WO2019074464A2 - The pharmaceutical combination comprising dapoxetine and phosphodiesterase type-5 - Google Patents

The pharmaceutical combination comprising dapoxetine and phosphodiesterase type-5 Download PDF

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Publication number
WO2019074464A2
WO2019074464A2 PCT/TR2018/050568 TR2018050568W WO2019074464A2 WO 2019074464 A2 WO2019074464 A2 WO 2019074464A2 TR 2018050568 W TR2018050568 W TR 2018050568W WO 2019074464 A2 WO2019074464 A2 WO 2019074464A2
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weight
capsule
pharmaceutical combination
pharmaceutically acceptable
polymorph
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PCT/TR2018/050568
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French (fr)
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WO2019074464A3 (en
Inventor
Ali TÜRKYILMAZ
Arzu Palantöken
Dicle Güner
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Montero Gida Sanayi Ve Ticaret Anonim Sirketi
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Priority to EP18865578.1A priority Critical patent/EP3694519A4/en
Publication of WO2019074464A2 publication Critical patent/WO2019074464A2/en
Publication of WO2019074464A3 publication Critical patent/WO2019074464A3/en

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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
    • A61K9/48—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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/501—Inorganic compounds

Definitions

  • the present invention relates to pharmaceutical combination comprising dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and a PDE-5 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof having a release profile comprises both immediate release and modified release.
  • Selective serotonin reuptake inhibitors are used in the long-term prophylaxis of many types of depression, including the endogenous type, recurrent depression, and in the treatment of obsessive-compulsive disorders, panic attack, social phobias, and the bulimia nervosa disease.
  • Dapoxetine which was first disclosed in the European patent publication EP 0288188 B1 is a selective serotonin reuptake inhibitor. Dapoxetine is used for the treatment of depression and premature ejaculation. Its chemical name is (S)-N, N-Dimethyl- 3-(naphthalen-1 -yloxy)-1 -phenylpropan-1 -amine and has a chemical structure shown with Formula I. Additionally, dapoxetine was first approved in Sweden and in Finland for use in the treatment of premature ejaculation.
  • dapoxetine is rapidly absorbed and rapidly enters the circulation by almost completely binding to plasma proteins. Therefore, it achieves the peak plasma concentration (C max ) in 1 hour following oral administration.
  • Orally-administered tablets of dapoxetine are commercially available under the name Priligy®, comprising 30 mg or 60 mg dapoxetine per tablet, as well as excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide (E171 ), triacetin, black iron oxide (E172) and yellow iron oxide (E172).
  • PDE5 inhibitor phosphodiesterase type 5 inhibitors
  • ED erectile dysfunction
  • PDE5 inhibitors block the phosphodiesterase enzyme in a selective and efficient manner, thus increasing the level of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum smooth muscle cells.
  • cGMP cyclic guanosine monophosphate
  • Most frequently used PDE5 inhibitors are avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil.
  • Tadalafil is a PDE5 inhibitor used in the treatment of ED and Pulmonary Arterial Hypertension (PAH). It has a longer half-life as compared to other PDE5 inhibitors (mean, 17,5 hours).
  • Orally-administered tablets of Tadalafil are commercially available under the name Cialis®, in the strength of 2.5 mg, 5 mg, 10 mg and 20 mg, as well as excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide (E171 ), triacetin, yellow iron oxide (E172), talc.
  • tadalafil (6R-trans)-6-(1 ,3-benzodioxol-5-yl)- 2,3,6,7,12, 12a-hexahydro-2-methyl-pyrazino [1 ',2':1 ,6] pyrido[3,4-b] indole-1 ,4-dione, with the chemical structure illustrated below with Formula II.
  • Tadalafil Formulations comprising a combination of selective serotonin reuptake inhibitors with PDE5 inhibitors are known in the prior art.
  • a formulation comprising a combination of phosphodiesterase inhibitors and dapoxetine.
  • dapoxetine and tadalafil mostly in oral pharmaceutical dosage forms. However, these active agents do not show a similar release profile.
  • dapoxetine The release rate of dapoxetine is quicker than tadalafil and the drug elimination rate in the serum is also fast, but tadalafil have short T-max, which means that the exhibition of the medicinal effects is fast, and have long half-life, showing extended time of the medicinal effect.
  • dapoxetine and tadalafil are used together there has been inconveniences, due to the difference of the duration of these effects, such as they have to be taken at different times to get the combined effect, or there's a discrepancy of the expression of the effects due to the difference of the duration of the effects when they are taken at the same time.
  • the pharmaceutical combination of this present invention is able to match the combination of dapoxetine with short half-life and tadalafil with a long half-life, by including two different release profile which are the immediate release and the modified release in tablet or capsule.
  • two different release profile which are the immediate release and the modified release in tablet or capsule.
  • Main object of the present invention is to provide a pharmaceutical formulation that allows to obtain safe and efficient plasma levels of each pharmacological agents in desired duration.
