WO2011030351A2

WO2011030351A2 - Taste - masked pharmaceutical compositions

Info

Publication number: WO2011030351A2
Application number: PCT/IN2010/000589
Authority: WO
Inventors: Pratibha Sudhir Pilgaonkar; Maharukh Tehmasp Rustomjee; Anilkumar Surendrakumar Gandhi
Original assignee: Rubicon Research Private Limited
Priority date: 2009-09-03
Filing date: 2010-09-03
Publication date: 2011-03-17
Also published as: WO2011030351A3

Abstract

The present invention relates to taste-masked pharmaceutical compositions comprising phosphodiesterase-5 (PDE-5) inhibitors. The taste-masked pharmaceutical compositions for oral administration comprise at least one PDE-5 inhibitor, at least one taste-masking agent; and at least one pharmaceutically acceptable excipient. Further the taste-masked PDE-5 inhibitor compositions are provided in the form of palatable formulations suitable for oral administration such as orally disintegrating tablets, bite-dispersion tablets, chewable tablets, dispersible tablets, effervescent tablets or the like. The invention also further relates to method for masking the objectionable taste of PDE-5 inhibitor.

Description

TASTE - MASKED PHARMACEUTICAL COMPOSITIONS

Field of Invention

The present invention relates to taste-masked pharmaceutical compositions comprising phosphodiesterase-5 (PDE-5) inhibitors. Particularly, the 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. The invention further relates to method for masking the objectionable taste of PDE-5 inhibitor.

Background of the invention

A wide variety of biological processes including cardiac muscle contraction, regulation of blood flow, neural transmission, glandular secretion, cell differentiation and gene expression are affected by intracellular levels of the biological second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These intracellular levels of cAMP and cGMP are regulated by cyclic nucleotide phosphodiesterases (PDEs). PDE enzymes are responsible for the hydrolysis of the cyclic nucleotides and have a critical role in regulating the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules. 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. Normal 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.

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. In patients with inflammatory and degenerative lung disorders such as chronic obstructive pulmonary disease (CQPD), adult respiratory distress syndrome (ARDS), acute lung injury (ALI), bronchitis, bronchial asthma, pulmonary fibroses, emphysema, interstitial pulmonary disorders and pneumonias where there can be partial or global respiratory failure, 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.

These 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. However, 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. Hence, it is desirable to have formulations that rapidly disintegrate and/or can be consumed even without water just by the action of saliva in the oral cavity. However for such rapidly disintegrating dosage forms, there is a need to mask the bitter taste of actives as the formulation remains in contact with the taste receptors in the mouth for a longer period of time. It is therefore desirable to have a formulation wherein bitter taste of the PDE-5 inhibitor is masked to provide taste-masked palatable, easy to administer formulations. As PDE-5 inhibitors, have low solubility in water, the dissolution rate and bioavailability of conventional formulations is likely to be poor. Many researchers have tried to overcome poor water solubility and increase the dissolution rate and bioavailability of these actives for faster therapeutic onset of drug as compared to marketed formulations. U.S Patent. No. 5,985,326 discloses that poor solubility of tadalafil has prompted the development of coprecipitate preparations with a polymer like hydroxypropyl methylcellulose phthalate whereby dissolution of the active is improved. U.S Patent. No. 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. Other efforts to decrease or modify particle size in order to facilitate the solubility of tadalafil have been described in European Patent Application 1875914 A1 , U.S Patent No. 7,417,044, European Patent 1843770 B1 and U.S Patent Application 2007/0104792. All these efforts have focused on increasing the solubility of the PDE-5 inhibitor either alone or in oral tablet formulations; however none of these have addressed the aspect of bitter.taste thereof which may lead to patient non compliance.

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. For very bitter actives such as sildenafil, incorporation of only a solubilization inhibitor may not provide the desired taste-masking and the bitter taste of the active may still be perceived.

A need thus exists for a dosage form that provides the convenience of a tablet formulation while also providing the desired ease of administration such as orally disintegrating tablets, chewab!e tablets, dispersible tablets, effervescent tablets, bite- dispersion tablets or the like. Furthermore that the PDE-5 inhibitors are bitter in taste, a need exists to provide the easy to administer, rapidly disintegrating dosage forms such as orally disintegrating tablets, chewable tablets, dispersible tablets, effervescent tablets, bite-dispersion tablets or the like in a taste-masked palatable formulations that have improved patient compliance.

After rigorous experimentation it was surprisingly found that the bitter taste of PDE-5 inhibitor such as tadalafil, sildenafil or vardenafil can be masked with taste-masking agents by 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.

Summary of the Invention

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. 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.

Detailed Description of the Invention

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.

