WO2011030351A2 - Compositions pharmaceutiques au goût masqué - Google Patents

Compositions pharmaceutiques au goût masqué Download PDF

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WO2011030351A2
WO2011030351A2 PCT/IN2010/000589 IN2010000589W WO2011030351A2 WO 2011030351 A2 WO2011030351 A2 WO 2011030351A2 IN 2010000589 W IN2010000589 W IN 2010000589W WO 2011030351 A2 WO2011030351 A2 WO 2011030351A2
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composition
taste
cyclodextrin
pde
glyceryl
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PCT/IN2010/000589
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WO2011030351A3 (fr
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Pratibha Sudhir Pilgaonkar
Maharukh Tehmasp Rustomjee
Anilkumar Surendrakumar Gandhi
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Rubicon Research Private Limited
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Publication of WO2011030351A3 publication Critical patent/WO2011030351A3/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present invention relates to taste-masked pharmaceutical compositions comprising phosphodiesterase-5 (PDE-5) inhibitors.
  • PDE-5 inhibitors suitable for oral administration in the form of orally disintegrating tablets, bite-dispersion tablets, chewable tablets, dispersible tablets, effervescent tablets or the like, wherein the bitter taste of PDE-5 inhibitor is masked thereby providing palatable formulations.
  • the invention further relates to method for masking the objectionable taste of PDE-5 inhibitor.
  • cyclic adenosine monophosphate cAMP
  • cGMP cyclic guanosine monophosphate
  • PDEs cyclic nucleotide phosphodiesterases
  • PDEs are a large family of proteins with some being highly specific for hydrolysis of either cAMP (PDE-4, PDE-7, PDE-8), or cGMP (PDE-5, PDE-6, PDE-9), and some having mixed specificity (PDE-1, PDE-2, PDE-3, PDE-10, PDE-11).
  • PDE-5 is a cGMP-specific PDE enzyme responsible for modulation of intracellular levels of this nucleotide. Elevation of cGMP levels causes activation of protein kinase G, which phosphbrylates PDE-5. Phosphorylation of PDE-5 stimulates its enzymatic activity and enhances cGMP binding affinity in the regulatory domain, leading to a decrease in intracellular cGMP levels.
  • PDE-5 receptors are found in varying concentrations in a number of tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle and have been recognized as an important therapeutic target.
  • PDE-5 is a key regulator of cGMP levels in the smooth muscle of the erectile corpus cavemosal tissue as, well as the lung tissue.
  • the physiological mechanism of erection involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This results in increased levels of cGMP producing smooth muscle relaxation in the arteries of corpus cavernosum, allowing inflow of blood and causing erection.
  • Erectile dysfunction or impotence is defined as the persistent inability to attain or maintain an erection adequate to permit satisfactory sexual performance.
  • erectile function requires the coordination of psychological, hormonal, neurological, vascular and anatomic function. Alteration of any of these factors is sufficient to cause erectile dysfunction. Further since cGMP plays a key role in this erection process, potential interventions for adequate smooth muscle relaxation include increasing level of intracellular cGMPs.
  • PDE-5 inhibitors Blocking the ability of PDE-5 to degrade cGMP, increases the amount of cGMP, resulting in penile arterial smooth muscle relaxation and increase in blood flow to the corpus . carvernosum. This increased blood flow provided by PDE-5 inhibitors has been used to. treat erectile dysfunction in men as well as sexual dysfunction in women. Because PDE- 5 is also present in the arterial wall smooth muscle within the lungs, PDE-5 inhibitors have also been explored for the treatment of pulmonary hypertension, a disease in which blood vessels in the lungs become abnormally narrow.
  • PDE-5 inhibitors may be used for the treatment and/or prevention of ischemia/reperfusion injury, angina and can also be administered to subjects during or after a heart attack (myocardial infarction) to prevent or lessen ischemic heart damage.
  • Another use for PDE-5 inhibitors involves improving pulmonary perfusion.
  • PDE-5 inhibitors may be administered to alleviate or reduce patient symptoms.
  • PDE5 inhibitors available for the treatment of sexual dysfunction such as erectile dysfunction, and other cardiac, pulmonary and vascular related conditions mainly include tadalafil, sildenafil, vardenafil, acetaldenafil, avanafil, udenafil, thiomethisosildenafil or salts or prodrugs thereof.
  • Tadalafil is commercially available from Lilly ICOS under the brand name Cialis ® for the treatment of erectile dysfunction.
  • Cialis ® is available as film-coated, almond-shaped tablets for oral administration in strengths of 2.5 mg, 5 mg, 10 mg or 20 mg of tadalafil base. The formulation is recommended to be swallowed as per need prior to anticipated sexual activity.
  • Aqueous solubility of tadalafil is reported to be about 2 pg/ml in water.
  • Sildenafil citrate is commercially developed by Pfizer, Inc. as VIAGRA® which is available as film-coated tablets.
  • Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/ml in water.
  • Vardenafil HCI is commercially developed by Bayer Healthcare as LEVITRA®, a film coated tablet. Vardenafil HCI is a nearly colorless, solid substance with a solubility of 0.11 mg/mL in water.
  • PDE-5 inhibitors such as tadalafil, sildenafil or vardenafil have a bitter taste and hence marketed formulations thereof are available in the form of film coated tablets to enhance palatability and patient compliance.
  • film coated tablets are needed to be swallowed, which makes it difficult to ensure administration of the tablets without water, in situation when the formulation is supposed to be taken as per need prior to sexual activity.
  • 7,182,958 discloses tadalafil formulations developed as a tablet or as dry, free-flowing particles filled in a gelatin shell where the drug is milled to get particles of defined size prior to addition of excipients.
  • U.S Patent Application 2008/0009502 describes preparation of solid composite of tadalafil with polymeric carrier that has enhanced dissolution rate as compared to the marketed formulation.
  • U S Patent Application 2002/0002172 disclose dosage forms comprising sildenafil citrate and a highly water soluble sugar in the form of a solid dispersion particularly to increase the water solubility and membrane permeability of sildenafil citrate to provide for increased bioavailability.
  • US Patent Application 2007/0031349 discloses rapidly absorbing oral formulations comprising PDE5 inhibitors along with an orally disintegrating carrier. These formulations provide rapid disintegration after introduction to the oral cavity, followed by buccal arid/or sublingual absorption. But the formulation does not attempt to particularly mask the bitter taste of PDE5 inhibitors and hence perception of bitter taste of PDE5 inhibitors is possible from such orally disintegrating preparations.
  • PCT Publication WO 2009/074995 discloses chewable solid pharmaceutical compositions comprising sildenafil citrate in the form of a sildenafil mask complex which is formed by sildenafil and a polyacrylic resin by a cationic exchange mechanism and wherein carbomer and powdered cellulose are additional excipients, which facilitate the formation of the sildenafil mask complex.
  • Such compositions are prepared by cumbersome and cost intensive processes.
  • U.S Patent Application 2006/0100214 discloses a fast dissolving and taste masked sildenafil solid dosage form comprising: (i) sildenafil granules comprising a salt of sildenafil, a solubilisation inhibitor and optionally a sweetening agent and (ii) one or more disintegrants wherein the disintegrants or combination of disintegrants are present in the form of agglomerates having an average agglomerated particle size of at least 50 pm.