  • the present invention relates to an easily-administrable combination of dapoxetine and PDE5 inhibitor or their pharmaceutically acceptable salt, solvate or polymorph, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.
  • combination means that when drugs are administered together, a combined action is obtained which is higher than the individual actions of the respective drugs when they are used separately.
  • using a lower dose of each drug to be combined according to the present invention will reduce the total dosage.
  • the dosages have not to be relatively less in all cases, but the drugs can be dosed less frequently or this may be beneficial in reducing the recurrence rate of side effects. These are advantageous in terms of patients to be treated.
  • modified release phase refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
  • immediate release phase refers to any pharmaceutical formulations that disintegrate rapidly after administration with enhanced rate of dissolution and get dissolved to release the medicaments.
  • neutral pellet refers drug free cores which can be coated by a solution or suspension of API with a binding agent. Also, it is known that preparing the formulations of two different actives having different release profiles is difficult to process and may require complex design of tablet, capsule formulations. Accordingly, it is required to show the release profiles at the same time to eliminate the undesired side effects. Thus, it is important to provide the efficiency of the formulation by providing a tablet or capsule formulation which helps to dissolve the both actives in same manner and same time.
  • a pharmaceutical combination formulation comprises dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and a PDE5 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein the formulation comprises both immediate release and modified release.
  • compositions can be made in one, two or three parts, or having core or different forms wherein at least one part is modified release formulation and at least one part is immediate release formulation in an oral administration.
  • Modified release formulations can be preferred. Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof.
  • both of modified release phase and immediate release phase may comprise dapoxetine and , further comprises at least one pharmaceutically acceptable excipient.
  • the ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 10:1 to 1 :10 by weight or 7:1 to 1 :7 by weight or 5:1 to 1 :5 by weight.
  • a PDE5 inhibitor is selected from the group comprising tadalafil, sildenafil, avanafil, lodenafil, mirodenafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil or mixtures thereof.
  • PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil.
  • the ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof to PDE5 inhibitor is in the range of between 30:1 to 1 :30 by weight.
  • the pharmaceutical combination administered orally is administered orally.
  • the pharmaceutical combination is in the form of capsule, tablet, strip, syrup, powder, pastilles, sachet, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions, emulsions or mixtures thereof.
  • the pharmaceutical combination is formulated as tablets including compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles.
  • the pharmaceutical combination is formulated as tablet. Tablet may comprise of different type of particles, for example; mini-tablets, pellets, granules, powders or mixtures thereof.
  • each type of particle comprises at least one active agent.
  • One embodiment of this present invention is directed to tablet coating, it can be applied, for example by spray-coating with a water-based film coating formulation.
  • An embodiment of this present invention the pharmaceutical combination is formulated as capsule. Capsule dosage form masks the bitter taste of dapoxetine as a result patient compliance is increased.
  • capsule dosage form can be prepared in capsule dosage form.
  • Capsule may comprise of different type of particles, for example; mini-capsules, mini- tablets, pellets, granules, powders or mixtures thereof.
  • the dosage unit form of dapoxetine and a PDE5 inhibitor or their pharmaceutically acceptable salt, solvate or polymorph is selected from mini-capsules, powders, granules, mini-tablets, pellets, beads or mixtures thereof and these dosage forms are filled into capsules.
  • the form of formulation is mini-capsule in capsule wherein the mini capsule comprises at least one active agent. Mini-capsule is located within a capsule.
  • the form of formulation is mini-tablets in capsule wherein a mini-tablet comprises at least one active agent. Mini-tablets is located within a capsule.
  • the form of formulation is pellet in capsule wherein pellet comprises at least one active agent.
  • Pellet is located within a capsule.
  • the form of formulation is powder in capsule. Powder is located within a capsule.
  • An embodiment of this present invention is to combine dapoxetine and PDE5 inhibitor agent in stable dosage form with desired dissolution profiles in capsule form.
  • the combination comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, diluents, dispersing agents, surfactant, modified release agents, lubricants, glidants, plasticizers, preservatives, sweeteners, flavorings, melting components, inert agents, stabilizers, antioxidants, coating agents, buffering agents, coloring agents or mixtures thereof.
  • Suitable fillers are selected from group comprising ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, sugars, glycose syrup, natural gums, gelatin, collagene, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, starch, corn starch, pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, liquid glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide,
  • Suitable disintegrants are selected from the group comprising polyvinilpyrrolidone, crospovidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion- exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate or mixtures thereof.
  • Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • Suitable dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.
  • Suitable surfactans are selected from the group comprising sodium lauryl sulfate, cetylpyridinium chloride, docusate sodium, lauric acid, polyoxyethylene sorbitan fatty acid esters (polysorbate), phospholipids, cetrimide or mixtures thereof.
  • Suitable modified release agents are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, pectin, polyglucoronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, lamb
  • the amount of the modified release agent is between 5.0% to 30.0% by weight.
  • modified release agents preferably are HPMC K100M or HPMC E4M, they can be used together or separately.
  • modified release agents is polyvinyl acetate or glyceryl behenate, they can be used together or separately.
