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WO2013123965A1 - A fixed dose pharmaceutical formulation - Google Patents

A fixed dose pharmaceutical formulation Download PDF

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Publication number
WO2013123965A1
WO2013123965A1 PCT/EP2012/052858 EP2012052858W WO2013123965A1 WO 2013123965 A1 WO2013123965 A1 WO 2013123965A1 EP 2012052858 W EP2012052858 W EP 2012052858W WO 2013123965 A1 WO2013123965 A1 WO 2013123965A1
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WO
WIPO (PCT)
Prior art keywords
tamsulosin
hard
capsule
dosage form
dutasteride
Prior art date
Application number
PCT/EP2012/052858
Other languages
French (fr)
Inventor
Denny Johan Marijn Van Den Heuvel
Original Assignee
Synthon Bv
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 Synthon Bv filed Critical Synthon Bv
Priority to PCT/EP2012/052858 priority Critical patent/WO2013123965A1/en
Publication of WO2013123965A1 publication Critical patent/WO2013123965A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • 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

Definitions

  • the present invention relates to a pharmaceutical formulation comprising a steroid 5- alpha reductase inhibitor in a fixed dose combination with an alpha- adrenergic blocker. More particularly, the present invention relates to a pharmaceutical formulation comprising a fixed dose combination of dutasteride or finasteride and tamsulosin.
  • compositions acting as inhibitors of the enzyme testosterone-5- alpha reductase are useful in the treatment and/or prevention of benign prostatic hyperplasia (BPH), prostate cancer and other androgen responsive or mediated diseases and conditions.
  • BPH benign prostatic hyperplasia
  • One example is dutasteride, an azasteroid compound of chemical name N-(2,5-Bis(trifluoro- methyl)-phenyl)-3 -oxo-4-aza-5alpha-androst- 1 -ene- 17beta-carboxamide, which is commercially available as, e.g., AVODART (GlaxoSmithKline).
  • finasteride a compound N-(l, l-dimethylethyl)-3-oxo-(5a,17P)-4-azaandrost-l-ene-17- carboxamide, which is commercially available as, e.g., PROSCAR (Merck)
  • FLOMAX Boehringer Ingelheim
  • the marketed form of tamsulosin is a hard capsule filled with a plurality of controlled release-pellets comprising a core comprising tamsulosin hydrochloride dispersed in a polymer matrix, and an outer layer comprising an enteric resistant polymer.
  • alpha-adrenergic blocker is doxazosin mesylate of chemical name (i3 ⁇ 4)-2- ⁇ 4-[(2,3-dihydro-l,4-benzodioxin-2-yl)carbonyl]piperazin-l-yl ⁇ -6,7- dimethoxyquinazolin-4-amine mesylate, which is marketed in a tablet form, e.g., under trade name CARDURA (Pfizer).
  • JALYN/DUODART comprises two different components:
  • the inactive ingredients in the soft-gelatin capsule shell are ferric oxide (yellow), gelatin (from certified BSE-free bovine sources), glycerin, and titanium dioxide.
  • Tamsulosin hydrochloride is formulated to a plurality of white to off-white pellets, containing, in total, 0.4 mg tamsulosin hydrochloride and the inactive ingredients: methacrylic acid copolymer, microcrystalline cellulose, talc, and triethyl citrate.
  • the above components are encapsulated in a size 00 hard-shell capsule made with the inactive ingredients of carrageenan, FD&C yellow 6, hypromellose, iron oxide red, potassium chloride, and titanium dioxide.
  • tamsulosin and dutasteride for treatment of BPH was first disclosed in WO03090753 (US 2003225118) by Boehringer Ingelheim.
  • the general disclosure notes that both components may be formulated into a solid dosage form for oral administration.
  • Suitable conventional preparations include inert conventional carriers and may be
  • a useful fixed dose formulation of dutasteride and tamsulosin hydrochloride has been disclosed in WO 2006055659.
  • the document suggests a hard shell capsule comprising an inner soft gelatin capsule containing dutasteride dissolved in a glyceride fatty acid ester.
  • the space between both capsules is filled with tamsulosin hydrochloride formulated as a plurality of multilayered beads, which comprise an inert core, a tamsulosin-comprising layer (with a binder) and a pH-independent layer (polymetacrylate polymer, ethyl cellulose and various combinations), advantageously also a pH-dependent (release-modifying) layer and outer cosmetic coating.
  • the marketed product DUODART is also a "capsule-in-capsule" formulation; it differs from the above in that the tamsulosin-comprising component is not formed by a plurality of multilayer beads but by that of homogeneous pellets coated by an enteric coating.
  • Such formulation possibility has been suggested in WO2010066268 of Synthon.
  • a disadvantage of the currently marketed DUODART combination product is that it has a relatively short shelf-life of 2 years with storage of the product below 30°C. It is however desirable to have a product with a longer shelf-life. It was found by the present inventor that the tamsulosin-comprising component may exhibit, under prolonged storage of the product, an unstable release rate of tamsulosin. The changes in the release rate might rise, as will be explained in more detail below, due to the interaction of the enteric coating of tamsulosin pellets with the material or content of the soft-gel capsule. A further problem relates to the size of the combination capsule product which does not allow easy swallowing by all patients in need of treatment for BPH.
  • the present invention relates to a fixed dose pharmaceutical combination of a 5-alpha reductase inhibitor with an alpha- adrenergic blocker.
  • the present invention relates to a dosage form comprising a fixed dose combination of 5-alpha reductase inhibitor and alpha-adrenergic blocker components, said dosage form comprising an inner hard-shell capsule being placed in an outer hard-shell capsule, wherein one component is placed in the inner capsule and the second component is placed in the space between the inner and outer hard-shell capsules.
  • the 5-alpha reductase inhibitor is dutasteride.
  • the alpha-adrenergic blocker is tamsulosin, preferably tamsulosin hydrochloride.
  • the dosage form comprises a fixed dose combination of dutasteride and tamsulosin components, wherein
  • a solution of dutasteride in a liquid vehicle is filled in the inner hard-shell capsule; b] a plurality of pellets and/or beads comprising tamsulosin or a salt thereof is placed in the space between the inner and outer hard-shell capsules.
  • the dosage form comprises a fixed dose combination of dutasteride and tamsulosin components, wherein
  • the inner hard-shell capsule and/or the outer hard-shell capsule is made of hard gelatin or hydroxypropylmethyl cellulose. More preferably, the inner and outer hardshell capsules are both made of hard gelatin.
  • the tamsulosin-comprising component is an enteric coated pellet comprising tamsulosin hydrochloride as the active ingredient, microcrystalline cellulose as the carrier matrix component in the pellet core and an acid resistant acrylic polymer in the coating.
  • the liquid vehicle carrying dutasteride is a glycerol ester with a fatty acid, advantageously in a combination with an antioxidant.