  • a solubilization inhibitor may not provide the desired taste-masking and the bitter taste of the active may still be perceived.
  • PDE-5 inhibitor such as tadalafil, sildenafil or vardenafil
  • taste-masking agents simple, cost-effective, easy to scale-up processes to obtain taste-masked pharmaceutical compositions that have adequate mechanical strength, stability, desired taste and in-vitro release profile.
  • the present invention relates to taste-masked pharmaceutical compositions comprising phosphodiesterase-5 inhibitor/s (PDE-5), at least one taste-masking agent and at least one pharmaceutically acceptable excipient.
  • PDE-5 phosphodiesterase-5 inhibitor/s
  • the present invention relates to taste- masked PDE-5 inhibitor compositions suitable for oral administration in the form of orally disintegrating tablets, bite-dispersion tablets, chewable tablets, dispersible tablets, effervescent tablets or the like, wherein the bitter taste of PDE-5 inhibitor is masked thereby providing palatable formulations.
  • Taste masking of bitter drugs which can be considered as "perceived reduction of an undesirable taste that would otherwise exist" is a challenge in formulation development.
  • Masking of the unpleasant taste of a drug improves the compliance of the patient and product value due to enhanced palatability.
  • the desire of improving the palatability has prompted the development of numerous formulations with improved performance and acceptability.
  • Taste-masking technologies and processes employed to achieve the same can, in certain instances, interfere with disintegration, affect stability, provide inadequate taste-masking for a given active or interfere with the bioavailability or pharmacokinetic properties of the drug. Therefore, it becomes important to develop taste-masking technology for an active agent that not only enhances the organoleptic properties of the dosage form containing the same, but also does not interfere with the rapid therapeutic onset and bioavailability of the drug.
  • the present inventors after thorough research, have developed taste-masked pharmaceutical composition that has adequate mechanical strength and wherein the bitter, unpleasant or otherwise undesirable taste of the active is masked, without compromising on its stability, handling characteristics and in-vitro release profile, using simple and cost effective processes.
  • the taste-masked pharmaceutical composition of the present invention comprises at least one PDE-5 inhibitor, at least one taste-masking agent and at least one pharmaceutically acceptable excipient.
  • PDE-5 inhibitor/s refers to any compound that can be employed for the treatment of sexual dysfunction such as, but not limited to, erectile dysfunction in a mammal, preferably a human, including, but not limited to a male or for prevention or treatment of pulmonary hypertension, ischemia/reperfusion injury, angina myocardial infarction, pulmonary perfusion, inflammatory and degenerative lung disorders and other cardiac, pulmonary and vascular related conditions, such as, but not limited to, tadalafil, sildenafil, avanafil, acetildenafil, vardenafil, udenafil, thiomethisosildenafil, lodenafil, mirodenafil, zaprinast, dipyridamole, pyrazolopyrimidinones, 5-(2-ethoxy-5-morpholinoacetylphenyl)-1 -methyl-3-n-propyl-1 ,6- dihydro-7H-pyr
  • the PDE-5 inhibitor employed in the compositions of the present invention may be in the form of free base or pharmaceutically acceptable salts, prodrugs, active metabolites, polymorphs, solvates, hydrates, .
  • PDE-5 inhibitor/s phosphodiesterase-5 inhibitor/s
  • cyclic nucleotide phosphodiesterase-5 inhibitor/s have been used interchangeably for the purpose of the present invention.
  • composition of the present invention Pharmaceutically effective amount of PDE-5 inhibitor is employed in the composition of the present invention.
  • effective amount refers to an amount effective to achieve desired preventive, therapeutic and/or beneficial effect.
  • the amount of PDE-5 inhibitor in the composition can vary from about 0.01 weight % to about 85 weight %, based on the total weight of the composition.
  • the amount of PDE-5 inhibitor in the composition can vary from about 0.02 weight % to about 75 weight %, based on the total weight of the composition.
  • the amount of PDE-5 inhibitor in the composition can vary from about 0.05 weight % to about 60 weight %, based on the total weight of the composition.
  • compositions of the present invention may be administered at a dose of about 0.01 mg to about 300 mg of PDE-5 inhibitor. In another embodiment the compositions of the present invention may be administered at a dose of about 0.1 mg to about 250 mg of PDE-5 inhibitor. In still another embodiment the compositions of the present invention may be administered at a dose of about 0.5 mg to about 200 mg of PDE-5 inhibitor.
  • the PDE-5 inhibitor employed for the present invention is tadalafil in the form of free base or its pharmaceutically acceptable salts, prodrugs, polymorphs, solvates, hydrates, active metabolites, enantiomers, optical isomers, tautomers or racemic mixtures.
  • the PDE-5 inhibitor employed for the present invention is sildenafil in the form of free base or its pharmaceutically acceptable salt such as, but not limited, to sildenafil citrate, or its prodrugs, polymorphs, solvates, hydrates, active metabolites, enantiomers, optical isomers, tautomers or racemic mixtures.
  • the PDE-5 inhibitor employed for the present invention is vardenafil in the form of free base or its pharmaceutically acceptable salt such as, but not limited to, vardenafil hydrochloride, or its prodrugs, polymorphs, solvates, hydrates, active metabolites, enantiomers, optical isomers, tautomers or racemic mixtures.
  • the PDE-5 inhibitor may be in the form of, but not limited to, powder, granules, pellets, beads, minitab!ets or the like.
  • PDE-5 inhibitor granules may be prepared by methods- such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
  • pellets of PDE-5 inhibitor may be prepared using extrusion spheronization.
  • PDE-5 inhibitor can be loaded on an inert carrier before taste-masking.
  • the inert carrier can be selected from, but not limited to, beads, pellets, spheres or similar particles that do not contain an active ingredient.
  • Non-limiting examples of inert carriers include microcrystalline cellulose, sugar or silicon dioxide.
  • PDE-5 inhibitor in the powder form, may be treated with a taste-masking agent.
  • Taste-masking agents employed for the purpose of the present invention include, but are not limited to, polymeric and/or non-polymeric pharmaceutically acceptable excipients, cyclodextrins, ion exchange resins, carbomers, adsorbents, sugar substitutes, or any combinations thereof.
  • the bitter or unpleasant taste of PDE-5 inhibitor is masked using pharmaceutically acceptable taste-masking agent by methods including, but not limited to, coating, physical mixing, melt granulation, complexation, adsorption, salt formation or the like, whereby the bitter or objectionable taste of the active is masked.
  • Polymeric pharmaceutically acceptable excipients suitable for compositions of the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, polyhydnc alcohols, poly(oxyethylene)-poly(oxypropylene) block copolymers (polbxamers), vinyl derivatives or polymers or copolymers thereof, acrylic acid derivatives or the like or any combinations thereof.
  • Cellulose derivatives include but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose
  • Saccharides or polysaccharides include but are not limited to, guar gum, xanthan gum, gum arabic, tragacanth or combinations thereof.
