WO2014003677A1 - Compositions pharmaceutiques comprenant des particules de dispersion solide contenant du tadalafil - Google Patents

Compositions pharmaceutiques comprenant des particules de dispersion solide contenant du tadalafil Download PDF

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Publication number
WO2014003677A1
WO2014003677A1 PCT/SE2013/050807 SE2013050807W WO2014003677A1 WO 2014003677 A1 WO2014003677 A1 WO 2014003677A1 SE 2013050807 W SE2013050807 W SE 2013050807W WO 2014003677 A1 WO2014003677 A1 WO 2014003677A1
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tadalafil
composition according
composition
solid dispersion
dispersing component
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PCT/SE2013/050807
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English (en)
Inventor
Gérald JESSON
Mustafa Demirbüker
Magnus Brisander
Anders Ringberg
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Xspray Microparticles Ab
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Publication of WO2014003677A1 publication Critical patent/WO2014003677A1/fr

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • compositions comprising solid dispersion particles containing tadalafil
  • the present invention relates to the field of pharmaceutical compositions and formulations comprising the PDE5 inhibitor tadalafil.
  • the present invention relates to a pharmaceutical composition comprising a solid dispersion product containing tadalafil and a polymeric dispersing component.
  • the present invention relates to a method of treating disorders, wherein inhibition of PDE5 is desired. Background of the invention
  • Tadalafil is an established type 5 cGMP-specific phosphodiesterase (PDE5) inhibitor, which is known as being useful in treatment of pulmonary arterial hypertension and sexual dysfunction disorders.
  • PDE5 cGMP-specific phosphodiesterase
  • tadalafil may be used to treat erectile dysfunction, where it is believed to increase penile blood flow resulting from the relaxation of penile arteries and the smooth muscle of the corpus cavernosum. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP relaxes smooth muscle and increases blood flow to the corpus cavernosum.
  • NO nitric oxide
  • the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP, and tadalafil inhibits PDE5.
  • the recommended tadalafil starting dose for most men is 10 mg, taken as needed before sexual activity (but not more than once daily).
  • the dose may be increased to 20 or 40 mg or decreased to 5 mg, per its efficacy and the man's personal tolerance of the drug.
  • Major objectives of formulation chemistry are to improve bioavailability, stability and convenience to the patient.
  • Bioavailability means the rate and extent to which an active substance or therapeutic is absorbed from a pharmaceutical form and becomes available at the site of action.
  • the most common and preferred method of delivery due to convenience, ease of ingestion and high patient compliance to treatment is the oral route of drug delivery.
  • EP1200092 discloses tadalafil as a free drug particulate form, as well as compositions comprising tadalafil, wherein the compound is present as solid particles not embedded in a polymeric co-precipitate.
  • US 5,985,326 discloses solid dispersions of inter alia tadalafil. Summary of the invention
  • the present invention relates to pharmaceutical compositions comprising solid dispersion particles of tadalafil and at least one polymeric dispersing component; which composition optionally further comprises at least one pharmaceutically acceptable solubilizer. Further, the present invention relates to methods of treating disorders such as sexual disorders or pulmonary disorders, such as pulmonary artierial hypertension, in a patient in need thereof, comprising administering a therapeutically effective amount of said composition.
  • Figure 1 provides a graph showing the concentration of tadalafil from solid dispersion compositions. The details of the compositions are described in Example 1 , in Table 1. Briefly, experiment 1 represents a composition, comprising raw tadalafil in crystalline form. Experiments 2 and 3 represent mixed raw, crystalline tadalafil with the polymeric dispersing components polyvinylpyrrolidone (PVP 30K) or polyvinyl acetate phthalate (PVAP). The experiments illustrated in the graphs were carried out at pH 6.5, in FaSSIF.
  • PVP 30K polyvinylpyrrolidone
  • PVAP polyvinyl acetate phthalate
  • Figure 2 provides a graph showing the concentration of tadalafil from solid dispersion compositions of the invention.
  • the details of the compositions are described in Example 1 , in Table 1 .
  • experiment 1 represents a composition, comprising raw tadalafil in crystalline form.
  • Experiments 4, 5 and 6 represent solid dispersion particles of tadalafil and the polymeric dispersing component polyvinylpyrrolidone (PVP 30K).
  • PVP 30K polymeric dispersing component polyvinylpyrrolidone
  • the experiments illustrated in the graphs were carried out at pH 6.5, in FaSSIF.
  • Figure 3 provides a graph showing the concentration of tadalafil from solid dispersion compositions of the invention. The details of the compositions are described in Example 1 , in Table 1 .
  • experiment 1 represents a composition, comprising raw tadalafil in crystalline form.