  • the fixed dose combination dosage form comprises 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride.
  • the invention also provides a hard-shell capsule filled with a solution of dutasteride in a liquid vehicle for use in medicine, said use comprising a co-administration of said capsule with tamsulosin in a fixed dose combination form.
  • the dosage form as specified above may be used as a medicament, particularly in the treatment of BPH. DETAILED DESCRIPTION OF THE PRESENT INVENTION
  • the present invention relates to an improved fixed-dose pharmaceutical combination of a 5-alpha reductase inhibitor with an alpha- adrenergic blocker.
  • the preferred 5-alpha reductase inhibitor is dutasteride
  • the preferred alpha-adrenergic blocker is tamsulosin, in particular tamsulosin hydrochloride.
  • dutasteride may be replaced in any composition of the invention, mutatis mutandis, by finasteride.
  • tamsulosin may be replaced in any composition of the present invention, mutatis mutandis, by doxazosin, in particular by doxazosin mesylate.
  • the notebookdutasteride is used as a generic name for the compound N-(2,5-Bis(trifluoromethyl)-phenyl)-3-oxo-4-aza-5alpha-androst-l-ene-17beta- carboxamide.
  • the compound is commercially available and/or may be produced by processes known in the art.
  • the starting dutasteride for making dutasteride compositions is in a solid form, which may be amorphous and/or crystalline.
  • the solid forms also may comprise hydrates or solvates of dutasteride, which are also within the meaning of misconduct of law dutasteride".
  • the propositiontamsulosin is a generic name for compound (R)-5-[ 2-[[2-(2-ethoxyphenoxy)ethyl]-amino] propyl]-2-methoxy-benzene- sulfonamide. It may form acid addition salts with inorganic or organic acids; in current medical practice, tamsulosin hydrochloride is the most preferred acid addition salt of tamsulosin. Thus, the invention will be further explained by using tamsulosin hydrochloride but it should be borne in mind that it is by no way limited thereto.
  • Tamsulosin and/or tamsulosin hydrochloride may be obtained commercially or may be synthesized by processes known in the art.
  • the present invention relates to a fixed dose combination of 5-alpha reductase inhibitor and alpha-adrenergic blocker components, which are physically separated but yet form a single dosage form (or dosage unit).
  • the dosage form comprising a fixed dose combination of 5-alpha reductase inhibitor and alpha-adrenergic blocker components comprises an inner hard-shell capsule being placed in an outer hard-shell capsule, wherein one component is placed in the inner hard-shell capsule and the second component is placed in the space between the inner and outer hard-shell capsules.
  • the 5-alpha reductase inhibitor component may be dutasteride and the alpha-adrenergic blocker component is tamsulosin or, preferably, tamsulosin hydrochloride.
  • the dosage form of the present invention preferably comprising dutasteride and tamsulosin components, may comprise two variant arrangements.
  • the dutasteride-comprising component comprises a solution of dutasteride in a liquid vehicle. This solution is filled in the inner hard-shell capsule.
  • the tamsulosin-comprising component is a plurality of essentially spherical pellets or beads. The plurality of pellets or beads is placed in the space between the inner and outer hard-shell capsules.
  • a plurality of pellets and/or beads comprising tamsulosin or a salt thereof, preferably tamsulosin hydrochloride, is filled in the inner hard-shell capsule.
  • a solution of dutasteride in a liquid vehicle is placed in the space between the inner and outer hard-shell capsules.
  • the outer hard-shell capsule, which forms the final dosage form (or dosage unit) comprises, in total, the therapeutic and/or prophylactic amounts of the both active substances.
  • the present invention provides for a dutasteride-comprising hard-shell capsule filled with a solution of dutasteride in a liquid vehicle for use in medicine, said use comprising a co-administration of said dutasteride capsule with tamsulosin in a fixed dose combination form.
  • the advantage of the technical solution of the present invention vis-a-vis the known technical solution typically represented by the marketed JALYN/DUODART dosage form is in that the capsule-in-capsule dosage form of the present invention does not comprise an inner capsule made of a soft shell material.
  • the JALYN/DUODART dosage form may suffer, under prolonged storage of the product, from an unstable release rate of tamsulosin. Without wishing to be bound by any theory, the inventor speculates that it is the material of the soft shell inner capsule, and in particular the glycerol present therein
  • the amount of glycerol present in the soft shell is about 35 per cent by weight
  • the controlled release/enteric release polymer in or on the tamsulosin pellets and act as a plasticizer of said polymer.
  • the controlled release and/or enteric release properties of the polymer may decrease over time and tamsulosin may be released more readily and prematurely, particularly and undesirably in the stomach environment.
  • the inner capsule does not comprise any such reactive material and thus effectively separates both components.
  • the inner and/or outer hard-shell capsules may be advantageously made of hard gelatin. Alternatively, they may be made of hydroxypropylmetyl cellulose.
  • tamsulosin component comprises a plurality of pellets or beads.
  • the "bead” as used herein has common meaning in the art and represents an essentially spherical multilayer particle comprising an inner inert core, on which a layer comprising tamsulosin and carrier is layered.
  • the bead may comprise also a further layer(s) comprising compounds regulating the release of tamsulosin from the bead in the human environment and, optionally, separating layers protecting the respective layers from mutual interaction or from interaction with the environment.
  • a suitable bead that may be used within the tamsulosin component has been disclosed in WO 2006/055659.
  • pellet as used herein has also common meaning in the art and represents an essentially spherical particle, in which tamsulosin is homogeneously distributed within a carrier matrix comprising a pellet-forming carrier, a release control agent and, optionally, water.
  • the pellet-forming carrier is an inert material that is able to bind active ingredient and other excipients into an essentially spherical particulate material.
  • the microcrystalline cellulose (crystalline cellulose in other terminology) serves as a suitable inert carrier matrix component.
  • alpha lactose, dextrin, mannitol, or chitosan, alone or in combination, may be used as pellet-forming carriers.
  • Preferred amount of the pellet-forming carrier is 50-95 mass %, calculated on a dry pellet core basis.
  • the release control agent is an excipient which allows releasing the active substance from the composition only under certain environmental conditions and/or by a certain release rate.
  • the preferred agent is a pharmaceutically acceptable polymer, most preferably a water permeable polymer.
  • various types of acrylic polymers, polyvinyl acetate and/or cellulose derivatives, (for instance ethyl cellulose, hydroxypropyl- methylcellulose and modified analogues) may be used.
  • Preferred amount of the release control agent/s in the composition is from 2.5 to 25 mass%, calculated on a dry pellet core basis.
  • An acrylic polymer is the preferred release control agent.
  • an "acrylic polymer” means a pharmaceutically acceptable polymer of acrylic acid, such as sold under brand name Carbopol, or a copolymer of methacrylic acid and/or an acrylic or methacrylic acid ester, such as sold under brand name Eudragit.