  • Polyhydric alcohols include but are not limited to, polyethylene glycol (PEG) or polypropylene glycol.
  • Vinyl derivatives, polymers and copolymers thereof include but are not limited to polyvinylacetate aqueous dispersion (Kollicoat SR 30D), copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol (Kollicoat IR), polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP) or combinations thereof.
  • Polyvinylacetate aqueous dispersion Kercoat SR 30D
  • copolymers of vinyl pyrrolidone copolymers of polyvinyl alcohol
  • Kollicoat IR copolymers of polyvinyl alcohol
  • PVP polyvinylacetoacetal phthalate
  • PVP polyvinylpyrrolidone
  • Acrylic acid derivatives include but are not limited to, methacrylic acids, polymethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g.
  • Eudragit ® those available from Rohm GmbH under the trademark Eudragit ® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethylacrylate methymethacrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof.
  • Eudragit EPO dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer
  • Eudragit RL and RS trimethylammonioethyl methacrylate copolymer
  • Eudragit NE30D and Eudragit NE40D ethylacrylate methymethacrylate copolymer
  • Non-polymeric pharmaceutically acceptable excipients suitable for compositions of the present invention include, but are not limited to, fats, oils, waxes, fatty acids, fatty acid esters, long chain monohydric alcohols and their esters, phospholipids, terpenes or combinations thereof.
  • Waxes are esters of fatty acids with long chain monohydi i ⁇ alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons.
  • Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes.
  • Waxes are also monoglyceryl esters, diglyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol are substituted by a fatty acid.
  • Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecen
  • Fatty acids employed in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated riqe bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and mixtures thereof.
  • Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof.
  • the fatty acids employed include, but not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof.
  • Long chain monohydric alcohols include, but are not limited to, cetyi alcohol, and stearyl alcohol and mixtures thereof.
  • the non-polymeric pharmaceutically acceptable excipients employed in the compositions of the present invention include, but not limited to, Cutina® (hydrogenated castor oil), Hydrobase® (hydrogenated soybean oil), Castorwax® (hydrogenated castor oil), Croduret® (hydrogenated castor oil), Carbowax®, Compritol® (glyceryl behenate), Sterotex® (hydrogenated cottonseed oil), Lubritab® (hydrogenated cottonseed oil), Apifil® (wax yellow), Akofine® (hydrogenated cottonseed oil), Softisan® (hydrogenated palm oil), Hydrocote® (hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (macrogolglycerides Lauriques), Precirol® (glyceryl palmitostearate), EmulcireTM (cetyl alcohol), Plurol® diisostearique (polyglyceryl diisostearate), Geleol® (glyceryl
  • lipids or waxes can also be employed in the form of an aqueous dispersion stabilized by surfactants and suitable stabilizers.
  • the active ingredient is physically mixed or blended with these polymeric or non- polymeric pharmaceutically acceptable excipients or is partially or completely coated with these excipients by any of the techniques known in the art, such as microencapsulation, hot melt granulation, melt extrusion, fluid bed coating, wet granulation, spray drying, dry granulation or roll compaction.
  • the non-polymeric pharmaceutically acceptable excipient may be incorporarated in the present invention in the form of physical blend, solid dispersion, solid solution or complex with the active.
  • Different processes may be employed to prepare the taste-masked composition of the active comprising the non-polymeric taste-masking agent including, but not limited to, melt granulation, solvent treatment, physical mixing, hot melt extrusion or spray drying of the dissolved non-polymeric taste-masking agent with the active.
  • the polymeric or non-polymeric pharmaceutically acceptable excipient can be applied alone or in combination with other suitable pharmaceutical excipients, to PDE-5 inhibitors, in the form of, but not limited to, powder, granules, beads, pellets, minitablets or the like to achieve the desired taste-masking.
  • the bitter taste of PDE-5 inhibitor is masked by using taste- masking agents, such as, but not limited to, cyciodextrins, ion exchange rss ⁇ ins or carbomers or derivatives thereof.
  • taste-masking agent employed in the formulation of the present invention is cydodextrin or a derivative thereof.
  • the bitter taste of PDE-5 inhibitor is masked by complexation with cyciodextrins or derivatives thereof.
  • Cyciodextrins are cyclic oligosaccharides formed from a-(1 , 4)-linked D-glucopyranose units, ⁇ , ⁇ and ⁇ -cyclodextrins consist of six, seven and eight units respectively. Cydodextrin makes an inclusion complex with the PDE-5 inhibitor by acting as a hydrophobic host cavity.
  • Suitable cyciodextrins for use in the formulation of the present invention include, but are not limited to, ⁇ , ⁇ and ⁇ -cyclodextrins, or alkylated, hydroxyalkylated, esterified, glycosylated or substituted derivatives thereof, such as (2,6- di-o-methyl)-P-cyclodextrin (DIMEB) (dimethyl ⁇ -cyclodextrin), randomly methylated- ⁇ - cyclodextrin (RAMEB), and hydroxypropyl ⁇ -cyclodextrin (HP CD), hydroxyethyl- ⁇ - cyclodextrin, dihydroxypropyl ⁇ -cyclodextrin, trimethyl ⁇ -cyclodextrin, hydroxymethyl- ⁇ - cydodextrin, ⁇ -cyclodextrin sulfate, ⁇ -cyclodextrin sulfonate, methyl ⁇ -cyclodextrin, sul
  • the complex of active with cyclodextrin can be prepared by various methods such as solution method, co-precipitation method, co- evaporation/ solid dispersion method, melting method neutralization method, slurry method, spray drying kneading method, and grinding method.
  • a physical mixture of PDE-5 inhibitor and cyclodextrin or a derivative thereof is employed in the composition of the present invention.
  • the compositions of the present invention comprise PDE-5 inhibitor and cyclodextrin or a derivative thereof in an uncomplexed form along with suitable pharmaceutically acceptable excipients.
  • the taste-masking agent employed in the compositions of the present invention is an ion-exchange resin.
  • the biter taste of PDE-5 inhibitor is masked by complexing with an ion-exchange resin
  • lon-exchange resins are solid and suitably insoluble high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium and are not absorbed by the body .
  • the resulting ion exchange is reversible and stoichiometric with, the displacement of one ionic species by another.
  • the drug-resin complexes effectively " mask the taste of a bitter or unpleasant tasting drug within the matrix of the ion-exchange material.
  • Appropriate selection of the ion-exchange resin is important so that the drug is ⁇ not released in the mouth, leading to perception of the bitter taste of the drug.
  • the present invention provides a taste-masked pharmaceutical composition wherein taste-masking is achieved by reversibly binding the active compound onto an ion- exchange resin, wherein the polymeric matrix of the ion-exchange resin has functional groups including, but not limited to, anionic groups, e.g., weakly acidic- carboxylic, esteric and phosphonic; strongly acidic- sulfonic and cationic groups, e.g., weakly basic- tertiary amine; strongly basic- quaternary amine.
  • anionic groups e.g., weakly acidic- carboxylic, esteric and phosphonic
  • strongly acidic- sulfonic and cationic groups e.g., weakly basic- tertiary amine
  • strongly basic- quaternary amine strongly basic- quaternary amine.