  • Experiments 7, 8 and 9 represent solid dispersion particles of tadalafil and the polymeric dispersing component polyvinyl acetate phthalate (PVAP).
  • PVAP polyvinyl acetate phthalate
  • Figure 4 provides a graph showing the concentration of tadalafil from solid dispersion compositions of the invention.
  • the details of the compositions are described in Example 1 , in Table 1 .
  • experiment 1 represents a composition, comprising raw tadalafil in crystalline form.
  • Experiment 21 represents solid dispersion particles of tadalafil and the polymeric dispersing component poly DL-lactide (PDL).
  • Experiment 22 represents solid dispersion particles of tadalafil and the polymeric dispersing component DL lactide/glycolide copolymer (PDLG).
  • the experiments illustrated in the graphs were carried out at pH 6.5, in FaSSIF.
  • Figure 5 provides a graph showing the concentration of tadalafil from solid dispersion compositions.
  • the details of the compositions are described in Example 2, in Table 3.
  • experiment 1 1 represents a composition, comprising raw tadalafil in crystalline form.
  • Experiments 12 and 13 represent mixed raw, crystalline tadalafil with the polymeric dispersing components polyvinylpyrrolidone (PVP 30K) or polyvinyl acetate phthalate (PVAP).
  • PVP 30K polyvinylpyrrolidone
  • PVAP polyvinyl acetate phthalate
  • Figure 6 provides a graph showing the concentration of tadalafil from solid dispersion compositions of the invention.
  • the details of the compositions are described in Example 2, in Table 3.
  • experiment 1 1 represents a composition, comprising raw tadalafil in crystalline form.
  • Experiments 14, 15 and 16 represent solid dispersion particles of tadalafil and the polymeric dispersing component polyvinylpyrrolidone (PVP 30K).
  • PVP 30K polymeric dispersing component polyvinylpyrrolidone
  • Figure 7 provides a graph showing the concentration of tadalafil from solid dispersion compositions of the invention.
  • the details of the compositions are described in Example 2, in Table 3.
  • experiment 1 1 represents a composition, comprising raw tadalafil in crystalline form.
  • Experiments 17, 18 and 19 represent solid dispersion particles of tadalafil and the polymeric dispersing component polyvinyl acetate phthalate (PVAP).
  • PVAP polyvinyl acetate phthalate
  • Figure 8 provides a graph showing the concentration of tadalafil from solid dispersion compositions of the invention.
  • the details of the compositions are described in Example 2, in Table 3.
  • experiment 1 1 represents a composition, comprising raw tadalafil in crystalline form.
  • Experiment 23 represents solid dispersion particles of tadalafil and the polymeric dispersing component poly DL-lactide (PDL).
  • Experiment 24 represents solid dispersion particles of tadalafil and the polymeric dispersing component DL lactide/glycolide copolymer (PDLG).
  • the experiments illustrated in the graphs were carried out at pH 1 .4, in SGF.
  • Figure 9 provides a graph showing that the compositions of the invention are amorphous as matured as measured by X-ray powder diffraction.
  • the upper trace represents Experiment 28, the middle trace represents Experiment 29 and the lower trace represents Experiment 30.
  • the details of the compositions are described in Example 3 and Table 5.
  • compositions containing a) solid dispersion particles comprising tadalafil and at least one dispersing component, preferably a polymeric dispersing component, and b) pharmaceutically acceptable excipients, such as a solubilizer.
  • solid dispersion refers to a system in a solid state, comprising at least two components, wherein one component is dispersed evenly throughout the other component or components.
  • solid dispersion is generally, but not limited to, solid dispersion particles comprising a matrix, typically hydrophilic and often soluble in an aqueous medium, and tadalafil dispersed therein.
  • the matrix can be either crystalline, partly crystalline, amorphous or a mixture thereof.
  • Tadalafil is present within the matrix or particles as an essentially amorphous form or essentially crystalline form, or a mixture thereof.
  • Solid dipersions can be classified into different categories, but are not limited to, for example: eutectics, amorphous precipitations in crystalline matrix, solid solutions (such as continuous solid solutions, discontinuous solid solutions, interstitial solid solutions), glass suspensions and glass solutions.
  • eutectics such as continuous solid solutions, discontinuous solid solutions, interstitial solid solutions
  • glass suspensions glass solutions.
  • the amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X- Ray Powder Diffraction (XRPD) as described elsewhere in the present disclosure.
  • tadalafil is meant the compound named (6R-frans)-6-(1 ,3- benzodioxol-5-yl)- 2,3,6,7, 12, 12a-hexahydro-2-methyl-pyrazino [1 ', 2':1 ,6] pyrido[3,4-Jb]indole-1 ,4-dione.