  • acrylic acid such as sold under brand name Carbopol
  • methacrylic acid and/or an acrylic or methacrylic acid ester such as sold under brand name Eudragit.
  • Such compounds are, e.g., defined in Handbook of Pharmaceutical excipients, edited by A.H.Kibbe, Pharmaceutical Press London, 3 rd ed. (2000).
  • the above pellet may comprise also at least one outer layer (a coating) comprising compounds regulating the release of tamsulosin from the composition in the human environment.
  • the outer layer is a gastroprotective layer, i.e. a layer protecting the tamsulosin against its release in the stomach environment.
  • the coat layer preferably comprises a pharmaceutically acceptable acid-resistant polymer material, more preferably an acid-resistant acrylic polymer.
  • the "acid-resistant acrylic polymer” is a specific kind of the above acrylic polymer having free carboxyl groups.
  • Such polymers are not soluble in acidic aqueous medium, while they are soluble in neutral or basic aqueous medium.
  • Preferred acid resistant acrylic polymers include the Eudragit L series, such as Eudragit L 30 D-55. This acrylic polymer is available as an aqueous suspension, also comprising a small amount of emulsifiers, and may be directly used for coating in suitable coating equipment.
  • the "acrylic polymer" used for the manufacturing of pellet core is advantageously identical with the "acid-resistant acrylic polymer" of the pellet coating.
  • the coat layer may, alternately or in combination, also comprise other acid resistant polymers such as cellulose acetate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate etc.
  • the coating composition may comprise other pharmaceutically acceptable excipients.
  • an anti-sticking agent such as talc
  • a plasticizer such as tri ethyl citrate can improve the characteristics of the final film coat.
  • the tamsulosin component within the fixed dose combination of the present invention comprises tamsulosin hydrochloride within a plurality of coated pellets.
  • the coated pellet comprises microcrystalline cellulose as the carrier matrix component and an acid resistant acrylic polymer as the gastroprotective release/controlling agent in the coating. Mixtures of coated and uncoated pellets may however also be used.
  • the plurality of pellets comprising the tamsulosin comprises a dose of between 0.1 to 1 mg of tamsulosin hydrochloride per one dosage unit, even more preferably 0.1, 0.2, 0.4 or 0.8 mg of tamsulosin hydrochloride per one dosage unit.
  • the pellets in the population have advantageously a size of less than 1.4 mm and, optionally, at least 90% of them have a size of more than 0.30 mm as well.
  • An average content of tamsulosin hydrochloride in the population of pellets is advantageously between 0.10 - 4.00 weight per cent, more particularly between 0.10 - 3 .00 weight per cent, even more particularly between 0.10 - 0.50 weight per cent, calculated on the mass of the dried pellet.
  • the pellets to be used in accordance with the present invention preferably exhibit a dissolution release profile, when measured as a plurality of pellets, wherein less than 25% of tamsulosin, preferably less than 15% of tamsulosin and most preferably less than 10% of tamsulosin is released during the first two hours in simulated gastric fluid in basket apparatus at 100 rpm. Accordingly, once the coated pellets are ingested, tamsulosin is released into the body at a rate that is characterized by minimizing the release during the pellets' residence time in the stomach environment.
  • the pellet core size and composition as well as the material and the relative amount of the coating are so selected that the resulting population of pellets exhibits at least one of the following release rates in simulated intestinal fluid (sometimes referred to herein as phosphate buffer of pH 6.8), using Ph.Eur. basket method at 100 rpm:
  • the pellets satisfy all two release rates.
  • SGF gastric fluid
  • SIF simulated intestinal fluid
  • SGF USP Simulated Gastric Fluid without pepsin
  • tamsulosin component 2010/066268 and/or made by a process disclosed therein may be used as the tamsulosin component.
  • the dutasteride component in the dosage form of the present invention is a solution of dutasteride in a liquid vehicle.
  • the solution comprises from 0.01 to 10.0 mg of dutasteride, most preferably 0.01, 0.05, 0.5, 1.0, 2.5, 5.0 or 10.0 mg.
  • the liquid vehicle of the fill typically comprises an ester, or a mixture of esters, of a fatty acid with a glycerol or propylene glycol.
  • An example of the suitable fatty acid is a caprylic or capric acid.
  • the ester- group may substitute one or more hydroxyl groups of the alcohol.
  • the preferred liquid vehicle includes CapmulTM, which comprises a mixture of mono- and diglycerides of caprylic /capric acids, and typically contains less than 3%, more specifically approx. 1.4%, of free glycerol.
  • the liquid vehicle may further comprise an antioxidant.
  • a suitable antioxidant include butylated hydroxytoluene, butylated hydroxyanisol or ascorbic acid.
  • a particularly preferred antioxidant is butylated hydroxytoluene.
  • the concentration of dutasteride in the liquid vehicle is advantageously from 0.1 to 5 weight per cent, typically about 0.5 weight per cent.
  • the dosage form of the present invention may be made, in the first variant, by a process comprising the steps of
  • the dosage form of the present invention may be made by a process comprising the steps of
  • Capsugel refers to applying a thin gelatin or HPMC band over the body and cap overlap. With sealing an ethanol mixture is sprayed between body and cap wherewith it is effetwelding" both parts together.
  • the size of the inner capsule is preferably so selected it can be filled with the desired therapeutic dose of a 5-alpha reductase inhibitor or alpha-adrenergic blocker component.
  • a size 5 capsule is the smallest commercially available hard-shell capsule.
  • the size of the outer capsule is so selected that it provides enough space between the surfaces of both capsules to fill it with the desired therapeutic dose of the second component.
  • Suitable inner hard-shell capsules are of size 2, size 3, size 4 or size 5.
  • Suitable outer hard-shell capsules are of size 0, size 1, size 2, size 2 EL (i.e. elongated) or size 3. Suitable combinations of inner and outer hard-shell capsules can easily be found by a person skilled in the art of encapsulation.
  • the inner hard-shell capsule is a size 5 capsule and the outer hard-shell capsule is a size 2 elongated or size 3 capsule.
  • a size 5 inner hard-shell capsule is filled with 0.5 mg of dutasteride and is placed inside a size 2 elongated capsule together with 0.4 mg of tamsulosin hydrochloride.
  • Capsules with the fixed dose combination of dutasteride and tamsulosin components of the present invention may be delivered for immediate use in a suitable package comprising advantageously from 5 to 100 capsules.
  • a suitable package comprising advantageously from 5 to 100 capsules.
  • Such package may comprise a blister pack comprising advantageously 10, 14, 20, 28 or 30 capsules, or a plastic or glass container/bottle containing the same amounts of capsules.
  • Any suitable pharmaceutically acceptable package material may be used in the production of the package unit.