  • modified release agents is Eudragit RS or Eudragit RL, they can be used together or separately.
  • Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, talc, waxe, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • the amount of the lubricant is between 0.1 % to 2.0% by weight.
  • Suitable glidants are selected from the group comprising talc, aluminium silicate, colloidal silicon dioxide, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof. At the present invention, the amount of the glidant is between 0.1 % to 5.0% by weight.
  • Suitable plasticizers are selected from the group comprising polyethylene glycols of different molecular weights, triacetin, tributyl citrate, triethyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols, propylene glycol or mixtures thereof.
  • Suitable preservatives are selected from the group comprising methyl paraben, propyl paraben and their salts (such as sodium, potassium), sodium benzoate, benzyl alcohol, citric acid, benzoic acid, m-cresol, phenol or mixtures thereof.
  • Suitable sweeteners are selected from the group comprising aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, polymethacrylates, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose or sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
  • Suitable flavoring agents are selected from the group comprising menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof.
  • Suitable melting components are selected from the group comprising gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene-polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylated monoglyceride, butil pthalybutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethly phthalate, ethyl phthalylethly glycolate, glycerin, propylene glycol, triacetin, triacetin citrate, tripropionin or mixtures thereof.
  • Suitable inert agents are located between the two molecules wherein the inert agent is selected from starch, lactose, sugar alcohol like D-mannitol, erythritol; lowsubstituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof.
  • Suitable stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof.
  • Suitable antioxidants are selected from the group comprising alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), erythorbic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium metabisulfite, sodium sulfite, thymol or mixtures thereof.
  • Suitable coating agent are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof or mixtures thereof.
  • the amount of the coating agent is between 2.0% to 40.0% by weight.
  • Suitable buffering agents are selected from the group comprising alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof.
  • the buffering agent is preferably citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate, glutamic acid or mixtures thereof.
  • Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
  • FD&C Food, Drug & Cosmetic
  • the tablets can be coated with coating agents, and mixtures of sweeteners or flavours have been used for masking the bitter taste.
  • the pharmaceutical composition of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • Example 1 the formulation comprising dapoxetine, a PDE5 inhibitor in tablet composition
  • Example 2 the formulation comprising dapoxetine and tadalafil in tablet composition
  • Agents Amount (% by weight of the total)
  • microcrystalline cellulose 5% to 50%
  • colloidal silicon dioxide 0.1 % to 5%
  • step (a) adding step (a) mixture to step (b) mixture and granulating
  • Example 3 the formulation comprising dapoxetine and tadalafil in bilayer tablet composition
  • Agents Amount (% by weight of the total) dapoxetine or a pharmaceutically acceptable 5% to 25%
  • microcrystalline cellulose 5% to 50%
  • colloidal silicon dioxide 0.1 % to 5%
  • step(a) Dissolving polyvinylpyrrolidone and sodium lauryl sulfate in water and granulating with step(a) mixture
  • both of modified release phase and immediate release phase may comprise dapoxetine and further comprises at least one pharmaceutically acceptable excipient.
  • the ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 5:1 to 1 :5 by weight.
  • Example 4 the formulation comprising dapoxetine and tadalafil in bilayer tablet composition
  • step(a) Dissolving polyvinylpyrrolidone and sodium lauryl sulfate in water and granulating with step(a) mixture
  • both of modified release phase and immediate release phase may comprise dapoxetine and further comprises at least one pharmaceutically acceptable excipient.
  • the ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 5:1 to 1 :5 by weight.
  • Example 5 the formulation comprising dapoxetine and tadalafil in bilayer tablet composition
  • Agents Amount (% by weight of the total)
  • Tadalafil or a pharmaceutically acceptable salt 1 % to 10% solvate or polymorph thereof
  • both of modified release phase and immediate release phase may comprise dapoxetine and further comprises at least one pharmaceutically acceptable excipient.
  • the ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 5:1 to 1 :5 by weight.
  • Example 6 the formulation comprising dapoxetine and tadalafil in capsule composition
  • Agents Amount (% by weight of the total)
  • Example 7 the formulation comprising dapoxetine and tadalafil in capsule composition
  • Process for example 7 a) Adding triethyl citrate, dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof, modified release agents with certain amount of water in homogenizer and mixing
  • step(d) Dissolving polyvinylpyrrolidone and sodium lauryl sulfate in water and granulating with step(d) mixture and drying, then sieving
  • Example 8 the formulation comprising dapoxetine and tadalafil in capsule composition

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Abstract

The present invention relates to pharmaceutical combination comprising dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and a PDE5 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof having a release profile comprises both immediate release and modified release.

Description

THE PHARMACEUTICAL COMBINATION COMPRISING DAPOXETINE AND
PHOSPHODIESTERASE TYPE-5 Field of the invention
The present invention relates to pharmaceutical combination comprising dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and a PDE-5 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof having a release profile comprises both immediate release and modified release.