  • An alternative name is (6R, 12aR)- 2,3,6,7, 12, 12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)- pyrazino(2', 1 ':6, 1 )pyrido(3,4-b)indole-1 ,4-dione.
  • the structure of tadalafil can be illustrated as:
  • dispersing component is meant a component present in the solid dispersion together with tadalafil and possibly one or more other drugs.
  • said dispersing component represents, but is not limited to, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. HPC ef, HPC If and HPC jf), hydroxypropyl methylcellulose (e.g. Methocel E3 and E15 and Pharmacoat 645), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (e.g. HPMCP-HP55), polyvinylpyrrolidone (e.g.
  • PVAP polyvinyl acetate phthalate
  • copolyvidone e.g. Kollidon VA 64
  • crospovidon e.g. Kollidon CL
  • methacrylic acid and ethylacrylate copolymer e.g. Kollicoat ME
  • methacrylate acid and methyl methacrylate copolymer e.g. Eudragit L100
  • polyethylene glycol e.g.
  • PEG20K DL lactide/glycolide copolymer
  • PLG poly DL-lactide
  • CAP cellulose acetate phthalate
  • hypromellose such as methylcellulose USP
  • hypromellose 2910 hypromellose 2906
  • hypromellose 2208 also known as Methocel K4M
  • aminoalkyl methacrylate copolymers e.g.
  • Eudragit RL100, RL PO or RS PO carbomer homopolymer Type A (e.g. Carbopol 971 P), carbomer homopolymer Type B (e.g. Carbopol 974P) , sodium dodecyl sulfate, d-alpha-tocopherol acid polyethylene glycol 1000 succinate (TPGS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus) and poloxamers (e.g. Pluronics, Lutrol 68, Lutrol F127, Kolliphor).
  • TPGS d-alpha-tocopherol acid polyethylene glycol 1000 succinate
  • Soluplus polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer
  • poloxamers e.g. Pluronics, Lutrol 68, Lutrol F127, Kolliphor
  • Hydroxypropyl methylcellulose and hypromellose within this definition, may also function as stabilizing agent, however, that would apply when they are present in the compositions but resides outside the solid dispersion particles.
  • the terms "polymer” or “polymeric” is here used to mean a compound that exhibits a polymeric structure, i.e. several monomers which have the same or similar structure which are covalently connecting to each other to form a larger structure, e.g. a polymeric chain that may be unbranched (straight) or branched.
  • a polymer generally consists of 20 or more monomers connected together, however less that 20 monomers connected together are here also referred to as polymers.
  • solubilizer a pharmaceutically acceptable detergent, such as an ionic, anionic, cationic, amphiphilic or non-ionic component.
  • the solubilizer may be a detergent devoid of polymeric structure or a detergent exhibiting a polymeric structure (surface active polymer), which preferably help to further improve the dissolution rate of the active agent.
  • the solubilizer may prevent emulsification of the active ingredient released from the pharmaceutical composition and/or prevent precipitation of the active ingredient(s) in the aqueous fluids of the small intestine tract.
  • a single solubilizer as well as a combination of two or more solubilizers may be used.
  • Solubilizers of the invention include but are not limited to polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (Soluplus), d-a-tocopherol acid polyethylene glycol 1000 succinate (TPGS), PEG-40 hydrogenated castor oil (Cremophor RH40), PEG-35 castor oil (Cremophor EL), PEG-40 stearate (MYRJ 540), hard fat (e.g. Gelucire 33/01 ), polyoxylglycerides (e.g. Gelucire 44/14), stearoyl polyoxylglycerides (e.g.
  • Solubilizers above may also function as dispersing components in the invention.
  • the solubilizer may be included in the solid dispersion particles, or may be included outside the particles as such but within the compostion.
  • stabilizing agent a pharmaceutically acceptable recipient that stabilizes the solid dispersion particles containing tadalafil.
  • Stabilizing agents of the invention include, but are not limited to, hypromellose, such as methylcellulose USP, hypromellose 2910, hypromellose 2906 and hypromellose 2208 (also known as Methocel K4M); ethylcellulose, such as ethylcellulose 10cP (also known as Ethocel standard 10 premium), paraffin, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, glyceryl behenate and talc.
  • AUC area under the curve
  • % solubilized at XX min such as “% solubilized at 60 min” is meant the concentration of tadalafil in solubilized form at a certain time, such as 60 minutes.
  • PVAP polyvinyl acetate phthalate
  • PVP 30K refers to polyvinylpyrrolidone K-30.
  • HPMCP-AS refers to hydroxypropyl
  • HPMCP HP55 refers to hydroxypropyl methyl cellulose phthalate.