  • the dosage form according to the present invention may be used as a medicament, for example, in the management of functional treatment of symptomatic benign prostatic hypertrophy or hyperplasia (BPH) or other disorders treatable by tamsulosin and/or dutasteride (the Disorders).
  • BPH benign prostatic hypertrophy or hyperplasia
  • the Disorders the physician will determine the actual dosage and administration regimen, which will be the most suitable for the individual patient.
  • Tamsulosin hydrochloride was mixed in a high shear mixer with talc and microcrystalline cellulose to form a homogeneous powder blend.
  • the coating suspension was prepared by mixing tri ethyl citrate, water, Eudragit L30 D-55 and talc.
  • the pellets were placed in a fluid bed coater and coated at 60oC through a spray nozzle of 1.8 mm until the amount of the coating suspension corresponding to 50% of the mass of the core pellets was consumed ( corresponds to 10% mass of the coating ).
  • 100 mg of the dutasteride solution was placed into a conventional hard gelatin capsule size 5 and the capsule was closed and sealed by applying a gelatin band around the body/cap overlap.
  • Tamsulosin pellets were filled into a hard gelatin capsule size 2EL in an amount corresponding to 0.4 mg of tamsulosin hydrochloride (ca. 178 mg). Subsequently, the closed capsule filled with the dutasteride solution was placed into the capsule and the outer capsule was closed by a cap.
  • Example 1 Following the description of Example 1, 0.4 mg tamsulosin hydrocloride-comprising pellets were made, using half the amount of excipients, in which the total mass of the pellets per capsule was 89.181 mg. These pellets were formulated into a size 3 outer hard gelatin capsule in combination with the size 5 hard gelatin capsule of Example 1 comprising 0.5 mg dutasteride.
  • a gelatin hard-shell capsule of size 5 was filled with the pellets of Example 2 comprising 0.4 mg tamsulosin hydrochloride and the capsule was closed and sealed by applying a gelatin band around the body/cap overlap.
  • 100 mg of dutasteride solution of Example 1 was placed into a size 3 hard gelatin capsule, the tamsulosin-comprising capsule was added and the outer capsule was closed and sealed by applying a gelatin band around the body/cap overlap.

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Abstract

The present invention relates to a dosage form comprising a fixed dose combination of a 5-alpha reductase inhibitor and an alpha- adrenergic blocker components, more in particular dutasteride and tamsulosin, said dosage form comprising an inner hard-shell capsule being placed in an outer hard-shell capsule, wherein one component is placed in the inner capsule and the second component is placed in the space between the inner and outer hard-shell capsules.

Description

A FIXED DOSE PHARMACEUTICAL FORMULATION
The present invention relates to a pharmaceutical formulation comprising a steroid 5- alpha reductase inhibitor in a fixed dose combination with an alpha- adrenergic blocker. More particularly, the present invention relates to a pharmaceutical formulation comprising a fixed dose combination of dutasteride or finasteride and tamsulosin.
BACKGROUND OF THE INVENTION
Pharmaceutically active substances acting as inhibitors of the enzyme testosterone-5- alpha reductase are useful in the treatment and/or prevention of benign prostatic hyperplasia (BPH), prostate cancer and other androgen responsive or mediated diseases and conditions. One example is dutasteride, an azasteroid compound of chemical name N-(2,5-Bis(trifluoro- methyl)-phenyl)-3 -oxo-4-aza-5alpha-androst- 1 -ene- 17beta-carboxamide, which is commercially available as, e.g., AVODART (GlaxoSmithKline). Another example is finasteride, a compound N-(l, l-dimethylethyl)-3-oxo-(5a,17P)-4-azaandrost-l-ene-17- carboxamide, which is commercially available as, e.g., PROSCAR (Merck)
Compounds exhibiting alpha-adrenergic blocking activity have also been proven as useful in the treatment of BPH. Typical example of such compound is tamsulosin
hydrochloride of chemical name (R)-5-[ 2-[[2-(2-ethoxyphenoxy)ethyl]-amino] propyl]-2- methoxy-benzenesulfonamide hydrochloride. It is marketed under various trade names including FLOMAX (Boehringer Ingelheim), for treatment of symptoms of BPH such as urinary volume and frequency problems. The marketed form of tamsulosin is a hard capsule filled with a plurality of controlled release-pellets comprising a core comprising tamsulosin hydrochloride dispersed in a polymer matrix, and an outer layer comprising an enteric resistant polymer. Another example of an alpha-adrenergic blocker is doxazosin mesylate of chemical name (i¾)-2-{4-[(2,3-dihydro-l,4-benzodioxin-2-yl)carbonyl]piperazin-l-yl}-6,7- dimethoxyquinazolin-4-amine mesylate, which is marketed in a tablet form, e.g., under trade name CARDURA (Pfizer).
It has been proven that the regimen of treatment for BPH and other diseases or conditions affected by a 5-alpha reductase inhibition and/or alpha-adrenergic blocking may be improved by providing a dosage form containing pharmaceutically acceptable amounts of the both two treatments. Accordingly, a single-capsule formulation of 0.5 mg dutasteride and 0.4 mg of tamsulosin hydrochloride was approved in 2010 both in the USA and in the EC
(JALYN/DUODART, GlaxoSmithKline) for treatment of symptomatic BPH.
JALYN/DUODART comprises two different components:
a] Oblong, opaque, dull-yellow soft gelatin capsule containing 0.5 mg of dutasteride dissolved in a mixture of butylated hydroxytoluene and mono-di-glycerides of caprylic/capric acid. The inactive ingredients in the soft-gelatin capsule shell are ferric oxide (yellow), gelatin (from certified BSE-free bovine sources), glycerin, and titanium dioxide.
b] Tamsulosin hydrochloride is formulated to a plurality of white to off-white pellets, containing, in total, 0.4 mg tamsulosin hydrochloride and the inactive ingredients: methacrylic acid copolymer, microcrystalline cellulose, talc, and triethyl citrate.
The above components are encapsulated in a size 00 hard-shell capsule made with the inactive ingredients of carrageenan, FD&C yellow 6, hypromellose, iron oxide red, potassium chloride, and titanium dioxide.
The combination of tamsulosin and dutasteride for treatment of BPH was first disclosed in WO03090753 (US 2003225118) by Boehringer Ingelheim. The general disclosure notes that both components may be formulated into a solid dosage form for oral administration. Suitable conventional preparations include inert conventional carriers and may be
incorporated in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories. Thus, the patent application just disclosed a possibility that both components may be formulated within a fixed dose combination, without providing a particularly preferred technical solution how the fixed combination may be formulated.
