • layer C comprises about 50 about 60% Eudragit L30D-55 as a pH dependent polymer, about 30 to about 40% of a mixture of Eudragit NE30D and ethyl cellulose as pH independent polymers, and about 5 to about 8% a PVA-PEG graft copolymer as a pore former, w/w total weight of layer C.
  • layer C comprises about 50 to about 55% Eudragit L30D-55 as a pH dependent polymer, about 30 to about 35% of a mixture of Eudragit NE30D and ethyl cellulose as pH independent polymers, and about 5 to about 6% a PVA-PEG graft copolymer as a pore former, w/w total weight of layer C.
  • layer C does not include talc.
  • the weight of layer C is about 11.0% to about 15.0% of the total weight of the bead. Preferably it is about 11.4 to about 15.0% of the total weight of the bead.
  • the sustained release beads of tamsulosin of the present invention comprises:
  • a layer B comprising ethyl cellulose and a PVA-PEG graft copolymer; wherein the layer B is coated with
  • a layer C comprising a polymethacrylic acid derivative, ethyl cellulose, an ethyl acrylate- methyl acrylate copolymer and a PVA-PEG graft copolymer.
  • the sustained release beads of tamsulosin of the present invention comprises:
  • a layer A comprising tamsulosin and povidone at a ratio of tamsulosin:povidone about 0.3:1; wherein the layer A is coated with
  • a layer B comprising ethyl cellulose and a PVA-PEG graft copolymer, in a ratio of about 8:1 to about 10:1; wherein the layer B is coated with
  • a layer C comprising a polymethacrylic acid derivative, ethyl cellulose, an ethyl acrylate- methyl acrylate copolymer and a PVA-PEG graft copolymer, in a ratio of about 9.3:3:3:1 (polymethacrylic acid derivative:ethyl cellulose: ethyl acrylate-methyl acrylate
  • the sustained release beads of tamsulosin of the present invention comprises:
  • a layer A comprising tamsulosin and povidone; wherein the layer A is coated with
  • a layer B comprising ethyl cellulose and a PVA-PEG graft copolymer; wherein the layer B is coated with
  • a layer C comprising a polymethacrylic acid derivative, ethyl cellulose, an ethyl acrylate-methyl acrylate copolymer and a PVA-PEG graft copolymer.
  • sustained release beads of tamsulosin of the present invention is as follows:
  • the sustained release beads of tamsulosin of the present invention using suitable methods.
  • layer A tamsulosin and binder, such as povidone
  • layer B tamsulosin and binder, such as povidone
  • Core beads may then be coated with first sustained release film coating (Layer B), prepared by mixing the required quantities of the componenets.
  • Layer C the second sustained release layer (Layer C) may be applied, prepared by mixing the components. Coating may be performed using a conventional bottom spray fluid bed coater fitted with Wuster insert.
  • the tamsulosin sustained release beads of the present invention is made using the following components: Table 6
  • Methacrylic Acid-Ethyl Acrylate Copolymer (Eudragit L30D-55) j 5.6 - 7.4
  • Glycerol Monostearate/TEC/Polysorabate 80 (PlasACRYL HTP20) j 1.1 - 1.5
  • some or all of the beads in the plurality or a portion of the plurality can further include one or more seal coats.
  • Seal coat materials can be, for example, hydroxypropyl methyl cellulose, or a proprietary coating such as Opadry which is commercially available from Colorcon of West Point, Pennsylvania; however, one of ordinary skill in the art will understand that various other seal coat materials may be used.
  • the seal coats may be of the same material or different materials. Seal coats may be positioned between the bead core and the first layer, between any of the various layers in the bead, and/or as the exterior layer of the bead, in which case the seal coat is a top coat.
  • the bead core, layer A, layer B, and layer C are separated by one or more intervening layers, such as a seal coat.
  • layer A, layer B and layer C are not separated by any intervening layers.