  • PDLG refers to DL lactide/glycolide copolymer
  • PDL poly DL-lactide
  • the dissolution mediums used for purposes of this invention are Fasted State Simulated Intestinal Fluid, referred to as FaSSIF, Fed State
  • FaSSIF media is tailored to represent a fasting state and has a pH of about 6.5 as well as specific osmolaric properties.
  • FeSSIF media is tailored to represent a fed state and has a pH of about 5 as well as specific osmolaric properties.
  • SGF is tailored to represent gastric fluid and has a pH of about 1.4 as well as specific osmolaric properties.
  • FaSSIF, FeSSIF and SGF media are generally used in in vitro models for dissolution of poorly water-soluble drugs. The choice of solution will be dependent on where in the small intestine tract and under what conditions (fasted or fed) the composition is desired to dissolve and be taken up.
  • amorphous form non-crystalline solid form.
  • the ease of dissolution may at least in part be attributed to the amount of energy required for dissolution of the components from a crystalline or amorphous solid phase.
  • Amorphous particles require less energy for dissolution as compared to crystalline particles of the same compound.
  • the amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X-Ray Powder Diffraction (XRPD) as described elsewhere in the present disclosure.
  • XRPD X-Ray Powder Diffraction
  • the term tadalafil as used herein is intended to encompass hydrates, solvates (alcoholates), N-oxides, pharmaceutically acceptable acid or base salts of tadalafil.
  • the solid dispersions included in the pharmaceutical compositions of the present invention typically comprises particles ("solid dispersion particles"), which are amorphous, partly amorphous, partly crystalline or crystalline forms.
  • the amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X-Ray Powder Diffraction (XRPD) as described elsewhere in the present disclosure.
  • solid dispersion particles containing drugs e.g. granulation, melt extrusion, spray drying, precipitation etc. all of which typically encompass starting with formation of a mixture in which tadalafil and the dispersing component are evenly distributed.
  • Potentially most of these processes can be used for manufacturing solid dispersion particles to be used in the present invention, i.e. a particular method can be used as long it enables
  • composition of the invention in which tadalafil has dissolution characteristics as described for the present invention elsewhere in the present disclosure.
  • Methods forming solid dispersion particles by precipitation are preferred based on results so far obtained.
  • Most of the methods given in the preceding paragraph are known to be performed in a batch mode or in a continuous mode where the latter in most cases are preferred, in particular if solid dispersion particles to be used in the present invention are to be manufactured.
  • Continuous processes in this context means that particle formation is continuously ongoing while at the same time continuously withdrawing/collecting/ retaining solid dispersion particles from the mixture after their formation. In the preferred methods, i.e.
  • the dispersing component may be present in either one or both of the two fluids or in a separate third fluid stream depending on its solubility characteristics.
  • the mixing of the two fluids is taking place in a mixing function, e.g. a mixing chamber.
  • the mixing function typically is associated with a particle formation and separation function permitting the mixed fluid stream to pass through while retaining the solid dispersion particles.
  • Agents modifying the particle characteristics without being incorporated into the particles may be added to either of the fluids before the mixing step.
  • the fluids typically are conventional liquids or supercritical fluids, where supercritical fluids also includes subcritical fluids (i.e. fluids for which only one of pressure and temperature is above its supercritical value).
  • supercritical fluids also includes subcritical fluids (i.e. fluids for which only one of pressure and temperature is above its supercritical value).
  • Typical combinations are a) conventional liquids for both the solution of tadalafil and the antisolvent, b) supercritical solution of tadalafil combined with conventional liquid for the anti-solvent, c) conventional liquid for the solution of tadalafil combined with supercritical fluid for the anti-solvent, and d) supercitical fluids for both of the two fluids.
  • the anti-solvent may be omitted.
  • a fluid stream, preferably supercritical, containing both tadalafil and the dispersing component is then allowed to expand into the particle formation function. It is preferred that at least one of the fluids is in a supercritical state in the precipitation methods described above. These kinds of precipitation methods are thoroughly discussed in WO 2005061090 (Censdelivery AB), WO 2009072950 (XSpray Microparticles AB), WO 2009072953 (XSpray Microparticles AB), WO 201 1 159218 (XSpray Microparticles AB) and references cited in these publications.
  • anti-solvent in this specification primarily refers to a fluid which is capable of precipitating tadalafil from a solution containing the tadalafil when mixed with the solution.
  • anti-solvent also applies to a liquid which is capable of precipitating a dispersing component from a solution containing this component.
  • solution encompasses that the solute is either a true solute or minutes particles of colloidal dimensions and less than the particles to be produced.