A useful fixed dose formulation of dutasteride and tamsulosin hydrochloride has been disclosed in WO 2006055659. The document suggests a hard shell capsule comprising an inner soft gelatin capsule containing dutasteride dissolved in a glyceride fatty acid ester. The space between both capsules is filled with tamsulosin hydrochloride formulated as a plurality of multilayered beads, which comprise an inert core, a tamsulosin-comprising layer (with a binder) and a pH-independent layer (polymetacrylate polymer, ethyl cellulose and various combinations), advantageously also a pH-dependent (release-modifying) layer and outer cosmetic coating.
The marketed product DUODART is also a "capsule-in-capsule" formulation; it differs from the above in that the tamsulosin-comprising component is not formed by a plurality of multilayer beads but by that of homogeneous pellets coated by an enteric coating. Such formulation possibility has been suggested in WO2010066268 of Synthon.
A disadvantage of the currently marketed DUODART combination product is that it has a relatively short shelf-life of 2 years with storage of the product below 30°C. It is however desirable to have a product with a longer shelf-life. It was found by the present inventor that the tamsulosin-comprising component may exhibit, under prolonged storage of the product, an unstable release rate of tamsulosin. The changes in the release rate might rise, as will be explained in more detail below, due to the interaction of the enteric coating of tamsulosin pellets with the material or content of the soft-gel capsule. A further problem relates to the size of the combination capsule product which does not allow easy swallowing by all patients in need of treatment for BPH. Also the manufacturing costs of a softgel capsule are relatively high and add to the total cost of the combination product. Accordingly, there is a need to provide an improved combination preparation of a steroid 5-alpha reductase inhibitor in a fixed dose combination with an alpha-adrenergic blocker. In particular, it would be beneficial to modify the existing dual-capsule composition comprising dutasteride and tamsulosin. In particular, such modified and/or improved composition should exhibit more stable release rate of tamsulosin also after long-term storage, be of a smaller size to improve patient compliance, and be easier to make to lower
manufacturing costs.
The above issues have been addressed in the present invention and specific
embodiments thereof.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a fixed dose pharmaceutical combination of a 5-alpha reductase inhibitor with an alpha- adrenergic blocker.
In a first main aspect, the present invention relates to a dosage form comprising a fixed dose combination of 5-alpha reductase inhibitor and alpha-adrenergic blocker components, said dosage form comprising an inner hard-shell capsule being placed in an outer hard-shell capsule, wherein one component is placed in the inner capsule and the second component is placed in the space between the inner and outer hard-shell capsules.
In a specific embodiment, the 5-alpha reductase inhibitor is dutasteride.
In a yet specific embodiment, the alpha-adrenergic blocker is tamsulosin, preferably tamsulosin hydrochloride.
More specifically, the dosage form comprises a fixed dose combination of dutasteride and tamsulosin components, wherein
a] a solution of dutasteride in a liquid vehicle is filled in the inner hard-shell capsule; b] a plurality of pellets and/or beads comprising tamsulosin or a salt thereof is placed in the space between the inner and outer hard-shell capsules.
Alternately, the dosage form comprises a fixed dose combination of dutasteride and tamsulosin components, wherein
a] a plurality of pellets and/or beads comprising tamsulosin or a salt thereof is filled in the inner hard-shell capsule;
b] a solution of dutasteride in a liquid vehicle is placed in the space between the inner and outer hard-shell capsules.
Preferably, the inner hard-shell capsule and/or the outer hard-shell capsule is made of hard gelatin or hydroxypropylmethyl cellulose. More preferably, the inner and outer hardshell capsules are both made of hard gelatin.
Preferably, the tamsulosin-comprising component is an enteric coated pellet comprising tamsulosin hydrochloride as the active ingredient, microcrystalline cellulose as the carrier matrix component in the pellet core and an acid resistant acrylic polymer in the coating.
Preferably, the liquid vehicle carrying dutasteride is a glycerol ester with a fatty acid, advantageously in a combination with an antioxidant.
In a particular embodiment, the fixed dose combination dosage form comprises 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride.
The invention also provides a hard-shell capsule filled with a solution of dutasteride in a liquid vehicle for use in medicine, said use comprising a co-administration of said capsule with tamsulosin in a fixed dose combination form.
The dosage form as specified above may be used as a medicament, particularly in the treatment of BPH. DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to an improved fixed-dose pharmaceutical combination of a 5-alpha reductase inhibitor with an alpha- adrenergic blocker. The preferred 5-alpha reductase inhibitor is dutasteride, and the preferred alpha-adrenergic blocker is tamsulosin, in particular tamsulosin hydrochloride.
Accordingly, the present invention will be illustrated on a combination of dutasteride and tamsulosin, while it is not strictly limited thereto. In particular, the dutasteride may be replaced in any composition of the invention, mutatis mutandis, by finasteride. The tamsulosin may be replaced in any composition of the present invention, mutatis mutandis, by doxazosin, in particular by doxazosin mesylate.
In the compositions of the invention the„dutasteride" is used as a generic name for the compound N-(2,5-Bis(trifluoromethyl)-phenyl)-3-oxo-4-aza-5alpha-androst-l-ene-17beta- carboxamide. The compound is commercially available and/or may be produced by processes known in the art. Preferably the starting dutasteride for making dutasteride compositions is in a solid form, which may be amorphous and/or crystalline. The solid forms also may comprise hydrates or solvates of dutasteride, which are also within the meaning of„ dutasteride".
The„tamsulosin", as used throughout the present invention, is a generic name for compound (R)-5-[ 2-[[2-(2-ethoxyphenoxy)ethyl]-amino] propyl]-2-methoxy-benzene- sulfonamide. It may form acid addition salts with inorganic or organic acids; in current medical practice, tamsulosin hydrochloride is the most preferred acid addition salt of tamsulosin. Thus, the invention will be further explained by using tamsulosin hydrochloride but it should be borne in mind that it is by no way limited thereto.
Tamsulosin and/or tamsulosin hydrochloride may be obtained commercially or may be synthesized by processes known in the art. The present invention relates to a fixed dose combination of 5-alpha reductase inhibitor and alpha-adrenergic blocker components, which are physically separated but yet form a single dosage form (or dosage unit). The dosage form comprising a fixed dose combination of 5-alpha reductase inhibitor and alpha-adrenergic blocker components comprises an inner hard-shell capsule being placed in an outer hard-shell capsule, wherein one component is placed in the inner hard-shell capsule and the second component is placed in the space between the inner and outer hard-shell capsules.
More specifically, the 5-alpha reductase inhibitor component may be dutasteride and the alpha-adrenergic blocker component is tamsulosin or, preferably, tamsulosin hydrochloride.
The dosage form of the present invention, preferably comprising dutasteride and tamsulosin components, may comprise two variant arrangements.
In the first variant, the dutasteride-comprising component comprises a solution of dutasteride in a liquid vehicle. This solution is filled in the inner hard-shell capsule. The tamsulosin-comprising component is a plurality of essentially spherical pellets or beads. The plurality of pellets or beads is placed in the space between the inner and outer hard-shell capsules.