  • suitable polymeric matrices include copolymers of acrylic and substituted acrylic acids; styrene and styrene derivatives; cellulose esters; vinyl and substituted vinyl esters; and polysulfonic acids and polysulfonic acid esters.
  • An ion-exchange resin having the polymeric matrix with an anionic functional group is a cation exchange resin and that having a cationic functional group is an anionic exchange resin.
  • the mobile or exchangeable moieties depending on the type of resin used, includes, but is not limited to, sodium, hydrogen, potassium, chloride or the like.
  • a cationic exchange resin is used as a taste-masking agent to mask the bitter taste of PDE-5 inhibitor.
  • Non-limiting examples of suitable cation exchange resin that may be employed include Amberlite ® IRP64 (porous copolymer of methacrylic acid and divinylbenzene), Amberlite ® IRP69 (sulfonated copolymer of styrene and divinylbenzene), Amberlite ® IRP88 (cross linked polymer of methacrylic acid and divinylbenzene), DOWEX ® RTM.
  • ion exchange resin can be used for complexation with PDE-5 inhibitor in a ratio of active to resin of about 1:0.1 to about 1:20.
  • These drug resinates can be prepared by methods such as, but not limiting to, blending, kneading, grinding, sieving, filling, compressing, lyophilization, spray-drying, fluid-bed drying or centrifugal granulation.
  • the taste-masking agent employed in the compositions of the present invention is a carbomer or a derivative thereof.
  • PDE-5 inhibitor is taste masked by complexing with carbomers such as carbomer 934, carbomer 971 , carbomer 974 or the like wherein the complex is held together by ionic bonding and gel properties of the carbomer, providing stable and palatable formulations.
  • carbomers such as carbomer 934, carbomer 971 , carbomer 974 or the like wherein the complex is held together by ionic bonding and gel properties of the carbomer, providing stable and palatable formulations.
  • These complexes can be prepared by mixing, blending or slurrying PDE5 inhibitor and carbomer together to allow the desired complex formation.
  • the bitter taste of PDE-5 inhibitor is masked by using as taste- masking agents, adsorbents that form adsorbates with the active.
  • Adsorbates can be formed by adsorbing or partially or significantly blending the active with an adsorbent selected from, but not limited to, magnesium aluminum silicate, bentonite, kaolite, sodium alginate, zeolite, activated granular carbon, silica gel, active aluminum, clay and mixtures thereof. These adsorbent materials surround the drug particles by forming a physical bond, by Van der Waals interactions, and hydrogen bonding force of attraction, so that the bitter taste of the drug is not perceived.
  • the adsorbate of PDE-5 inhibitor can be formed by mixing or blending the active with the adsorbent in high or moderate shear mixers like planetary mixer or rapid mixer granulator. Alternatively, adsorbate can be formed by wet granulation involving the adsorbent and PDE-5 inhibitor in any conventional granulation equipment.
  • a sugar substitute is employed as a taste-masking agent that masks the bitter taste of PDE-5 inhibitor by salt formation.
  • the bitter taste of PDE-5 inhibitor is masked using equimolar amounts of sugar substitutes, such as, but not limited to, cyclamate, saccharin, acesulfame or a mixture of at least two of the sugar substitutes by salt formation.
  • sugar substitutes such as, but not limited to, cyclamate, saccharin, acesulfame or a mixture of at least two of the sugar substitutes by salt formation.
  • Such a treatment results in the formation of taste-masked PDE-5 inhibitors that have the desired taste and also improved patient compliance.
  • Such a taste-masked salt can be incorporated in pharmaceutical compositions for oral administration.
  • the amount of taste-masking agent employed for the preparation of taste-masked PDE-5 inhibitor compositions of the present invention can be in the range from about 1% to about 95% by weight of the composition. In another embodiment the amount of taste-masking agent employed for the preparation of taste-masked PDE-5 inhibitor compositions of the present invention can be in the range from about 2% to about 75% by weight of the composition. In another embodiment the amount of taste- masking agent employed for the preparation of taste-masked PDE-5 inhibitor compositions of the present invention can be in the range from about 5% to about 60% by weight of the composition.
  • the taste masked PDE-5 inhibitor of the present invention in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like can be administered as such or are suitable for incorporation into various oral dosage forms including, but not limited to, orally disintegrating, dispersible, bite-dispersion, chewable or effervescent tablets, sprinkle granules, quick melt wafers, lozenge, dry suspensions or syrups for reconstitution, chewing gum or the like.
  • These oral formulations may contain from about 5% to about 95% of taste-masked PDE-5 inhibitor.
  • the taste masked PDE-5 inhibitor composition for oral administration can be provided in the form of various dosage forms, such as but not limited to orally disintegrating, dispersible, chewable or effervescent tablets, sprinkle granules, quick melt wafers, lozenge, dry suspensions or syrups for reconstitution, chewing gum or the like.
  • the taste-masked formulations may be so designed that the in vitro dissolution and bioavailability of the PDE-5 inhibitor is not compromised.
  • the taste-masked PDE-5 inhibitor may further optionally comprise one or more pharmaceutically acceptable excipients, such as but not limited to, diluents, binders, disintegrants, superdisintegrants, sweetener, flavor or the like.
  • the taste-masked PDE- 5 inhibitor formulations of the present invention may further comprise at least one pharmaceutically acceptable excipient including, but not limited to, binder, disintegrant, superdisintegrant, diluent, salivating agent, surfactant, flavor, sweetener, colorant, souring agent, viscolizer, glidant, lubricant, solubilizer, stabilizer or the like, depending on the dosage form.
  • taste-masked PDE-5 inhibitor formulation of the present invention is in the form of orally disintegrating tablets.
  • taste-masked PDE-5 inhibitor is incorporated in an orally disintegrating tablet.
  • Orally disintegrating tablets (ODTs) disintegrate/dissolve in the mouth rapidly without administering extra water, providing the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation.
  • the orally disintegrating tablets comprising PDE-5 inhibitor can further comprise as filler, binder or disinteggrant, a directly compressible coprocessed excipient.
  • PCT Application WO2007113856 describes directly compressible coprocessed excipient comprising of at least one water soluble excipient and water insoluble inorganic excipient such as calcium silicate.
  • compositions of the present invention may include in addition to the taste- masked PDE-5 inhibitor, at least one taste-masking agent and directly compressible coprocessed excipient, one or more pharmaceutically acceptable excipients, such as, but not limited to, binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, souring agents, viscolizers, glidants or lubricants, solubilizers, or stabilizers.
  • pharmaceutically acceptable excipients such as, but not limited to, binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, souring agents, viscolizers, glidants or lubricants, solubilizers, or stabilizers.
  • superdisintegrants include, but are not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems. Further, the disintegrants can be selected from, but not limiting to, crospovidone, calcium silicate and starch.
  • the amount of superdisintegrant employed in the composition is- about 2% to about 30 % by weight of the said dosage form.
  • binders include, but are not limited to, starch, pregelatinized starch, polyvinyl pyrrolidone (PVP), Copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.
  • suitable diluents include, but are not limited to, starch, microcrystal!ine cellulose, lactose, xylitol, mannitol, maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dicalcium phosphate, and the like or any combinations thereof.