  • a preferred particle formation system is the "Right Size system” developed by XSpray microparticles AB, Sweden. A detailed description of the technology can be found in the WO-publications given in the preceding paragraph. An important characteristic of the system is that the two fluid streams should merge within a nozzle at an angle in the interval 45°-135°, with preference for about 90° and sprayed into a particle
  • the system allows for producing particles of predetermined size and/or morphology.
  • the Right Size system and apparatus will be described using the non-limiting example of using tadalafil in the form of a liquid solution and CO2 as anti-solvent for tadalafil.
  • the dispersing component may then be present in either one or both of the tadalafil solution and the anti-solvent fluid depending on the solubility
  • This basic system consists of one pumping set-up for the tadalafil dissolved in a liquid solvent and one pumping set-up for an anti-solvent, for example CO2, however other anti-solvents may be used when suitable.
  • Each pumping set-up includes instruments such as a flow meter and a pressure meter that are used to control the process conditions. These two pumping set-ups are fluidically connected at a spray nozzle.
  • a stream of tadalafil solution is mixed with a stream of CO2 under flow conditions within the spray nozzle.
  • the mixed stream is then sprayed at the outlet of the nozzle into a precipitation vessel under controlled conditions (typically pressure and temperature).
  • CO2 acts as an anti- solvent.
  • Tadalafil precipitates to form an essentially amorphous phase and/or an essentially crystalline phase dispersed within a carrier matrix, which during the process is formed as fine particles containing the matrix. Particles are retained in the vessel by a filtering set-up.
  • a back pressure regulator is typically used to control the pressure inside the precipitation vessel.
  • a pumping set-up control is set up for the modifier and the modifier is mixed with the CO2 in a mixer before entering the nozzle.
  • the system operator When using the system, the system operator typically starts with equilibrating the system by pumping CO2, an "tadalafil-like solution" (a solution similar in composition to the tadalafil solution but containing no tadalafil, no dispersing component,and no excipient) and the modifier (if used) through the system until flow rates, pressure and temperature have reached a desired steady state.
  • Critical parameters for setting up the system are tadalafil solution composition, tadalafil solution flow rate, CO2 flow rate, CO2 pressure and temperature, nature and
  • the "tadalafil-like solution" is exchanged for the tadalafil solution and particles are produced and retained downstream of the mixing, e.g.
  • the system is typically cleaned by pumping the "tadalafil-like solution" through the system.
  • the particles are dried by flushing CO2 through the retained particles in order to extract any remaining solvent.
  • the precipitation vessel is then
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising solid dispersion particles containing tadalafil and at least one dispersing component; which composition optionally further comprises at least one pharmaceutically acceptable solubilizer.
  • said dispersing component is a polymeric dispersing component.
  • said solid dispersion particles are prepared by a solid dispersion process using CO2 as antisolvent.
  • Such solid dispersion particles may be produced by a process utilizing CO2, for the formation of solid dispersion particles containing tadalafil and the dispersing component, as discussed in this specification.
  • said dispersing component in said solid dispersion particles is a pharmaceutically acceptable polymer selected from methacrylate acid and methyl methacrylate copolymer, d- alpha-tocopherol acid polyethylene glycol 1000 succinate, methyl cellulose, polyethylene glycol, hypromellose acetate succinate,
  • said dispersing component is selected from polyvinylpyrrolidone, polyvinyl acetate phthalate, DL lactide/glycolide copolymer and poly DL-lactide.
  • the weight ratio (w/w) between tadalafil and the polymeric dispersing component varies, typically from about 1 : 1000 to about 100: 1 , such as from about 1 :100 to about 100: 10.
  • said weight ratio is from about 1 :20 to about 20: 1 , such as from about 1 :6 to about 6: 1 .
  • said weight ratio is from about 1 :5, to about 1 :3.
  • tadalafil in said solid dispersion particles is present in amorphous form.
  • the polymeric dispersing component is selected from polyvinylpyrrolidone and polyvinyl acetate phthalate, more preferably polyvinylpyrrolidone.
  • both tadalafil and said dispersing component is present in amorphous form.
  • At least one stabilizing agent is added.
  • said at least one stabilizing agent is present outside the solid dispersion particles but within the composition.
  • said at least one stablilizing agent is selected from hypromellose, ethylcellulose, paraffin, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, glyceryl behenate and talc.
  • two stabilizing agents are added, said agents being hypromellose and ethylcellulose.
  • both tadalafil and said dispersing component is present in amorphous form after one month of storage, such as after one month of storage in 30°C and 60% relative humidity.
  • a composition which produces a solubility increase of tadalafil in a dissolution medium, said increase measured as the area under the curve (AUC) during 60 to 90 minutes, in said dissolution medium and compared with the AUC obtained with tadalafil in crystalline, raw form in said dissolution medium. Said increase may be from to about 2: 1 to about 100: 1 , or more, wherein 1 represents AUC obtained with tadalafil in crystalline, raw form.