  • the present invention also includes a method for the treatment or prophylaxis of an androgen mediated disease or condition, comprising administration of an oral solid dosage form, a solid dispersion of dutasteride or a pharmaceutical composition in a fixed dosage form of the present invention.
  • the disease or condition may be BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease.
  • the disease or condition is BPH or prostate cancer.
  • the present invention provides a method for the treatment of an androgen mediated disease or condition (such as BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an oral solid dosage form, a solid dispersion of dutasteride or a pharmaceutical composition in a fixed dosage form of the present invention.
  • the disease or condition is BPH or prostate cancer.
  • the subject in need of treatment is a mammal.
  • the subject is a human.
  • the present invention also provides an oral solid dosage form, a solid dispersion of dutasteride or a pharmaceutical composition in a fixed dosage form of the present invention for the treatment or prophylaxis of an androgen mediated disease or condition.
  • the disease or condition may be BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease.
  • the disease or condition is BPH or prostate cancer.
  • an oral solid dosage form a solid dispersion of dutasteride or a
  • compositions in a fixed dosage form of the present invention for use in therapy.
  • an oral solid dosage form a solid dispersion of dutasteride or a pharmaceutical composition in a fixed dosage form of the present invention, for use in the treatment of an androgen mediated disease or condition (such as BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease).
  • an androgen mediated disease or condition such as BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease.
  • the disease or condition is BPH or prostate cancer.
  • an oral solid dosage form a solid dispersion of dutasteride or a pharmaceutical composition in a fixed dosage form of the present invention, in the manufacture of a medicament for use in the treatment of an androgen mediated disease or condition (such as BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease).
  • an androgen mediated disease or condition such as BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease.
  • the disease or condition is BPH or prostate cancer.
  • the present invention also provides the use of an oral solid dosage form, a solid dispersion of dutasteride or a pharmaceutical composition in a fixed dosage form of the present invention for the treatment or prophylaxis of an androgen mediated disease or condition.
  • the disease or condition may be BPH, prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and alopecia (including male pattern baldness), or hormone related diseases, e.g., polycystic ovary disease.
  • the disease or condition is BPH or prostate cancer.
  • the tamsulosin component described herein could be utilized in a pharmaceutical formulation of tamsulosin that does not include dutasteride.
  • the tamsulosin component is provided in a capsule, for example, as described above.
  • Other potential therapeutic components to the oral solid dosage form or the fixed dose combination of the present invention, by coadministration or by inclusion in the dosage form, include vitamins, minerals, growth promoting agents, growth hormone secretagogues, growth hormone releasing factor and its analogs, growth hormone and its analogs, 30 somatomedins, an alpha-adrenergic agonist, serotonin 5-HT o agonists, bisphosphonates, testosterone, SARMs and/or with other modulators of nuclear hormone receptors, and/or therapies for unstable bladder, including Vesicare TM.
  • An anti-oxidant optionally may be used in the composition. Suitable antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbic acid. A particularly preferred anti-oxidant is butylated hydroxytoluene. Antioxidants may be used alone or in combination.
  • dutasteride solid dispersions were made according to the following method:
  • excipient pre-blend was performed by mixing copovidone and colloidal silicon dioxide in a high shear mixer (GEA Aeromatic Fielder PMA 65), sorbitan monolaurate was then gradually added to the blend with continued mixing.
  • the excipient pre-blend was added to dutasteride drug substance and blended in a tumble-blender for 25 min.
  • the active blend was fed at a rate of 1.5 kg/hr into a twin- screw extruder (Leistritz 18mm) fitted with a 2.5mm aperture die. Cooling of the extruded strand was performed using a cooling conveyor prior to being fed into a pelletizer, the pelletized material was collected and then milled using a rotor mill before being screened.
  • Copovidone colloidal silicon dioxide and dutasteride were blended for 26 min in a tumble blender.
  • the blend and sorbitan monolaurate were co-fed into a twin-screw extruder (such as Leistritz 27mm Micro) with a 3.0mm aperture 5-hole die fitted.