  • lubricant examples include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate.
  • the tablet compositions of the invention may also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
  • the said compositions may also include salivating agents such as, but not limited to, micronised polyethylene glycol, sodium chloride or precipitated micronised silica to improve the disintegration properties of the -' ⁇ said compositions.
  • solubilizers include, but are not limited to cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine, and mixtures thereof.
  • compositions of the present invention may also include stabilizers -such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like.
  • stabilizers such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like.
  • surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof.
  • Souring agents include, but are not limited to, monosodium fumarate and/or citric acid.
  • compositions of the present invention may optionally include viscolizers agents such as polyalkylene oxides; polyols; starch and starch-based polymers; chitosan; polysaccharide gums; polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, gum acacia, gum tragacanth, xanthan gum, guar gum and polyvinyl alcohol and copolymers and mixtures thereof.
  • viscolizers agents such as polyalkylene oxides; polyols; starch and starch-based polymers; chitosan; polysaccharide gums; polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, gum acacia, gum
  • compositions of the present invention comprise at least one sweetener such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; and/or one or more flavors, such as, but not limited to, mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, tutty frutty flavor.magnasweet 135, key lime flavor, grape flavor, trusil art 511815, and fruit extracts.
  • sweetener such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate
  • flavors such as, but not limited to, mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, tutty fr
  • the orally disintegrating tablet compositions can be prepared by any of the known non limiting techniques such as freeze-drying, molding and sublimation, compression, cotton candy process, mass extrusion, etc or with use of specialized excipients such as effervescent couple, highly micronized agents, coprocessed excipients or the like:-
  • the orally disintegrating tablet formulations based on taste-masked PDE-5 inhibitor dissolve or disintegrate in the oral cavity, preferably within about 60 seconds.
  • the taste-masked PDE-5 inhibitor is incorporated in bite-dispersion tablets.
  • Bite-dispersion tablets are meant to be taken without water and disperse easily, and quickly, after a gentle bite when taken orally.
  • These tablets comprise various pharmaceutically acceptable excipients as have been discussed under orally disintegrating tablets in addition to excipients which may be specifically employed for bite-dispersion tablets.
  • the taste-masked PDE-5 inhibitor is incorporated in chewable tablets.
  • Ghewable tablets are taken slowly by chewing or sucking in the mouth, and enable taste-masked active contained therein to be orally administered without water.
  • These chewable tablets comprise various pharmaceutically acceptable excipients as have been discussed under orally disintegrating tablets in addition to excipients which may be specifically employed for chewable tablets.
  • taste-masked PDE-5 inhibitor is incorporated in an effervescent tablet. Effervescent tablets are intended to be dissolved or dispersed in water before administration and generally contain acid substances and carbonates or bicarbonates, which react rapidly in the presence of water releasing carbon dioxide. These tablets comprise various pharmaceutically acceptable excipients as have been discussed under dispersible tablets.
  • the effervescent tablets can comprise effervescent couples selected from, but not limited to, thermolabile gas-generating agents such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and an acid source such as citric acid, maleic acid or tartaric acid.
  • thermolabile gas-generating agents such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and an acid source such as citric acid, maleic acid or tartaric acid.
  • taste-masked PDE-5 inhibitor is incorporated in dispersible tablets.
  • Dispersible tablet refers to a tablet which disperses in aqueous phase, e.g. in water before administration.
  • a water-dispersible tablet according to the British Pharmacopoeia and European Pharmacopoeia, should meet the requirements of ; the test for dispersible tablets as regards dispersion time ( ⁇ 3 minutes) and dispersion- quality (i.e. to pass through a 710 m sieve).
  • the dispersible tablet compositions comprising taste-masked PDE-5 inhibitor can further comprise in addition to pharmaceutically acceptable excipients as disclosed under orally disintegrating tablets, one or more viscolizers.
  • viscolizers which can be used include but are not limited to: polyalkylene oxides such as polyethylene oxide; cellulose ethers such as hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, microcrystalline cellulose; gums such as gum arable alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, karaya, whelan; polyols such as dipropylene glycol, polypropylene glycol, propylene glycol, polyethylene glycol (PEG), sorbitol and glycerol; carbopol, starch and starch-based polymers
  • the preferred viscolizers are hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene oxide, sodium carboxy methylcellulose, microcrystalline cellulose, guar gam, xanthan gum, alginates and combinations thereof.
  • the weight percent of the viscolizer in the dispersible tablet dosage form is about 2 to 75 weight percent, preferably about 10 to 70 weight percent, and most preferably about 5 to 50 weight percent.
  • the viscolizers act to control sedimentation rate of dispersed active thereby producing homogeneous dispersions when the dispersible tablets are dispersed in water before administration thus ensuring substantially uniform dosing. They rapidly generate viscosity when the dispersible tablets come in contact with water, and a homogenous suspension is formed, which can be easily swallowed by children and the elderly, with minimal effect " of the release properties of the biologically active ingredient.
  • tablette and “tablet composition” and “tablet formulation” are used ' synonymously within the context of the present invention. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation and extrusion/ melt granulation. In one embodiment, the process is direct compression which involves compression of taste- masked drug-excipient blend after mixing them for a definite time period. The tablet may vary in shape such as oval, triangle, almond, peanut, parallelogram, round, pentagonal, hexagonal, and trapezoidal. The preferred shapes are round, oval and parallelogram forms.
  • the taste-masked PDE-5 inhibitor can be incorporated in sprinkle granules, quick melt wafers, lozenge, suspensions, syrups, dry suspensions or syrups for reconstitution, chewing gum or the like.
  • the various dosage forms as described in the present invention comprising taste- masked PDE-5 inhibitor are preferably immediate release dosage forms that release the taste-masked PDE-5 inhibitor instantly upon reaching either stomach or intestine.
  • the compositions disclosed in present invention can also be adapted to develop a formulation wherein taste-masked PDE-5 inhibitor is released in a controlled manner over a period of time, for example, from about 2 to about 24 hours.
  • PDE-5 inhibitor is treated with polymeric, non-polymeric pharmaceutically acceptable excipients described above or any combinations thereof.
  • the amount of such polymeric or non-polymeric excipients not only ensures masking of the objectionable taste of the active but also controls the release of PDE-5 inhibitor.
  • pellets or granules or the like of PDE-5 inhibitor are prepared comprising at least one release retardant in combination with one or more pharmaceutically acceptable excipients.
  • Suitable release retardants can be polymeric or non-polymeric pharmaceutically acceptable excipients or agents and include, but are not limited to, cellulose ethers, such as hydroxypropylmethylcellulose (HP C), hydroxypropylcellulose (MPC), hydroxyethylcellulose, ethyl cellulose and " carboxymethylcellulose sodium; polysaccharides, such as carageenan, guar gum, xanthan gum, tragacanth and ceratonia; polymethacrylates, such as copolymers of acrylic and methacrylic acid esters containing quarternary ammonium groups; cellulose esters, such as cellulose acetate; acrylic acid polymers, such as carbomers; waxes, such as hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax and microcrystalline wax; al
  • pellets or granules or the like can be further coated using excipients described above in order to achieve taste-masking and controlled release of PDE-5 inhibitor.