  • a composition which provides at least 20% solubilized tadalafil after 20 minutes as measured in a dissolution medium.
  • composition which provides at least 40% solubilized tadalafil after 20 minutes as measured in a dissolution medium.
  • percentage of solubilized tadalafil after the times may also refer to the solid dispersion particles as such, not only tadalafil.
  • a composition wherein tadalafil, in said particles, is present, at least partly, in crystalline form.
  • said polymeric dispersing component, in said particles is selected from polyvinyl acetate phthalate, polyvinylpyrrolidone, poly DL- lactide and DL lactide/glyco!ide copolymer. More preferably, said polymeric dispersing component, in said particles, is polyvinyl acetate phthalate.
  • Multilayer tablets may be advantagous if it is desired to deliver tadalafil or at least one other active agent in combination with tadalafil, in one tablet. Multilayer tablets may further be advantagous if it is desired to control the release characteristics of the active agent(s).
  • an outer layer may compise an initial dose by including the active agent into one of the outer layer while inner layers comprise an maintainance dose which is release slowly.
  • the dissolution characteristics of the inner and outer layers may be varied as desired by choosing different agents and/or solubilizers within and between the layers.
  • the in vitro test conditions mimic the in vivo environment as closely as possible, for example pH and osmolarity.
  • the pH is between 6 and 7. Therefore, the solution may hold a pH from about pH 6 to about pH 7, such as about pH 6.5.
  • the solution has a pH from about pH 1 to about pH 8, such as about pH 6.5, such as about pH 5, or such as about pH 1 .4.
  • composition wherein the dissolution medium represents a Fasted Simulated State Intestinal Fluid (FaSSIF).
  • Fasted Simulated State Intestinal Fluid Fasted Simulated State Intestinal Fluid
  • the solution may hold a pH from about pH 4.5 to about pH 6, such as about pH 5.
  • the dissolution medium represents a Fed Simulated State
  • Intestinal Fluid typically, for gastric uptake, the pH is between 1 and 2. Therefore, the solution may hold a pH from about pH 1 to about pH 2, such as about pH 1 .4.
  • composition wherein the dissolution medium represents a Simulated Gastric Fluid (SGF).
  • SGF Simulated Gastric Fluid
  • dissolution medium will be dependent on where in the small intestine tract and under what conditions (fasted or fed) the composition is desired to dissolve and be taken up. Recepies and preparation of these solutions are available by the manufacturer (e.g. biorelevant.com, United Kingdom).
  • a solubihzer present in the composition may be an integral part of the solid dispersion particles possibly acting as a dispersing component, or be separate from the particles.
  • composition wherein said solubihzer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer and d-alpha-tocopherol acid polyethylene glycol 1000 succinate.
  • solubilizer is polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol copolymer.
  • the amount of tadalafil in the solid dispersion particles is from 5% by weight to about 50% by weight, from 10% by weight to about 40% by weight, from about 10% by weight to about 30% by weight, such as about 25%.
  • compositions wherein the solid dispersion particles has an average particle size of less than about 5000 nm. In another embodiment of this aspect, there is provided a composition, wherein the solid dispersion particles has an average particle size of less than about 1000 nm, preferably less than 500 nm. Other particle sizes may be convenient for specific applications.
  • the solid dispersion particles may be present as agglomorates, i.e. to larger particles each of which comprises several primary particles.
  • composition of the invention for use in therapy.
  • composition of the invention in for use in the treatment of a disease selected from
  • composition of the invention for use in the treatment of sexual dysfunction, such as male erectile dysfunction or female sexual arousal disorder.
  • composition of the invention, for use, wherein said composition is provided during food intake.
  • compositions of the invention are formulated for oral administration, such as wherein said composition is administered with amounts of up to a maximum of 40 mg tadalafil per day.
  • said composition may be administered with amounts of up to a maximum of 20 mg tadalafil per day.
  • vasospasms a composition of the invention.
  • a method of treating a patient suffering from sexual dysfunction comprising administering to a patient in need thereof, a therapeutically effective amount of a composition of the invention.
  • said sexual dysfunction is selected from male erectile dysfunction or female sexual arousal disorder.
  • tadalafil in the compositions of the present invention required for use in treatment will vary with the route of administration, the nature of the condition for which treatment is required and the age, weight and condition of the patient and will be ultimately at the discretion of the attendant physician. In general however a suitable dose may be in the range of from about 0.005 to about 80 mg/kg of body weight per day, preferably in the range of 0.5 to 10 mg/kg/day.