  • the extrudate was cooled and crushed into flakes using a chill roller before being fed into a cone mill followed by a centrifugal sifter.
  • the components were each pre-sieved through a 20-mesh (850pm) or equivalent sieve and mesh.
  • the dutasteride, Avicel PH102, Mannitol 100SD (if present), croscarmellose sodium and crospovidone (if present) were blended for 10 minutes using a blender.
  • the magnesium stearate was then added to the mixture and blending was continued for approximately 2 minutes.
  • the resulting blend was then compressed using a suitable rotary tablet press (e.g. a Korsch XL100 or equivalent).
  • In-process controls for tablet weight and hardness were applied at appropriate intervals throughout the compression run and adjustments to the tablet press were made as necessary. All tablets had a tensile strength (MPa) greater or equal to 1.7 and a disintegration time less than 10 minutes using a standard USP test in water.
  • MPa tensile strength
  • Tamsulosin sustained release beads of the present invention were prepared according to Table 9 below. Briefly, layer A consisting of tamsulosin and povidone was prepared by dissolving the drug substance and povidone in purified water, and the solution was applied to the substrate microcrystalline cellulose beads. Core beads were then coated with first sustained release film coating (Layer B) of aqueous polymeric dispersion, prepared by mixing the required quantities of aqueous dispersion of ethyl cellulose with triethyl citrate and PVA-PEG graft copolymer.
  • Layer B first sustained release film coating
  • a second sustained release layer (Layer B) was applied, prepared by mixing the polymeric dispersion of Eurdragit L30 D55 and Eudragit NE30 with the aqueous dispersion of ethyl cellulose, plasacryl HTP20 and PVA-PEG graft copolymer. Beads were coated using a conventional bottom spray fluid bed coater fitted with Wuster insert.
  • Methacrylic Acid-Ethyl Acrylate Copolymer (Eudragit L30D-55) 5.6 - 7.4
  • Ethyl Acrylate-Methyl Acrylate Copolymer (Eudragit NE30D) 1.8 - 2.4
  • Tamsulosin sustained release beads of the present invention were prepared according to the method set out in Example 3 using the components below: Table 11
  • Methacrylic Acid-Ethyl Acrylate Copolymer (Eudragit L30D-55) 6.5
  • Dutasteride HME was prepared as described in Example 1. Tamsulosin sustained release beads were prepared as described in Example 3. Beads and granules were filled into hypromellose, size 1 hard capsule shells using an automatic, intermittent motion filling machine (a Harro Hofliger Modu-C MS encapsulator). The dosage equates to 5mg dutasteride and 0.2mg tamsulosin per capsule.
  • Example 6 Tamsulosin sustained release beads dissolution test Dissolution of tamsulosin sustained release beads of the invention made according to Example 3 were tested under the following conditions:
  • Number of vessels 12 vessels or more under each testing condition.
  • Apparatus JP paddle or basket apparatus.
  • the testing time is normally 24 hours, but at pH 1.2, the test may be
  • the test can be stopped at the time when the average dissolution of reference product reaches 85%.
  • Test solutions The 1st and 2nd fluids for the dissolution test (JP16) are used as pH 1.2 and 6.8 test solutions, respectively.
  • Diluted Mcllvaine buffers pH adjusted by 0.05mol/L disodium hydrogen phosphate and 0.025mol/L citric acid are used for other pH solutions.
  • dutasteride capsules were tested in a pilot pharmacokinetic study:
  • Dutasteride 0.5mg/capsule
  • Tamsulosin beads component
  • Dutasteride HME 0.5mg/capsule Copovidone: 100.5mg/capsule
  • Sorbitan Monolaurate lOmg/capsule
  • Dutasteride HME 0.5mg/capsule
  • Copovidone 103.5mg/capsule
  • Sorbitan Monolaurate lOmg/capsule
  • Tamsulosin beads component
  • Trial 1 (GlaxoSmithKline study number 117057;
  • Enrolled subjects were allowed to participate in only one of the cohorts, i.e. each subject received all study treatments under only one condition (fasted or fed).