Background of the invention
Selective serotonin reuptake inhibitors (SSRI) are used in the long-term prophylaxis of many types of depression, including the endogenous type, recurrent depression, and in the treatment of obsessive-compulsive disorders, panic attack, social phobias, and the bulimia nervosa disease. Dapoxetine, which was first disclosed in the European patent publication EP 0288188 B1 is a selective serotonin reuptake inhibitor. Dapoxetine is used for the treatment of depression and premature ejaculation. Its chemical name is (S)-N, N-Dimethyl- 3-(naphthalen-1 -yloxy)-1 -phenylpropan-1 -amine and has a chemical structure shown with Formula I. Additionally, dapoxetine was first approved in Sweden and in Finland for use in the treatment of premature ejaculation.
Figure imgf000002_0001
Formula I: Dapoxetine
Following oral administration, dapoxetine is rapidly absorbed and rapidly enters the circulation by almost completely binding to plasma proteins. Therefore, it achieves the peak plasma concentration (Cmax) in 1 hour following oral administration. Orally-administered tablets of dapoxetine are commercially available under the name Priligy®, comprising 30 mg or 60 mg dapoxetine per tablet, as well as excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide (E171 ), triacetin, black iron oxide (E172) and yellow iron oxide (E172). On the other hand, phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are used in the treatment of erectile dysfunction (ED). PDE5 inhibitors block the phosphodiesterase enzyme in a selective and efficient manner, thus increasing the level of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum smooth muscle cells. Most frequently used PDE5 inhibitors are avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil.
Tadalafil is a PDE5 inhibitor used in the treatment of ED and Pulmonary Arterial Hypertension (PAH). It has a longer half-life as compared to other PDE5 inhibitors (mean, 17,5 hours). Orally-administered tablets of Tadalafil are commercially available under the name Cialis®, in the strength of 2.5 mg, 5 mg, 10 mg and 20 mg, as well as excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide (E171 ), triacetin, yellow iron oxide (E172), talc. The chemical designation of tadalafil is (6R-trans)-6-(1 ,3-benzodioxol-5-yl)- 2,3,6,7,12, 12a-hexahydro-2-methyl-pyrazino [1 ',2':1 ,6] pyrido[3,4-b] indole-1 ,4-dione, with the chemical structure illustrated below with Formula II.
Figure imgf000003_0001
Formula II: Tadalafil Formulations comprising a combination of selective serotonin reuptake inhibitors with PDE5 inhibitors are known in the prior art. The patent publication WO03000343, for example, discloses the use of a formulation comprising a combination of phosphodiesterase inhibitors and dapoxetine. In prior art, there are also several patents which disclose combination with dapoxetine and tadalafil mostly in oral pharmaceutical dosage forms. However, these active agents do not show a similar release profile. The release rate of dapoxetine is quicker than tadalafil and the drug elimination rate in the serum is also fast, but tadalafil have short T-max, which means that the exhibition of the medicinal effects is fast, and have long half-life, showing extended time of the medicinal effect. When dapoxetine and tadalafil are used together there has been inconveniences, due to the difference of the duration of these effects, such as they have to be taken at different times to get the combined effect, or there's a discrepancy of the expression of the effects due to the difference of the duration of the effects when they are taken at the same time. Therefore, the pharmaceutical combination of this present invention, is able to match the combination of dapoxetine with short half-life and tadalafil with a long half-life, by including two different release profile which are the immediate release and the modified release in tablet or capsule. Detailed description of the Invention
Main object of the present invention is to provide a pharmaceutical formulation that allows to obtain safe and efficient plasma levels of each pharmacological agents in desired duration. The present invention relates to an easily-administrable combination of dapoxetine and PDE5 inhibitor or their pharmaceutically acceptable salt, solvate or polymorph, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.
The term "combination" means that when drugs are administered together, a combined action is obtained which is higher than the individual actions of the respective drugs when they are used separately. On the other hand, using a lower dose of each drug to be combined according to the present invention will reduce the total dosage. Put differently, the dosages have not to be relatively less in all cases, but the drugs can be dosed less frequently or this may be beneficial in reducing the recurrence rate of side effects. These are advantageous in terms of patients to be treated.
The term "modified release phase" refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
The term "immediate release phase" refers to any pharmaceutical formulations that disintegrate rapidly after administration with enhanced rate of dissolution and get dissolved to release the medicaments.
The term "neutral pellet" refers drug free cores which can be coated by a solution or suspension of API with a binding agent. Also, it is known that preparing the formulations of two different actives having different release profiles is difficult to process and may require complex design of tablet, capsule formulations. Accordingly, it is required to show the release profiles at the same time to eliminate the undesired side effects. Thus, it is important to provide the efficiency of the formulation by providing a tablet or capsule formulation which helps to dissolve the both actives in same manner and same time.
A pharmaceutical combination formulation comprises dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and a PDE5 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein the formulation comprises both immediate release and modified release.
Pharmaceutical formulations can be made in one, two or three parts, or having core or different forms wherein at least one part is modified release formulation and at least one part is immediate release formulation in an oral administration.