  • the desired dose is conveniently presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
  • the desired dose may also be, for example, once every two days, once every three days, or even once a week.
  • composition is conveniently administered in unit dosage form; for example containing 0.5 to 500 mg, conveniently 1 to 100 mg, most conveniently 5 to 75 mg of tadalafil per unit dosage form.
  • compositions of the invention will normally be administrated via the orally, or by parenteral, intravenous, intramuscular, subcutaneous or other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in a pharmaceutically acceptable dosage form.
  • compositions may be administered at varying doses.
  • compositions include but are not limited to those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compositions may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy.
  • Pharmaceutical compositions suitable for oral administration are conveniently presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of tadalafil.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • the compositions of the invention may be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents.
  • compositions may be adapted to give sustained release of tadalafil.
  • the following examples are provided to illustrate various embodiments of the present invention and shall not be considered as limiting in scope.
  • T represents tadalafil
  • P represents the polymeric dispersing component
  • T+P represents a physical mix of raw, crystalline tadalafil with the polymeric dispersing component
  • T/P represents a solid dispersion product of tadalafil and the polymeric dispersing component
  • the method consists of adding the wished amount of powder into a glass vial and then pouring in it the appropriate medium (typically FaSSIF or SGF).
  • the medium was prepared in accordance with the manufacturer's instructions (biorelevant.com, United Kingdom).
  • the amount of powder added depends on the wished "total tadalafil concentration". For some experiments where powders with high drug loads were tested and compared, the real amount of tadalafil in the solid dispersion was not taken in account. For other experiments, the drug load was first estimated by HPLC and the amount of powder to obtain the drug concentration was calculated.
  • the powder was added in a 8 ml_ glass bottle and 7 ml_ of solution was added (typically FaSSIF or SGF) and were put on a shaker (approximately 1 rotation per minute) for dissolution. Samples of 500 ⁇ where taken after different times, and subsequently centrifuged at approximately 15000 g for 3 minutes. The resulting supernatant was then analyzed by HPLC (C-ie column Eclipse, 4.6 mm x 15 cm, 1 ml_/min, detection at 270 nM). Generally samples were taken after 5, 30 and 90 min and eventually 150 min.
  • HPLC C-ie column Eclipse, 4.6 mm x 15 cm, 1 ml_/min, detection at 270 nM
  • compositions were prepared as follows:
  • tadalafil (T) and polymeric dispersing component (P) were diluted in TFE or a DMSO/TFE mixture.
  • the resulting tadalafil solution was subsequently precipitated by using CO2 as antisolvent as described above.
  • Tadalafil solution and CO2 were pumped respectivelty at 1 ml/min and 100 g/min through a lab size XSpray's RigthSize noozle. The temperature and pressure of the process are given in the tables below.
  • the powder produced was collected and its drug load was determined by HPLC analysis.
  • the amount or grade of amorphous form or crystalline form in the solid dispersion particles were measured by X-Ray Powder Diffraction (XRD).
  • X-Ray Powder Diffraction (XRD) experiments were XRD experiments were run on a MiniFlex 600 diffractometer (Rigaku Corporation, Tokyo, Japan) set in Bragg-Brentano geometry.
  • the diffractometer was equipped with a 5.0 deg incident soller slit, 1 .25 deg divergence slit, 5.0 deg reciving soller slit and a high 1 D speed silicon strip detector, D/teX Ultra.
  • a representative sample was placed on a zero background quarts single crystal specimen support with a 10.0 mm x 0.2 mm cavity (Rigaku Corporation, Tokyo, Japan).
  • Experiments were run using Cu Ka radiation (40kV and 15 mA) at ambient temperature and humidity.
  • Scans were run in continuous mode in the range 2-40° 2D using a scan speed of 0.4 deg/min and step size of 0.02 deg. Data collection was done using instrument control software MiniFlex Guidance version 1 .2.01 and pattern analysis was done using PDXL 2 version 2.1 .2.0 (all software being from Rigaku Corporation, Tokyo, Japan).
  • Example 1 Compositions with tadalafil - solubility at pH 6.5.
  • FaSSIF dissolution medium Representative results in FaSSIF dissolution medium are provided below in Table 1 and 2, where Table 1 provides data of concentration of tadalafil (mg/L) after 3, 20, 45 and 90 minutes dissolution, whereas Table 2 provides data of the Area Under the Curve (AUC - mg/min/L) during 90 minutes dissolution and the AUC increase of compositions and percentage solubilized tadalafil after 90 minutes dissolution compared to tadalafil in raw form added to the dissolution medium (experiments 1 -9 and 21 -22).