  • the amount of release retardant in the formulation is from about 1 to 90% by weight of the dosage form. In one embodiment, the amount of release retardant in the formulation is about 5 to 80% by weight of the dosage form.
  • the present invention discloses a process for preparing taste-masked pharmaceutical composition of PDE-5 inhibitor comprising: (a) coating an PDE-5 inhibitor with at least one taste-masking agent to form a taste-masked PDE-5 inhibitor;
  • step (b) blending the taste-masked PDE-5 inhibitor of step (a) with other excipients, except lubricant, to form a uniform powder mix;
  • step (c) lubricating the powder mix of step (b);
  • step (d) compressing the powder mix of step (c) into a orally disintegrating tablet composition
  • At least one taste-masking agent is a polymeric pharmaceutically acceptable excipient, a non-poiyrneric pharmaceutically acceptable excipient, or a combination thereof.
  • the present invention further discloses a process for preparing a taste-masked pharmaceutical composition of PDE-5 inhibitor comprising:
  • step (b) blending the mix of step (a) with other excipients, except lubricant, to form a ⁇ uniform powder mix;
  • step (c) lubricating the powder mix of step (b);
  • step (d) compressing the powder mix of step (c) into a orally disintegrating tablet composition
  • At least one taste-masking agent is a polymeric pharmaceutically acceptable excipient, a non-polymeric pharmaceutically acceptable excipient, or a combination thereof.
  • the present invention also discloses a process for preparing a taste-masked pharmaceutical formulation of PDE-5 inhibitor comprising:
  • step (b) blending the taste-masked PDE-5 inhibitor of step (a) with other excipients, except lubricant, to form a uniform powder mix;
  • step (c) lubricating the powder mix of step (b);
  • step (d) compressing the powder mix of step (c) into a orally disintegrating tablet composition
  • At least one taste-masking agent is an ion exchange resin, a carbomer, a cyclodextrin or a derivative thereof.
  • the present invention also discloses a process for preparing a taste-masked pharmaceutical formulation of PDE-5 inhibitor comprising:
  • step (b) blending the taste-masked PDE-5 inhibitor of step (a) with other excipients, except lubricant, to form a uniform powder mix;
  • step (c) lubricating the powder mix of step (b);
  • step (d) compressing the powder mix of step (c) into an orally disintegrating tablet composition
  • At least one taste-masking agent is an adsorbent.
  • the present invention further provides a method of for the treatment of sexual dysfunction such as, but not limited to, erectile dysfunction in a mammal, preferably a human, including, but not limited to a male or for prevention or treatment of pulmonary hypertension, ischemia/reperfusion injury, angina myocardial infarction, pulmonary perfusion, inflammatory and degenerative lung disorders and other cardiac, pulmonary and vascular related conditions comprising administering to a patient in need thereof formulation of the present invention comprising an PDE-5 inhibitor, at least one taste- masking agent and at least one pharmaceutically acceptable excipient.
  • sexual dysfunction such as, but not limited to, erectile dysfunction in a mammal, preferably a human, including, but not limited to a male or for prevention or treatment of pulmonary hypertension, ischemia/reperfusion injury, angina myocardial infarction, pulmonary perfusion, inflammatory and degenerative lung disorders and other cardiac, pulmonary and vascular related conditions
  • administering to a patient in need thereof formulation of the present invention
  • composition of the present invention comprising PDE-5 inhibitor, at least one taste-masking agent and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of sexual dysfunction such as, but not limited to, erectile dysfunction in a mammal, preferably a human, including, but not limited to a male or for prevention or treatment of pulmonary hypertension, ischemia/reperfusion injury, angina myocardial infarction, pulmonary perfusion, inflammatory and degenerative lung disorders and other cardiac, pulmonary and vascular related conditions.
  • the taste-masked PDE-5 inhibitor compositions of the present invention may be adapted to deliver one or more active agents in addition to PDE-5 inhibitor.
  • the taste-masked PDE-5 inhibitor compositions of the present invention may be coadministered with compositions of other active agents.
  • the active agent that may be combined with the PDE-5 inhibitor includes, but is not limited to, finasteride, dutasteride, izonsteride, idronoxil, epristeride, serenoa repens, PHL 00801 , atropine, fluvoxate, hyoscine, oxybutynin, darifenacin, tolterodine, (+)-N,N-diisopropyl-3-(2-hydroxy-5- hydroxymethylphenyl)-3-phehylpropylamine, propantheline, propiverine, trospium, solifenacin, fesoterodine, 3-alpha-androstanediol, ambrisentan, roflumilast, cilomilast or the like or mixtures thereof.
  • Example 1 Taste-masked tadalafil orally disintegrating tablets
  • the orally disintegrating tablets comprising tadalafil were prepared as per the following composition
  • Table 1 Composition of orally disintegrating tadalafil tablets
  • Directly compressible excipient comprising mannitol 59.0
  • Flavor (Tutty Frutty) 0.5
  • Tadaiafil was dry mixed with glyceryl behenate and blended with other excipients except lubricant to get a uniform powder mix.
  • the blend was lubricated and compressed to form tablets with acceptable taste and pleasant mouthfeel having the following parameters:
  • Example 2 Taste-masked tadaiafil bite- dispersion tablets
  • Coating solution was prepared by melting hydrogenated vegetable oil in water bath and adding glyceryl mono & dicaprate in molten wax. Aspartame was dissolved in hot solution of hydroxypropyl methyl cellulose E5 and this aqueous phase was added to above oily phase. The system was homogenized and cooled to room temperature to which flavor and aspartame were added to obtain a coating solution.
  • Drug blend was coated with coating composition using top spray assembly to weight gain of 40 %.
  • Table 4 Composition of taste-masked bite -dispersion tablets of tadalafil
  • the tablets had pleasant and acceptable mouth feel along with desirable disintegration time.
  • Example 3 Taste-masked tadalafil orally disintegrating tablets
  • Flavor (Tutty Frutty) 1.0
  • Tadalafil was thoroughly mixed with basic butylated methacrylate copolymer and granulated using aqueous povidone solution. These granules were dried and then blended with other excipients except lubricant to get a uniform mass. The mass was lubricated and compressed into tablets having following parameters: ⁇ * Hardness (N) 28-38
  • Example 4 Dispersible tablets of taste-masked tadalafil
  • Tadalafil was layered on 200mg non-pareil beads and these drug-loaded beads were further coated with a combination of ethyl cellulose and hydroxypropyl methylceliulose (20:80) to a weight gain of about 20%.
  • Example 5 Orally disintegrating tablets of taste-masked tadalafil
  • Table 7 Composition of orally disintegrating tadalafil tablets
  • Directly compressible excipient comprising mannitol and
  • Tadalafii in solution form was complexed with a cationic ion exchange resin by stirring for 3 hours.
  • Complexed tadalafii was separated, dried and blended with other excipients in a blender to get a uniform mass except lubricant.