Modified release formulations can be preferred. Modified release formulations are selected from the group comprising controlled release, sustained release, delayed release, extended release, repeat action system or mixtures thereof.
An embodiment of this present invention, both of modified release phase and immediate release phase may comprise dapoxetine and , further comprises at least one pharmaceutically acceptable excipient. The ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 10:1 to 1 :10 by weight or 7:1 to 1 :7 by weight or 5:1 to 1 :5 by weight.
An embodiment of this present invention, a PDE5 inhibitor is selected from the group comprising tadalafil, sildenafil, avanafil, lodenafil, mirodenafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil or mixtures thereof.
An embodiment of this present invention, PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil. An embodiment of this present invention, the ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof to PDE5 inhibitor is in the range of between 30:1 to 1 :30 by weight. An embodiment of this present invention, the pharmaceutical combination administered orally.
An embodiment of this present invention, the pharmaceutical combination is in the form of capsule, tablet, strip, syrup, powder, pastilles, sachet, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions, emulsions or mixtures thereof.
An embodiment of this present invention, the pharmaceutical combination is formulated as tablets including compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles. In this present invention, the pharmaceutical combination is formulated as tablet. Tablet may comprise of different type of particles, for example; mini-tablets, pellets, granules, powders or mixtures thereof.
An embodiment of this present invention, each type of particle comprises at least one active agent.
One embodiment of this present invention is directed to tablet coating, it can be applied, for example by spray-coating with a water-based film coating formulation. An embodiment of this present invention, the pharmaceutical combination is formulated as capsule. Capsule dosage form masks the bitter taste of dapoxetine as a result patient compliance is increased.
In this present invention, pharmaceutical combination can be prepared in capsule dosage form. Capsule may comprise of different type of particles, for example; mini-capsules, mini- tablets, pellets, granules, powders or mixtures thereof. In this present invention, the dosage unit form of dapoxetine and a PDE5 inhibitor or their pharmaceutically acceptable salt, solvate or polymorph is selected from mini-capsules, powders, granules, mini-tablets, pellets, beads or mixtures thereof and these dosage forms are filled into capsules.
An embodiment of this present invention, the form of formulation is mini-capsule in capsule wherein the mini capsule comprises at least one active agent. Mini-capsule is located within a capsule. An embodiment of this present invention, the form of formulation is mini-tablets in capsule wherein a mini-tablet comprises at least one active agent. Mini-tablets is located within a capsule.
An embodiment of this present invention, the form of formulation is pellet in capsule wherein pellet comprises at least one active agent. Pellet is located within a capsule.
An embodiment of this present invention, the form of formulation is powder in capsule. Powder is located within a capsule. An embodiment of this present invention is to combine dapoxetine and PDE5 inhibitor agent in stable dosage form with desired dissolution profiles in capsule form.
An embodiment of this present invention, the combination comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, diluents, dispersing agents, surfactant, modified release agents, lubricants, glidants, plasticizers, preservatives, sweeteners, flavorings, melting components, inert agents, stabilizers, antioxidants, coating agents, buffering agents, coloring agents or mixtures thereof.
Suitable fillers are selected from group comprising ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, talc, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof. At the present invention, the amount of filler is between 5.0% to 55.0% by weight.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, sugars, glycose syrup, natural gums, gelatin, collagene, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, starch, corn starch, pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, liquid glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, bentonite, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
Suitable disintegrants are selected from the group comprising polyvinilpyrrolidone, crospovidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion- exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate or mixtures thereof.
Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
Suitable dispersing agents are selected from the group comprising calcium silicate, magnesium aluminum silicate, sorbitan esters, aluminum oxide, phospholipids, poloxamer or mixtures thereof.
Suitable surfactans are selected from the group comprising sodium lauryl sulfate, cetylpyridinium chloride, docusate sodium, lauric acid, polyoxyethylene sorbitan fatty acid esters (polysorbate), phospholipids, cetrimide or mixtures thereof.
At the present invention, the amount of the surfactant is between 0.1 % to 5.0% by weight. Suitable modified release agents are selected from the group comprising ethyl acrylate, polymethacrylates ( Eudragit ), ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, pectin, polyglucoronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, lambda carregeenan, iota carregeenan, furcellaran, xanthan gum, a polymer of acrylic acid, Carbopol 934, 940, 941 or 974P , agar, guar gum, psyllium seed gum, gellan gum, locust bean gum, tara gum, tamarind gum, gum arabic, curdlan, galactomannan, glucomannan, glyceryl behenate, nitrocellulose, methylcellulose, proteoglycan, glycerol, propylene glycol, macrogols, dibutyl sebacetate, citrate esters, triacetin, castor oil, acetylated monoglycerides, fractionated coconut oil, hydrogenated vegetable oil, hydrogenated castor oil, carnauba wax, candellia wax, beeswax, paraffin wax, stearic acid, cetyl alcohol, cetostearyl alcohol, gelucire (stearyl macrogolglyceride) or a mixtures thereof.
At the present invention, the amount of the modified release agent is between 5.0% to 30.0% by weight.