In the second variant, a plurality of pellets and/or beads comprising tamsulosin or a salt thereof, preferably tamsulosin hydrochloride, is filled in the inner hard-shell capsule. A solution of dutasteride in a liquid vehicle is placed in the space between the inner and outer hard-shell capsules.
The outer hard-shell capsule, which forms the final dosage form (or dosage unit) comprises, in total, the therapeutic and/or prophylactic amounts of the both active substances.
Specifically, the present invention provides for a dutasteride-comprising hard-shell capsule filled with a solution of dutasteride in a liquid vehicle for use in medicine, said use comprising a co-administration of said dutasteride capsule with tamsulosin in a fixed dose combination form.
The advantage of the technical solution of the present invention vis-a-vis the known technical solution typically represented by the marketed JALYN/DUODART dosage form, is in that the capsule-in-capsule dosage form of the present invention does not comprise an inner capsule made of a soft shell material. As mentioned above, the JALYN/DUODART dosage form may suffer, under prolonged storage of the product, from an unstable release rate of tamsulosin. Without wishing to be bound by any theory, the inventor speculates that it is the material of the soft shell inner capsule, and in particular the glycerol present therein
(typically, the amount of glycerol present in the soft shell is about 35 per cent by weight), which may interact with the controlled release/enteric release polymer in or on the tamsulosin pellets and act as a plasticizer of said polymer. As a result of such interaction, the controlled release and/or enteric release properties of the polymer may decrease over time and tamsulosin may be released more readily and prematurely, particularly and undesirably in the stomach environment. Within the composition of the present invention, the inner capsule does not comprise any such reactive material and thus effectively separates both components.
The inner and/or outer hard-shell capsules may be advantageously made of hard gelatin. Alternatively, they may be made of hydroxypropylmetyl cellulose.
Advantageously, commercially available hard-shell capsules of suitable standardized sizes may be used as the inner capsules, which is an advantage over soft-gel capsules of the prior art that must be made just before filling. Furthermore, a relatively thin shell of a hardshell capsule allows, at the same outer volume, larger effective inner volume, which can be filled with the tamsulosin-comprising pellets. This gives a possibility to use also smaller outer capsule, which makes the swallowing easier. The tamsulosin component comprises a plurality of pellets or beads. The "bead" as used herein has common meaning in the art and represents an essentially spherical multilayer particle comprising an inner inert core, on which a layer comprising tamsulosin and carrier is layered. Optionally, the bead may comprise also a further layer(s) comprising compounds regulating the release of tamsulosin from the bead in the human environment and, optionally, separating layers protecting the respective layers from mutual interaction or from interaction with the environment.
A suitable bead that may be used within the tamsulosin component has been disclosed in WO 2006/055659.
The "pellet" as used herein has also common meaning in the art and represents an essentially spherical particle, in which tamsulosin is homogeneously distributed within a carrier matrix comprising a pellet-forming carrier, a release control agent and, optionally, water. The pellet-forming carrier is an inert material that is able to bind active ingredient and other excipients into an essentially spherical particulate material. In the preferred
composition, the microcrystalline cellulose (crystalline cellulose in other terminology) serves as a suitable inert carrier matrix component. Also alpha lactose, dextrin, mannitol, or chitosan, alone or in combination, may be used as pellet-forming carriers. Preferred amount of the pellet-forming carrier is 50-95 mass %, calculated on a dry pellet core basis.
The release control agent is an excipient which allows releasing the active substance from the composition only under certain environmental conditions and/or by a certain release rate. Within the invention, the preferred agent is a pharmaceutically acceptable polymer, most preferably a water permeable polymer. For instance, various types of acrylic polymers, polyvinyl acetate and/or cellulose derivatives, (for instance ethyl cellulose, hydroxypropyl- methylcellulose and modified analogues) may be used. Preferred amount of the release control agent/s in the composition is from 2.5 to 25 mass%, calculated on a dry pellet core basis. An acrylic polymer is the preferred release control agent. Within the invention, an "acrylic polymer" means a pharmaceutically acceptable polymer of acrylic acid, such as sold under brand name Carbopol, or a copolymer of methacrylic acid and/or an acrylic or methacrylic acid ester, such as sold under brand name Eudragit. Such compounds are, e.g., defined in Handbook of Pharmaceutical excipients, edited by A.H.Kibbe, Pharmaceutical Press London, 3rd ed. (2000).
Advantageously, the above pellet may comprise also at least one outer layer (a coating) comprising compounds regulating the release of tamsulosin from the composition in the human environment. Advantageously, the outer layer is a gastroprotective layer, i.e. a layer protecting the tamsulosin against its release in the stomach environment. Typically, it is desirable that less than 10% of tamsulosin is released from the composition in the stomach. Accordingly, the coat layer preferably comprises a pharmaceutically acceptable acid-resistant polymer material, more preferably an acid-resistant acrylic polymer. The "acid-resistant acrylic polymer" is a specific kind of the above acrylic polymer having free carboxyl groups. Such polymers are not soluble in acidic aqueous medium, while they are soluble in neutral or basic aqueous medium. Preferred acid resistant acrylic polymers include the Eudragit L series, such as Eudragit L 30 D-55. This acrylic polymer is available as an aqueous suspension, also comprising a small amount of emulsifiers, and may be directly used for coating in suitable coating equipment. In a particular aspect of the invention, the "acrylic polymer" used for the manufacturing of pellet core is advantageously identical with the "acid-resistant acrylic polymer" of the pellet coating.
The coat layer may, alternately or in combination, also comprise other acid resistant polymers such as cellulose acetate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate etc. In addition, the coating composition may comprise other pharmaceutically acceptable excipients. For example, an anti-sticking agent, such as talc, may be added to the coating composition to avoid stickiness of the coated granules during the process. Similarly, a plasticizer such as tri ethyl citrate can improve the characteristics of the final film coat.
Due to overall simplicity, a tamsulosin-comprising pellet is preferred over the bead. Thus, preferably, the tamsulosin component within the fixed dose combination of the present invention comprises tamsulosin hydrochloride within a plurality of coated pellets. More preferably, the coated pellet comprises microcrystalline cellulose as the carrier matrix component and an acid resistant acrylic polymer as the gastroprotective release/controlling agent in the coating. Mixtures of coated and uncoated pellets may however also be used.
The plurality of pellets comprising the tamsulosin comprises a dose of between 0.1 to 1 mg of tamsulosin hydrochloride per one dosage unit, even more preferably 0.1, 0.2, 0.4 or 0.8 mg of tamsulosin hydrochloride per one dosage unit.
The pellets in the population have advantageously a size of less than 1.4 mm and, optionally, at least 90% of them have a size of more than 0.30 mm as well.