  • Table 1 provides data of concentration of tadalafil (mg/L) after 3, 20, 45 and 90 minutes dissolution
  • Table 2 provides data of the Area Under the Curve (AUC - mg/min/L) during 90 minutes dissolution and the AUC increase of compositions and percentage solubilized tadalafil after 90 minutes dissolution compared to tadalafil in raw form added to the dissolution medium (experiments 1 -9 and 21
  • Example 2 Compositions with tadalafil - solubility at pH 1.4.
  • Table 3 provides data of concentration of tadalafil (mg/L) after 7, 20, 40 and 60 minutes dissolution
  • Table 4 provides data of the Area Under the Curve (AUC - mg/min/L) during 60 minutes dissolution, percentage solubilized tadalafil after 60 minutes dissolution and the AUC increase of compositions, compared to tadalafil in raw form added to the dissolution medium (experiments 1 1 -19 and 23-24).
  • Table 3 provides data of concentration of tadalafil (mg/L) after 7, 20, 40 and 60 minutes dissolution
  • AUC Area Under the Curve
  • Example 3 Composition of granules with Tadalafil / PVP 30K solid dispersion particles and stabilizing agents their stability
  • the compositions are as set out in Table 5.
  • XRD X-Ray Powder Diffraction
  • the diffractometer was equipped with a 5.0 deg incident soller slit, 1 .25 deg divergence slit, 5.0 deg reciving soller slit and a high 1 D speed silicon strip detector, D/teX Ultra.
  • a representative sample was placed on a zero background quarts single crystal specimen support with a 10.0 mm x 0.2 mm cavity (Rigaku Corporation, Tokyo, Japan).
  • Experiments were run using Cu Ka radiation (40kV and 15 mA) at ambient temperature and humidity. Scans were run in continuous mode in the range 2-40° 2D using a scan speed of 0.4 deg/min and step size of 0.02 deg.

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant des particules de dispersion solide contenant du tadalafil et un composant dispersant; laquelle composition comprend en outre de manière facultative un agent de solubilisation pharmaceutiquement acceptable. En outre, la présente invention concerne une méthode de traitement de troubles chez un patient nécessitant un tel traitement, qui consiste à administrer une quantité thérapeutiquement efficace de ladite composition.
PCT/SE2013/050807 2012-06-28 2013-06-27 Compositions pharmaceutiques comprenant des particules de dispersion solide contenant du tadalafil WO2014003677A1 (fr)

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WO2015000853A1 (fr) * 2013-07-05 2015-01-08 Synthon B.V. Composition pharmaceutique comprenant une dispersion solide de tadalafil
EP3466951A1 (fr) 2014-07-23 2019-04-10 KRKA, d.d., Novo mesto Procédé de préparation d'inhibiteur de cgmp-phosphodiestérase et formulation pharmaceutique orale comprenant des co-précipités de tadalafil
WO2019154896A1 (fr) * 2018-02-07 2019-08-15 Sapiotec Gmbh Formulations pharmaceutiques, procédé de fabrication d'une formulation pharmaceutique et médicament comprenant une telle formulation pharmaceutique
CN114028349A (zh) * 2021-10-12 2022-02-11 南京恒正药物研究院有限公司 一种他达拉非口崩片
US11633536B2 (en) 2014-12-04 2023-04-25 Medtronic Minimed, Inc. Advance diagnosis of operating mode viability
CN117257804A (zh) * 2023-10-17 2023-12-22 深圳市新阳唯康科技有限公司 达拉非尼药物组合物及其制备方法和应用

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WO2015000853A1 (fr) * 2013-07-05 2015-01-08 Synthon B.V. Composition pharmaceutique comprenant une dispersion solide de tadalafil
EP3466951A1 (fr) 2014-07-23 2019-04-10 KRKA, d.d., Novo mesto Procédé de préparation d'inhibiteur de cgmp-phosphodiestérase et formulation pharmaceutique orale comprenant des co-précipités de tadalafil
US11633536B2 (en) 2014-12-04 2023-04-25 Medtronic Minimed, Inc. Advance diagnosis of operating mode viability
WO2019154896A1 (fr) * 2018-02-07 2019-08-15 Sapiotec Gmbh Formulations pharmaceutiques, procédé de fabrication d'une formulation pharmaceutique et médicament comprenant une telle formulation pharmaceutique
CN112040984A (zh) * 2018-02-07 2020-12-04 斯码瓦有限公司 药物制剂、制备药物制剂的方法和包含其的药物
CN114028349A (zh) * 2021-10-12 2022-02-11 南京恒正药物研究院有限公司 一种他达拉非口崩片
CN117257804A (zh) * 2023-10-17 2023-12-22 深圳市新阳唯康科技有限公司 达拉非尼药物组合物及其制备方法和应用

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