An embodiment of this present invention, modified release agents preferably are HPMC K100M or HPMC E4M, they can be used together or separately.
An embodiment of this present invention, modified release agents is polyvinyl acetate or glyceryl behenate, they can be used together or separately.
An embodiment of this present invention, modified release agents is Eudragit RS or Eudragit RL, they can be used together or separately. Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, zinc stearate, talc, waxe, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
At the present invention, the amount of the lubricant is between 0.1 % to 2.0% by weight. Suitable glidants are selected from the group comprising talc, aluminium silicate, colloidal silicon dioxide, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof. At the present invention, the amount of the glidant is between 0.1 % to 5.0% by weight.
Suitable plasticizers are selected from the group comprising polyethylene glycols of different molecular weights, triacetin, tributyl citrate, triethyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols, propylene glycol or mixtures thereof.
Suitable preservatives are selected from the group comprising methyl paraben, propyl paraben and their salts (such as sodium, potassium), sodium benzoate, benzyl alcohol, citric acid, benzoic acid, m-cresol, phenol or mixtures thereof.
Suitable sweeteners are selected from the group comprising aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, polymethacrylates, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose or sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
Suitable flavoring agents are selected from the group comprising menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof. Suitable melting components are selected from the group comprising gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene-polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylated monoglyceride, butil pthalybutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethly phthalate, ethyl phthalylethly glycolate, glycerin, propylene glycol, triacetin, triacetin citrate, tripropionin or mixtures thereof.
Suitable inert agents are located between the two molecules wherein the inert agent is selected from starch, lactose, sugar alcohol like D-mannitol, erythritol; lowsubstituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof. Suitable stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof.
Suitable antioxidants are selected from the group comprising alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), erythorbic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium metabisulfite, sodium sulfite, thymol or mixtures thereof.
Suitable coating agent are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof or mixtures thereof.
At the present invention, the amount of the coating agent is between 2.0% to 40.0% by weight.
Suitable buffering agents are selected from the group comprising alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof. The buffering agent is preferably citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate, glutamic acid or mixtures thereof.
Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof. The most frequently encountered problem in oral dapoxetine formulations is the bitter taste. The tablets can be coated with coating agents, and mixtures of sweeteners or flavours have been used for masking the bitter taste. The pharmaceutical composition of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
Example 1 : the formulation comprising dapoxetine, a PDE5 inhibitor in tablet composition
Figure imgf000012_0001
Example 2: the formulation comprising dapoxetine and tadalafil in tablet composition
Agents Amount (% by weight of the total)
dapoxetine or a pharmaceutically acceptable 5% to 25%
salt, solvate or polymorph thereof
Tadalafil or a pharmaceutically acceptable 1 % to 10%
salt, solvate or polymorph thereof
calcium phosphate dehydrate 5% to 50%
microcrystalline cellulose 5% to 50%
sodium lauryl sulfate 0.1 % to 5%
Modified release agents 5% to 30%
colloidal silicon dioxide 0.1 % to 5%
magnesium stearate 0.1 % to 2%
Opadry 2% to 5% f Mdiidlh Idilhtoe reease pasemmeae reease pase
Process for example 2:
a) Mixing calcium phosphate dehydrate, tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, microcrystalline cellulose and a portion of modified release agents
b) dissolving sodium lauryl sulfate in water
c) adding step (a) mixture to step (b) mixture and granulating
d) drying the granules
e) adding dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof, the other part of modified release agents, colloidal silicon dioxide and mixing f) adding magnesium stearate then mixing
g) compressing the total mixture into tablets
h) then coating the tablets with Opadry
Example 3: the formulation comprising dapoxetine and tadalafil in bilayer tablet composition
Agents Amount (% by weight of the total) dapoxetine or a pharmaceutically acceptable 5% to 25%
salt, solvate or polymorph thereof
calcium phosphate dihydrate 5% to 50%
microcrystalline cellulose 5% to 70%
Modified release agents 5% to 30%
glyceryl behenate 5% to 30%
magnesium stearate 0.1 % to 5%
Tadalafil or a pharmaceutically acceptable 1 % to 10%
salt, solvate or polymorph thereof
mannitol 5% to 50%
microcrystalline cellulose 5% to 50%
polyvinylpyrrolidone 0.1 % to 5%
crospovidone 2% to 20%
sodium lauryl sulfate 0.1 % to 5%
colloidal silicon dioxide 0.1 % to 5%
magnesium stearate 0.1 % to 2%
Opadry 2% to 5% Process for example 3:
•Modified release phase
a) Mixing dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof, calcium phosphate dehydrate, microcrystalline cellulose and a portion of modified release agents and glyceryl behenate in fluidized bed
b) Obtaining granule by spraying with water and drying, then sieving
c) Adding the other part of modified release and glyceryl behenate agents and mixing d) Adding magnesium stearate then mixing 'Immediate release phase
a) Mixing tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, mannitol, half of crospovidone and half of microcrystalline cellulose
b) Dissolving polyvinylpyrrolidone and sodium lauryl sulfate in water and granulating with step(a) mixture
c) drying the granules and sieving
d) adding the other half of crospovidone and microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate and mixing
e) Then, pressing layers to form bilayer tablet
f) then coating the bilayer tablets with coating agent
Also, both of modified release phase and immediate release phase may comprise dapoxetine and further comprises at least one pharmaceutically acceptable excipient. The ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 5:1 to 1 :5 by weight.