An average content of tamsulosin hydrochloride in the population of pellets is advantageously between 0.10 - 4.00 weight per cent, more particularly between 0.10 - 3 .00 weight per cent, even more particularly between 0.10 - 0.50 weight per cent, calculated on the mass of the dried pellet.
The pellets to be used in accordance with the present invention preferably exhibit a dissolution release profile, when measured as a plurality of pellets, wherein less than 25% of tamsulosin, preferably less than 15% of tamsulosin and most preferably less than 10% of tamsulosin is released during the first two hours in simulated gastric fluid in basket apparatus at 100 rpm. Accordingly, once the coated pellets are ingested, tamsulosin is released into the body at a rate that is characterized by minimizing the release during the pellets' residence time in the stomach environment. More advantageously, the pellet core size and composition as well as the material and the relative amount of the coating are so selected that the resulting population of pellets exhibits at least one of the following release rates in simulated intestinal fluid (sometimes referred to herein as phosphate buffer of pH 6.8), using Ph.Eur. basket method at 100 rpm:
30-65%, preferably 40-60% of the tamsulosin in one hour, and/or
more than 80% of the tamsulosin in six hours.
More preferably, the pellets satisfy all two release rates.
For clarity sake, the composition of simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), although well known in the art as standard solutions, are set forth below:
SGF (USP Simulated Gastric Fluid without pepsin) composition:
HC1 qs pH 1.2
NaCl 0.2 %
water qs 1000 ml
SIF (USP Simulated Intestinal Fluid without pancreatin) composition:
KH2P04 6.8 g
NaOH qs pH 6.8
water qs 1000 ml
Advantageously, a plurality of pellets as disclosed in WO 2004/043449 or WO
2010/066268 and/or made by a process disclosed therein may be used as the tamsulosin component.
The dutasteride component in the dosage form of the present invention is a solution of dutasteride in a liquid vehicle. Preferably, the solution comprises from 0.01 to 10.0 mg of dutasteride, most preferably 0.01, 0.05, 0.5, 1.0, 2.5, 5.0 or 10.0 mg. The liquid vehicle of the fill typically comprises an ester, or a mixture of esters, of a fatty acid with a glycerol or propylene glycol. An example of the suitable fatty acid is a caprylic or capric acid. The ester- group may substitute one or more hydroxyl groups of the alcohol. The preferred liquid vehicle includes Capmul™, which comprises a mixture of mono- and diglycerides of caprylic /capric acids, and typically contains less than 3%, more specifically approx. 1.4%, of free glycerol. The liquid vehicle may further comprise an antioxidant. A suitable antioxidant include butylated hydroxytoluene, butylated hydroxyanisol or ascorbic acid. A particularly preferred antioxidant is butylated hydroxytoluene.
The concentration of dutasteride in the liquid vehicle is advantageously from 0.1 to 5 weight per cent, typically about 0.5 weight per cent.
The dosage form of the present invention may be made, in the first variant, by a process comprising the steps of
a] Filling an (inner) hard-shell capsule with a solution of dutasteride in a liquid vehicle comprising the therapeutic dose of dutasteride
b] Filling an (outer) hard-shell capsule with a plurality of tamsulosin-comprising pellets or beads comprising, in total, the therapeutic dose of tamsulosin
c] Placing the closed inner hard-shell capsule in the outer hard-shell capsule body and closing the outer hard-shell capsule body by a capsule cap.
In the second variant, the dosage form of the present invention may be made by a process comprising the steps of
a] Filling an (inner) hard-shell capsule with a plurality of tamsulosin-comprising pellets or beads comprising, in total, the therapeutic dose of tamsulosin
b] Filling an (outer) hard shell capsule with a solution of dutasteride in a liquid vehicle comprising the therapeutic dose of dutasteride
c] Placing the closed inner hard-shell capsule in the outer hard-shell capsule body and closing the outer hard-shell capsule body by a capsule cap. The inner capsule in the first variant as well as both capsules in the second variant need to be made leakfree by tight closing the body and cap. Suitable ways of tight closing are, e.g., a banding technology (Encap) or liquid encapsulation microspray sealing technology
(Capsugel). Banding refers to applying a thin gelatin or HPMC band over the body and cap overlap. With sealing an ethanol mixture is sprayed between body and cap wherewith it is „welding" both parts together.
The size of the inner capsule is preferably so selected it can be filled with the desired therapeutic dose of a 5-alpha reductase inhibitor or alpha-adrenergic blocker component. A size 5 capsule is the smallest commercially available hard-shell capsule. The size of the outer capsule is so selected that it provides enough space between the surfaces of both capsules to fill it with the desired therapeutic dose of the second component. Suitable inner hard-shell capsules are of size 2, size 3, size 4 or size 5. Suitable outer hard-shell capsules are of size 0, size 1, size 2, size 2 EL (i.e. elongated) or size 3. Suitable combinations of inner and outer hard-shell capsules can easily be found by a person skilled in the art of encapsulation.
In a specific embodiment the inner hard-shell capsule is a size 5 capsule and the outer hard-shell capsule is a size 2 elongated or size 3 capsule. In a more specific embodiment, a size 5 inner hard-shell capsule is filled with 0.5 mg of dutasteride and is placed inside a size 2 elongated capsule together with 0.4 mg of tamsulosin hydrochloride.
Capsules with the fixed dose combination of dutasteride and tamsulosin components of the present invention may be delivered for immediate use in a suitable package comprising advantageously from 5 to 100 capsules. Such package may comprise a blister pack comprising advantageously 10, 14, 20, 28 or 30 capsules, or a plastic or glass container/bottle containing the same amounts of capsules. Any suitable pharmaceutically acceptable package material may be used in the production of the package unit. The dosage form according to the present invention may be used as a medicament, for example, in the management of functional treatment of symptomatic benign prostatic hypertrophy or hyperplasia (BPH) or other disorders treatable by tamsulosin and/or dutasteride (the Disorders). In practice, the physician will determine the actual dosage and administration regimen, which will be the most suitable for the individual patient.
The invention is further illustrated by the following Examples, but should not be construed as being limited thereto.
EXAMPLES
Example 1
a] Tamsulosin-comprising pellets
Pellet composition:
Figure imgf000016_0001
Ingredients mg/capsule pellet coating
Pellet cores 162.215
Eudragit L 30 D-55 10.815
Talc 4.325
Tri ethyl citrate 1.081
2
Water (demineralized) 2
Total mass of the coating 16.221
Total mass of the pellets 178.436
1 After drying to the content of volatiles of between 2-4°/
2
Fully removed during coating process
Manufacturing process:
• Tamsulosin hydrochloride was mixed in a high shear mixer with talc and microcrystalline cellulose to form a homogeneous powder blend.
• A suspension of Eudragit, tri ethyl citrate and water was prepared in a separate vessel.
• The suspension was added to the powder blend and the mixture was granulated at 95 rpm.