  • In vitro dissolution testing for tamsulosin hydrochloride modified release beads was conducted using pH 1.2, pH 3, water, pH 7.5 using United States Pharmacopoeia (USP) Apparatus I and II at different paddle and basket speeds and one condition using 1% w/v polysorbate surfactant.
  • USP United States Pharmacopoeia
  • Tamsulosin beads in FDCl and FDC2 were shown to be equivalent to the reference product of commercially available tamsulosin orally disintegrating tablets (Harnal D ® ) in the following in vitro dissolution tests:
  • the 90% CIs for the geometric mean ratios for AUQo-t) and Cmax compared to the coadministered reference products fell within the accepted bioequivalence range of 0.80-1.25 when administered in the fed state but did not meet accepted bioequivalence criteria when administered in the fasted state.
  • the 90% CIs for the geometric mean ratios for AUC(o-t) and Cmax fell within the accepted bioequivalence range of 0.80-1.25 when administered in both the fed and fasted states.
  • Tamsulosin modified release beads in FDC3 was shown to be equivalent or similar to the reference product in the following in vitro dissolution tests:
  • FDC3 formulation 3 of the fixed-dose combination of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg); ref: coadministered reference products (one dutasteride 0.5 mg capsule [Avolve®] and one tamsulosin hydrochloride 0.2 mg tablet [Harnal D®]); AUQo-t): area under the concentration -time curve from time zero to time of the last quantifiable concentration; AUQo- ⁇ ): area under the concentration-time curve from time zero to infinity; Cmax: maximum observed concentration; CI: confidence interval; CVw(%): within-subject coefficient of variation; n : number of results available for analysis.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme posologique solide orale de dutastéride, comprenant des combinaisons de doses fixes avec de la tamsulosine. L'invention concerne également un procédé de préparation et des utilisations, en particulier pour la HPB (Hypertrophie bénigne de la prostate) et d'autres maladies ou affections médiées par les androgènes.
PCT/US2017/063900 2016-12-01 2017-11-30 Forme posologique pharmaceutique WO2018102526A1 (fr)

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US2016064334 2016-12-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210186951A1 (en) * 2018-05-19 2021-06-24 Zim Laboratories Limited Pharmaceutical composition of tamsulosin and dutasteride

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050176692A1 (en) * 2004-02-09 2005-08-11 University Of Washington Oral androgen therapy using modulators of testosterone bioavailability
WO2012076516A1 (fr) * 2010-12-06 2012-06-14 Krka, Tovarna Zdravil, D.D., Novo Mesto Compositions pharmaceutiques comprenant du dutastéride
WO2016114521A1 (fr) * 2015-01-14 2016-07-21 동아에스티 주식회사 Composition de dutastéride sous forme de comprimé présentant une stabilité améliorée
WO2016145138A1 (fr) * 2015-03-10 2016-09-15 Shionogi Inc. Dispersions solides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050176692A1 (en) * 2004-02-09 2005-08-11 University Of Washington Oral androgen therapy using modulators of testosterone bioavailability
WO2012076516A1 (fr) * 2010-12-06 2012-06-14 Krka, Tovarna Zdravil, D.D., Novo Mesto Compositions pharmaceutiques comprenant du dutastéride
WO2016114521A1 (fr) * 2015-01-14 2016-07-21 동아에스티 주식회사 Composition de dutastéride sous forme de comprimé présentant une stabilité améliorée
WO2016145138A1 (fr) * 2015-03-10 2016-09-15 Shionogi Inc. Dispersions solides

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210186951A1 (en) * 2018-05-19 2021-06-24 Zim Laboratories Limited Pharmaceutical composition of tamsulosin and dutasteride
US11771691B2 (en) * 2018-05-19 2023-10-03 Zim Laboratories Limited Pharmaceutical composition of Tamsulosin and Dutasteride

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