Example 4: the formulation comprising dapoxetine and tadalafil in bilayer tablet composition
Figure imgf000015_0001
Process for example 4:
• Modified release phase
a) Adding triethyl citrate, dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof, modified release agents with certain amount of water in homogenizer and mixing
b) Adding neutral pellet in fluidized bed and spraying pellet with step(a) mixture and a bit drying,
c) Adding suspension of silicon dioxide and drying, then sieving
d) adding magnesium stearate, microcrystalline cellulose then mixing
• Immediate release phase
a) Mixing tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, mannitol, half of crospovidone ;
b) Dissolving polyvinylpyrrolidone and sodium lauryl sulfate in water and granulating with step(a) mixture
c) drying the granules and sieving
d) adding the other half of crospovidone, colloidal silicon dioxide, magnesium stearate and mixing
e) Then, pressing phase to form bilayer tablet
f) then coating the bilayer tablets with coating agent
Also, both of modified release phase and immediate release phase may comprise dapoxetine and further comprises at least one pharmaceutically acceptable excipient. The ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 5:1 to 1 :5 by weight.
Example 5: the formulation comprising dapoxetine and tadalafil in bilayer tablet composition
Agents Amount (% by weight of the total)
dapoxetine or a pharmaceutically acceptable salt, 5% to 25% solvate or polymorph thereof
ω microcrystalline cellulose 5% to 70%
__:
Q.
ω
ω glyceryl behenate 5% to 20%
ω
ω Polyvinyl acetate/ polyvinylpyrrolidone 5% to 20%
"Ο
ω colloidal silicon dioxide 0.1 % to 5%
¾
ο
Έ magnesium stearate 0.1 % to 2%
Tadalafil or a pharmaceutically acceptable salt, 1 % to 10% solvate or polymorph thereof
Polymethacrylates (Eudragit EPO) 5% to 40%
ω
ω
ω sodium lauryl sulfate 0.1 % to 5%
ω pregelatinized starch 2% to 30%
Ε polyethylene glycol 1 % to 5% Process for example 5:
• Modified release phase
a) Melting glyceryl behenate on hot melt extrusion and then mixing dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof
b) Obtaining pellet and drying, then sieving
c) Adding microcrystalline cellulose, polyvinyl acetate/ polyvinylpyrrolidone, colloidal silicon dioxide and mixing
d) adding magnesium stearate then mixing
e) Then, pressing to form tablet
• Immediate release mixture
f)Adding polymethacrylates, sodium lauryl sulfate, tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, pregelatinized starch, polyethylene glycol with certain amount of water in homogenizer and mixing
g) Then, coating tablet including dapoxetine with step(f) mixture
Also, both of modified release phase and immediate release phase may comprise dapoxetine and further comprises at least one pharmaceutically acceptable excipient. The ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in modified release phase to dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in immediate release phase is in the range of between 5:1 to 1 :5 by weight.
Example 6: the formulation comprising dapoxetine and tadalafil in capsule composition
Agents Amount (% by weight of the total)
dapoxetine or a pharmaceutically acceptable 15% to 35%
salt, solvate or polymorph thereof
Tadalafil or a pharmaceutically acceptable 0.5% to 20%
salt, solvate or polymorph thereof
Modified release agents 5% to 50%
glidant 0.1 % to 3%
Coating agent 5% to 40%
surfactant 0.1 % to 5%
filler 2% to 30%
plasticizier 1 % to 5% Example 7: the formulation comprising dapoxetine and tadalafil in capsule composition
Figure imgf000018_0001
Process for example 7: a) Adding triethyl citrate, dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof, modified release agents with certain amount of water in homogenizer and mixing
b) Adding neutral pellet in fluidized bed and spraying pellet with step(a) mixture and a bit drying,
c) Adding suspension of silicon dioxide and drying, then sieving
d) Mixing tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, mannitol, half of crospovidone and microcrystalline cellulose
e) Dissolving polyvinylpyrrolidone and sodium lauryl sulfate in water and granulating with step(d) mixture and drying, then sieving
f) mixing step (c) mixture with step (e) mixture
g) adding colloidal silicon dioxide and the other half of crospovidone and microcrystalline cellulose, then mixing
h) filling the mixture into capsules Example 8: the formulation comprising dapoxetine and tadalafil in capsule composition
Figure imgf000019_0001
Process for example 8:
a) Melting glyceryl behenate or Gelucire on hot melt extrusion and then mixing dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof b) Obtaining pellets and drying
c) Adding silicon dioxide and drying, then sieving pellets
d) Mixing polymethacrylates, sodium lauryl sulfate, tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, pregelatinized starch, polyethylene glycol with certain amount of water in homogenizer
e) Then, coating modified release pellet including dapoxetine with step(d) mixture

Claims

1 . A pharmaceutical combination comprising dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and a PDE5 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein the formulation comprises both immediate release and modified release phase.