  • the mass was lubricated and compressed into tablets having following parameters:
  • Example 6 Bite dispersion tablets of tadalafii
  • Table 8 Composition of tadalafii bite-dispersion tablet
  • Directly compressible excipient comprising mannitol and 190.0 calcium silicate
  • Tadalafil was melt granulated with stearoyl macrogol glycerides. The granules were then blended with other excipients except lubricant in a blender to get a uniform powder mix. The mix was lubricated and compressed into tablets. Tablets with desired taste masking, friability and disintegration time were obtained. The formulation was palatable with pleasant mouth feel.
  • Example 7 Orally disintegrating tablet of sildenafil citrate eq 25mg base
  • Table 9 Composition of sildenafil citrate orally disintegrating tablet
  • Sildenafil citrate equivalent to 25mg base was melt granulated with lauroyl macrogol glycerides. The granules were then blended with other excipients except lubricant in a blender to get a uniform powder mix. The mix was lubricated and compressed to form palatable orally disintegrating tablets with desired friability and disintegration time.
  • Example 8 Orally disintegrating tablet of vardenafil hydrochloride
  • Drug blend was coated with coating composition using bottom spray assembly to weight gain of 30 %.
  • Table 2 Composition of taste-masked orally disintegrating tablet of vardenafil hydrochloride
  • Citric acid USP 15.0

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Abstract

La présente invention concerne des compositions pharmaceutiques au goût masqué comprenant des inhibiteurs de phosphodiestérase-5 (PDE-5). Lesdites compositions pharmaceutiques au goût masqué pour administration orale comprennent au moins un inhibiteur de PDE-5, au moins un agent masqueur de goût, et au moins un excipient pharmaceutiquement acceptable. En outre, les compositions d'inhibiteur de PDE-5 au goût masqué sont fournies sous la forme de formulations au goût agréable adaptées à une administration orale, telle que des comprimés à désintégration orale, des comprimés à dispersion rapide, des comprimés croquables, des comprimés dispersibles, et des comprimés effervescents ou analogues. L'invention porte en outre sur un procédé de masquage du goût désagréable de l'inhibiteur de PDE-5.
PCT/IN2010/000589 2009-09-03 2010-09-03 Compositions pharmaceutiques au goût masqué WO2011030351A2 (fr)

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WO2013077533A1 (fr) * 2011-11-25 2013-05-30 한국유나이티드제약 주식회사 Comprimés de citrate de sildénafil à croquer dans lesquels l'amertume est masquée, et procédé de fabrication associé
WO2013084191A1 (fr) * 2011-12-08 2013-06-13 Laboratorios Liomont S.A. De C.V. Comprimé orodispersible de sildénafil et procédé de préparation correspondant
KR20130064699A (ko) * 2011-12-08 2013-06-18 에스케이케미칼주식회사 미로데나필 또는 이의 약학적으로 허용 가능한 염을 함유하는 구강 투여용 필름
WO2013109221A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Nouvelles formulations effervescentes comprenant une composition édulcorante
WO2013109230A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Compositions pharmaceutiques contenant du tadalafil
CN103271885A (zh) * 2013-05-23 2013-09-04 浙江华海药业股份有限公司 他达拉非口腔崩解片及其制备方法
EP2641477A1 (fr) * 2012-03-19 2013-09-25 Symrise AG Compositions de matière
WO2014092358A1 (fr) * 2012-12-14 2014-06-19 Hanmi Pharm. Co., Ltd. Comprimé à mâcher contenant un inhibiteur de la phosphodiésterase de type 5
US20140271847A1 (en) * 2013-03-13 2014-09-18 SatisPharma, LLC Formulations and methods for rapid penile erections
WO2014148883A1 (fr) * 2013-03-20 2014-09-25 Natureceuticals Sdn Bhd Formulations d'herbes médicinales
WO2014196916A1 (fr) 2013-06-03 2014-12-11 Mcneil Ab Forme dosifiée pharmaceutique solide de libération d'au moins un principe pharmaceutique actif dans la cavité buccale
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KR101485177B1 (ko) * 2014-02-10 2015-01-23 한국유나이티드제약 주식회사 쓴맛이 차폐된 실데나필 시트레이트의 저작정 및 그 제조방법
CN104352461A (zh) * 2013-04-28 2015-02-18 南京海融医药科技有限公司 他达拉非的口服药物制剂
WO2015089105A1 (fr) * 2013-12-09 2015-06-18 Respira Therapeutics, Inc. Formulations en poudre d'inhibiteur pde5 et procédés y associés
US20150182629A1 (en) * 2012-07-02 2015-07-02 Hetero Research Foundation Stable compositions of fesoterodine
CN105213333A (zh) * 2014-06-30 2016-01-06 深圳海王药业有限公司 一种他达拉非药物组合物及其制备方法
CN104644574B (zh) * 2013-11-18 2017-08-01 深圳海王医药科技研究院有限公司 一种枸橼酸西地那非掩味制剂
CN107694476A (zh) * 2017-07-25 2018-02-16 江苏远鸿新材料科技有限公司 一种高强度球型干燥剂的成型制造方法
JP2018508487A (ja) * 2015-02-02 2018-03-29 ファニン ファーマシューティカル カンパニー リミテッドＷｈａｎｉｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ． Ｃｏ．， Ｌｔｄ． デュタステリド含有固体分散体及びこれを含む組成物
US10010638B2 (en) 2016-06-14 2018-07-03 S. C. Johnson & Son, Inc. Wax melt with filler
WO2019081451A1 (fr) * 2017-10-26 2019-05-02 Mw Encap Limited Formulations remplies liquides d'inhibiteurs de pde5
US10342886B2 (en) 2016-01-26 2019-07-09 S.C. Johnson & Son, Inc. Extruded wax melt and method of producing same
IT201800003507A1 (it) * 2018-03-13 2019-09-13 Fulton Medicinali S P A Compressa sublinguale comprendente sildenafil citrato
WO2020047311A1 (fr) * 2018-08-31 2020-03-05 Imara Inc. Inhibiteurs de pde9 pour le traitement de la drépanocytose
CN111110683A (zh) * 2018-10-31 2020-05-08 广东东阳光药业有限公司 一种索利那新掩味组合物及其制备方法
WO2020212931A1 (fr) * 2019-04-18 2020-10-22 Vigorous Solutions Ltd. Compositions liquides de citrate de sildénafil
US11179338B1 (en) 2021-04-09 2021-11-23 Auson Pharmaceuticals Inc. Powder for oral suspension containing tadalafil
CN114173761A (zh) * 2019-07-26 2022-03-11 核心医药化学有限公司 包含乌地那非的药物组合物
CN114957332A (zh) * 2022-05-30 2022-08-30 苏州正永生物医药有限公司 一种阿伐那非磷酸酯类化合物及其制备方法和应用
US11491161B2 (en) 2016-12-14 2022-11-08 Respira Therapeutics, Inc. Methods and compositions for treatment of pulmonary hypertension and other lung disorders
US11608342B2 (en) 2015-07-07 2023-03-21 H. Lundbeck A/S PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases
CN115990140A (zh) * 2023-02-15 2023-04-21 北京悦康科创医药科技股份有限公司 一种那非类化合物冻干片及其制备方法
CN117243927A (zh) * 2023-10-17 2023-12-19 深圳市泰力生物医药有限公司 含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法
EP4316468A1 (fr) * 2022-08-03 2024-02-07 Recordati Industria Chimica E Farmaceutica SPA Complexation innovante d'extrait de serenoa lipido-stérol avec du tadalafil
US12006319B2 (en) 2020-12-02 2024-06-11 Cardurion Pharmaceuticals, Inc. Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one

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WO2013084191A1 (fr) * 2011-12-08 2013-06-13 Laboratorios Liomont S.A. De C.V. Comprimé orodispersible de sildénafil et procédé de préparation correspondant
KR20130064699A (ko) * 2011-12-08 2013-06-18 에스케이케미칼주식회사 미로데나필 또는 이의 약학적으로 허용 가능한 염을 함유하는 구강 투여용 필름
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WO2013109221A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Nouvelles formulations effervescentes comprenant une composition édulcorante
WO2013109230A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Compositions pharmaceutiques contenant du tadalafil
US8828473B2 (en) 2012-03-19 2014-09-09 Symrise Ag Substance mixtures
EP2641477A1 (fr) * 2012-03-19 2013-09-25 Symrise AG Compositions de matière
US20150182629A1 (en) * 2012-07-02 2015-07-02 Hetero Research Foundation Stable compositions of fesoterodine
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US20140271847A1 (en) * 2013-03-13 2014-09-18 SatisPharma, LLC Formulations and methods for rapid penile erections
WO2014148883A1 (fr) * 2013-03-20 2014-09-25 Natureceuticals Sdn Bhd Formulations d'herbes médicinales
CN104352461A (zh) * 2013-04-28 2015-02-18 南京海融医药科技有限公司 他达拉非的口服药物制剂
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WO2014196916A1 (fr) 2013-06-03 2014-12-11 Mcneil Ab Forme dosifiée pharmaceutique solide de libération d'au moins un principe pharmaceutique actif dans la cavité buccale
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WO2014209022A1 (fr) * 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Formule de comprimé à mâcher comprenant du tadalafil ou l'un de ses sels pharmaceutiquement acceptables
KR102239291B1 (ko) * 2013-06-28 2021-04-14 한미약품 주식회사 타다라필 또는 이의 약학적으로 허용가능한 염을 포함하는 저작정 제제
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US11911390B2 (en) * 2013-12-09 2024-02-27 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto
WO2015089105A1 (fr) * 2013-12-09 2015-06-18 Respira Therapeutics, Inc. Formulations en poudre d'inhibiteur pde5 et procédés y associés
US11806314B2 (en) 2013-12-09 2023-11-07 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto
US20160317542A1 (en) * 2013-12-09 2016-11-03 Respira Therapeutics, Inc. Pde5 inhibitor powder formulations and methods relating thereto
US20220016126A1 (en) * 2013-12-09 2022-01-20 Respira Therapeutics, Inc. Pde5 inhibitor powder formulations and methods relating thereto
KR101485177B1 (ko) * 2014-02-10 2015-01-23 한국유나이티드제약 주식회사 쓴맛이 차폐된 실데나필 시트레이트의 저작정 및 그 제조방법
CN105213333A (zh) * 2014-06-30 2016-01-06 深圳海王药业有限公司 一种他达拉非药物组合物及其制备方法
JP2018508487A (ja) * 2015-02-02 2018-03-29 ファニン ファーマシューティカル カンパニー リミテッドＷｈａｎｉｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ． Ｃｏ．， Ｌｔｄ． デュタステリド含有固体分散体及びこれを含む組成物
US11608342B2 (en) 2015-07-07 2023-03-21 H. Lundbeck A/S PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases
US10342886B2 (en) 2016-01-26 2019-07-09 S.C. Johnson & Son, Inc. Extruded wax melt and method of producing same
US10010638B2 (en) 2016-06-14 2018-07-03 S. C. Johnson & Son, Inc. Wax melt with filler
US11491160B2 (en) 2016-12-14 2022-11-08 Respira Therapeutics, Inc. Methods and compositions for treatment of pulmonary hypertension and other lung disorders
US11491161B2 (en) 2016-12-14 2022-11-08 Respira Therapeutics, Inc. Methods and compositions for treatment of pulmonary hypertension and other lung disorders
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CN107694476A (zh) * 2017-07-25 2018-02-16 江苏远鸿新材料科技有限公司 一种高强度球型干燥剂的成型制造方法
WO2019081451A1 (fr) * 2017-10-26 2019-05-02 Mw Encap Limited Formulations remplies liquides d'inhibiteurs de pde5
CN111356450A (zh) * 2017-10-26 2020-06-30 兆瓦恩卡普有限公司 Pde5抑制剂的液体填充制剂
US20210007979A1 (en) * 2018-03-13 2021-01-14 Fulton Medicinal S.P.A. Sublingual tablet comprising sildenafil citrate
IT201800003507A1 (it) * 2018-03-13 2019-09-13 Fulton Medicinali S P A Compressa sublinguale comprendente sildenafil citrato
WO2019174995A1 (fr) 2018-03-13 2019-09-19 Fulton Medicinali S.P.A. Comprimé sublingual comprenant du citrate de sildénafil
WO2020047311A1 (fr) * 2018-08-31 2020-03-05 Imara Inc. Inhibiteurs de pde9 pour le traitement de la drépanocytose
CN111110683B (zh) * 2018-10-31 2023-08-15 广东东阳光药业股份有限公司 一种索利那新掩味组合物及其制备方法
CN111110683A (zh) * 2018-10-31 2020-05-08 广东东阳光药业有限公司 一种索利那新掩味组合物及其制备方法
WO2020212931A1 (fr) * 2019-04-18 2020-10-22 Vigorous Solutions Ltd. Compositions liquides de citrate de sildénafil
CN114173761A (zh) * 2019-07-26 2022-03-11 核心医药化学有限公司 包含乌地那非的药物组合物
EP4005556A4 (fr) * 2019-07-26 2023-08-02 Corepharm Bio Co., Ltd. Composition pharmaceutique comprenant de l'udénafil
CN114173761B (zh) * 2019-07-26 2024-04-19 核心医药化学有限公司 包含乌地那非的药物组合物
US12006319B2 (en) 2020-12-02 2024-06-11 Cardurion Pharmaceuticals, Inc. Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one
WO2022216294A1 (fr) * 2021-04-09 2022-10-13 Auson Pharmaceuticals Inc. Poudre pour suspension orale contenant du tadalafil
US11179338B1 (en) 2021-04-09 2021-11-23 Auson Pharmaceuticals Inc. Powder for oral suspension containing tadalafil
CN114957332A (zh) * 2022-05-30 2022-08-30 苏州正永生物医药有限公司 一种阿伐那非磷酸酯类化合物及其制备方法和应用
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CN115990140A (zh) * 2023-02-15 2023-04-21 北京悦康科创医药科技股份有限公司 一种那非类化合物冻干片及其制备方法
CN117243927A (zh) * 2023-10-17 2023-12-19 深圳市泰力生物医药有限公司 含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法

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