• The produced granulate was extruded and spheronised at the following setting: o Feeder speed: 20 rpm, o Impeller speed: 20 rpm, o Sieve aperture: 1.0 mm, o Shuttle box filing time: approx. 184 seconds, o Spheroniser speed: 500 rpm, o Spheronizer time: 3 minutes. • The formed pellets were dried in a fluid bed dryer until the loss on drying (LOD) value of between 2-4%.
• The coating suspension was prepared by mixing tri ethyl citrate, water, Eudragit L30 D-55 and talc.
• The pellets were placed in a fluid bed coater and coated at 60oC through a spray nozzle of 1.8 mm until the amount of the coating suspension corresponding to 50% of the mass of the core pellets was consumed ( corresponds to 10% mass of the coating ).
• The coated pellets were sieved through a 1.4 mm screen. b] Dutasteride solution
Composition
Figure imgf000018_0001
Process
• Under nitrogen blanket, the MDC was melted at 40oC under stirring and BHT was added to the vessel.
• Dutasteride was added under stitrring and the mixture was stirred until the dissolution was complete.
• The solution was cooled to 25oC and maintained under nitrogen until encapsulation. c] Encapsulation
100 mg of the dutasteride solution was placed into a conventional hard gelatin capsule size 5 and the capsule was closed and sealed by applying a gelatin band around the body/cap overlap.
Tamsulosin pellets were filled into a hard gelatin capsule size 2EL in an amount corresponding to 0.4 mg of tamsulosin hydrochloride (ca. 178 mg). Subsequently, the closed capsule filled with the dutasteride solution was placed into the capsule and the outer capsule was closed by a cap.
Example 2
Following the description of Example 1, 0.4 mg tamsulosin hydrocloride-comprising pellets were made, using half the amount of excipients, in which the total mass of the pellets per capsule was 89.181 mg. These pellets were formulated into a size 3 outer hard gelatin capsule in combination with the size 5 hard gelatin capsule of Example 1 comprising 0.5 mg dutasteride.
Example 3
A gelatin hard-shell capsule of size 5 was filled with the pellets of Example 2 comprising 0.4 mg tamsulosin hydrochloride and the capsule was closed and sealed by applying a gelatin band around the body/cap overlap. 100 mg of dutasteride solution of Example 1 was placed into a size 3 hard gelatin capsule, the tamsulosin-comprising capsule was added and the outer capsule was closed and sealed by applying a gelatin band around the body/cap overlap.

Claims

A dosage form comprising a fixed dose combination of 5-alpha reductase inhibitor and alpha-adrenergic blocker components, said dosage form comprising an inner hard-shell capsule being placed in an outer hard-shell capsule, wherein one component is placed in the inner hard-shell capsule and the second component is placed in the space between the inner and outer hard-shell capsules.
The dosage form according to claim 1, wherein the 5-alpha reductase inhibitor is dutasteride.
The dosage form according to claim 1 or 2, wherein the alpha-adrenergic blocker is tamsulosin or tamsulosin hydrochloride.
A dosage form according to any one of claims 1-3 comprising a fixed dose combination of dutasteride and tamsulosin components, wherein
a] a solution of dutasteride in a liquid vehicle is filled in the inner hard-shell capsule; and
b] a plurality of pellets and/or beads comprising tamsulosin or a salt thereof is placed in the space between the inner and outer hard-shell capsules.
A dosage form according to any one of claims 1-3 comprising a fixed dose combination of dutasteride and tamsulosin components, wherein
a] a plurality of pellets and/or beads comprising tamsulosin or a salt thereof is filled in the inner hard-shell capsule; and
b] a solution of dutasteride in a liquid vehicle is placed in the space between the inner and outer hard-shell capsules.
6. The dosage form according to any one of claims 1-5, wherein the inner hard-shell capsule and/or the outer hard-shell capsule is made of hard gelatin or
hydroxypropylmethyl cellulose.
7. The dosage form according to any one of claims 1-6, wherein the tamsulosin- comprising component is an enteric coated pellet comprising tamsulosin hydrochloride as the active ingredient, microcrystalline cellulose as the carrier matrix component in the pellet core and an acid resistant acrylic polymer in the coating.
8. The dosage form according to any one of claims 1-7, wherein the liquid vehicle carrying dutasteride is a glycerol ester with a fatty acid, advantageously in a combination with an antioxidant.
9. The dosage form according to any one of claims 1-8 comprising 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride.
10. The dosage form according to any one of claims 1-9, wherein the inner hard-shell
capsule is a size 5 capsule and the outer hard-shell capsule is a size 2 elongated or size 3 capsule.
11. The dosage form according to any one of claims 1-10, wherein the inner hard-shell capsule and the outer hard-shell capsule are made of hard gelatin.
12. The dosage form according to any one of claims 1-11 for use as a medicament.
13. The dosage form according to any one of claims 1-11 for use in the treatment of benign prostatic hyperplasia (BPH).
14. A hard-shell capsule filled with a solution of dutasteride in a liquid vehicle for use in medicine, said use comprising a co-administration of said capsule with tamsulosin in a fixed dose combination form.
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EP3473244A1 (en) 2017-10-20 2019-04-24 Veru Inc. Controlled release oral tamsulosin hydrochloride
EP3473245A1 (en) 2017-10-20 2019-04-24 Veru Inc. Controlled release oral tamsulosin hydrochloride
CN108066347B (en) * 2016-11-16 2021-02-02 深圳万和制药有限公司 Orally disintegrating tablet pharmaceutical composition comprising tamsulosin and dutasteride
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WO2017192808A1 (en) * 2016-05-04 2017-11-09 Aspen Park Pharmaceuticals, Inc. Delayed release oral tamsulosin hydrochloride
CN109562071A (en) * 2016-05-04 2019-04-02 艾森潘帕克制药股份有限公司 Sustained release oral hydrochloride Tamsulosin
CN108066347B (en) * 2016-11-16 2021-02-02 深圳万和制药有限公司 Orally disintegrating tablet pharmaceutical composition comprising tamsulosin and dutasteride
EP3473244A1 (en) 2017-10-20 2019-04-24 Veru Inc. Controlled release oral tamsulosin hydrochloride
EP3473245A1 (en) 2017-10-20 2019-04-24 Veru Inc. Controlled release oral tamsulosin hydrochloride
CN109602718A (en) * 2018-12-24 2019-04-12 江苏辰星药业股份有限公司 A kind of enteric plant soft capsule and preparation method thereof
US20220339112A1 (en) * 2021-04-08 2022-10-27 Patrick Harris Targeted chemical delivery capsule
EP4370209A4 (en) * 2021-07-15 2025-05-07 Incannex Healthcare Ltd Composition with cannabidiol and hydroxychloroquine in a fixed-dose combination capsule

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