2. The pharmaceutical combination according to claim 1 , wherein the PDE5 inhibitor is selected from the group comprising avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil or mixtures thereof.
3. The pharmaceutical combination according to claim 2, wherein the PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil.
4. The pharmaceutical combination according to any preceding claims, wherein the ratio of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof to tadalafil is in the range of between 30:1 to 1 :30 by weight.
5. The pharmaceutical combination according to claim 1 , wherein the pharmaceutical composition is administered orally.
6. The pharmaceutical combination according to claim 5, wherein the combination is in the form of capsule, tablet, strip, syrup, powder, pastilles, sachet, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions or emulsions.
7. The pharmaceutical combination according to claim 6, wherein the combination is in the form of capsule.
8. The pharmaceutical combination according to claim 7, wherein the combination is in the form of mini-capsule, powder, granules, mini-tablet, pellets, beads or mixtures thereof in a capsule.
9. The pharmaceutical combination according to claim 8, wherein the form of combination is mini-capsule in the capsule which mini-capsule is located within the capsule.
10. The pharmaceutical combination according to claim 9, wherein the mini capsule comprises at least one active agent.
1 1 . The pharmaceutical combination according to claim 8, wherein the form of combination is mini-tablets in a capsule which mini-tablets is located within the capsule.
12. The pharmaceutical combination according to claim 1 1 , wherein a mini-tablet comprises at least one active agent.
13. The pharmaceutical combination according to claim 8, wherein the form of combination is pellet in a capsule which pellet is located within the capsule.
14. The pharmaceutical combination according to claim 8, wherein the form of combination is powder in a capsule which powder is located within the capsule.
15. The pharmaceutical combination according to any preceding claims, wherein the combination comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, diluents, dispersing agents, surfactant, modified release agents, lubricants, glidants, plasticizers, preservatives, sweeteners, flavorings, melting components, inert agent, stabilizers, antioxidants, coating agents, buffering agents, coloring agents or mixtures thereof.
16. The pharmaceutical combination according to any preceding claims, comprising; a) 15.0% to 35.0% by weight of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof
b) 0.5% to 20.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof
c) 10.0% to 25.0% by weight of neutral pellet
d) 1 .0% to 5.0% by weight of triethyl citrate
e) 10.0% to 30.0% by weight of modified release agents
f) 0.1 % to 3.0% by weight of silicon dioxide
g) 10.0% to 40.0% by weight of mannitol
h) 10.0% to 40.0% by weight of microcrystalline cellulose
i) 0.5% to 6.0% by weight of polyvinylpyrrolidone
j) 0.1 % to 3.0% by weight of sodium lauryl sulfate
k) 10.0% to 30.0% by weight of crospovidone
I) 0.1 % to 3.0% by weight of colloidal silicon dioxide
17. Process for preparing the pharmaceutical combination according to claim 16, comprising the following steps;
a) adding triethyl citrate, dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof, modified release agents with certain amount of water in homogenizer and mixing
b) adding neutral pellet in fluidized bed and spraying pellet with step(a) mixture and a bit drying,
c) adding suspension of silicon dioxide and drying, then sieving
d) mixing tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, mannitol, half of crospovidone and microcrystalline cellulose
e) dissolving polyvinylpyrrolidone and sodium lauryl sulfate in water and granulating with step(d) mixture and drying, then sieving
f) mixing step (c) mixture with step (e) mixture
g) adding colloidal silicon dioxide and the other half of crospovidone and microcrystalline cellulose, then mixing
h) filling the mixture into capsules
18. The pharmaceutical combination according to any preceding claims, comprising; a) 15.0% to 35.0% by weight of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof
b) 0.5% to 20.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof
c) 5.0% to 50.0% by weight of glyceryl behenate or gelucire
d) 0.1 % to 3.0% by weight of silicon dioxide
e) 5.0% to 40.0% by weight of polymethacrylates
f) 0.1 % to 5.0% by weight of sodium lauryl sulfate
g) 2.0% to 30.0% by weight of pregelatinized starch
h) 1 .0% to 5.0% by weight of polyethylene glycol 19. Process for preparing the pharmaceutical combination according to claim 18, comprising the following steps;
a) melting glyceryl behenate or gelucire on hot melt extrusion and then mixing dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof b) obtaining pellets and drying
c) adding silicon dioxide and drying, then sieving pellets d) mixing polymethacrylates, sodium lauryl sulfate, tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof, pregelatinized starch, polyethylene glycol with certain amount of water in homogenizer
e) then, coating modified release pellet including dapoxetine with step(d) mixture
PCT/TR2018/050568 2017-10-09 2018-10-08 The pharmaceutical combination comprising dapoxetine and phosphodiesterase type-5 WO2019074464A2 (en)

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