The term "PDE-5 inhibitor/s", as employed herein 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-pyrazolo[4,3-]pyrimidin-7-one, 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1- methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4- methyl-1 -piperazinylsulfonyl)-phenyl]-1 -methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3- d]pyhmidin-7-one, 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n- prop yl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-propyl)-1- piperazinylsulfonyl)-phenyl]-1-methyl-3-n-pr opyl-1 , 6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl)phenyl]-1- methyl-3 -n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[5-[4-(2- hydroxyethyl)-1 -piperazinylsulfonyl]-2-n-propoxyphenyl]-1 -methyl-3-n-propyl-1 ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-methyl-1-iperazinylcarbonyl)phenyl]- 1-methyl-3-n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-5- (1 -methyl-2-imidazolyl)phenyl]-1 -methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one, 1 ,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2- propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-1 ,2-dihydro-2-oxypyridine-3- carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one, 7-methylthio-4-oxo-2- (2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrirnidine,6-hydroxy-2-(2- propoxyphenyl)pyrimidine-4-carboxamide, 1 -ethyl-3-methylimidazo[1 ,5a]quinoxalin-4(5H)- one,4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline, 5-ethyl-8-[3-(N- cyclohexyl-N-methylcarbamoyl)-propyloxy]-4,5-dihydro-4-oxo -pyrido[3,2-e]-pyrrolo1,2- a] pyrazine, 5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1

- b] purin]4'(5'H)-one, 1 -[6-chioro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2- yl)piperidine-4-carboxylic acid, (6R, 9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyi-

3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]-purin-4-one

phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4-one,1-cyd^

pyridyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimid-4-one,2-butyl-1-(2-chlorobenzyl)6-ethoxy- carbonylbenzimidazole, 2-(4-carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6- nitroquinazoline or 2-ph nyl-8-ethoxycycloheptimidazole. 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, . enantiomers, optical isomers, tautomers or racemic mixtures thereof. The terms "PDE-5 inhibitor/s", "phosphodiesterase-5 inhibitor/s" or "cyclic nucleotide phosphodiesterase-5 inhibitor/s" have been used interchangeably for the purpose of the present invention.

Pharmaceutically effective amount of PDE-5 inhibitor is employed in the composition of the present invention. The term "effective amount" refers to an amount effective to achieve desired preventive, therapeutic and/or beneficial effect. In one embodiment 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. In another embodiment 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. In still another embodiment, 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. In one embodiment the 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. In one embodiment 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. In another embodiment 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. In still another embodiment 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. In an aspect of the present invention, pellets of PDE-5 inhibitor may be prepared using extrusion spheronization. In another aspect of the present invention, 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. In a yet another embodiment, 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 acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof.

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.

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. 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. 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. Specific examples include but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof. 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 tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides, stearoyl macrogolglycerides, and combinations thereof.

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. In one embodiment 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.

In one embodiment, 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), Emulcire™ (cetyl alcohol), Plurol® diisostearique (polyglyceryl diisostearate), Geleol® (glyceryl stearate),and mixtures thereof.

In another embodiment, 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. In one embodiment, 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.

In another embodiment, 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.

In one embodiment, taste-masking agent employed in the formulation of the present invention is cydodextrin or a derivative thereof. In another embodiment, 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, α, β and γ-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, α, β and γ-cyclodextrins, or alkylated, hydroxyalkylated, esterified, glycosylated or substituted derivatives thereof, such as (2,6- di-o-methyl)-P-cyclodextrin (DIMEB) (dimethyl^-cyclodextrin), randomly methylated-β- cyclodextrin (RAMEB), and hydroxypropyl^-cyclodextrin (HP CD), hydroxyethyl-β- cyclodextrin, dihydroxypropyl^-cyclodextrin, trimethyl^-cyclodextrin, hydroxymethyl-β- cydodextrin, β-cyclodextrin sulfate, β-cyclodextrin sulfonate, methyl^-cyclodextrin, sulfobutyl ether cydodextrin (SBE-CD) (β-cyclodextrin sulfobutyl ether), glucosyl-a- cyclodextrin, glucosyl^-cyclodextrin, diglucosyl^-cyclodextrin, maltosyl-Y-cyclodextrin, maltosyl-Y-cyclodextrin, maltosyl-Y-cyclodextrin, maltotriosyl-β cydodextrin, maltotriosyl- Y-cyclodextrin, dimaltosyl^-cyclodextrin and mixtures thereof such as maltosyl-β- cyclodextrin/dimaltosyl-p-cyclodextrin. 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. In one embodiment a physical mixture of PDE-5 inhibitor and cyclodextrin or a derivative thereof is employed in the composition of the present invention. In one embodiment, 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. In one embodiment, the taste-masking agent employed in the compositions of the present invention is an ion-exchange resin. In another embodiment, 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. Additionally 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. In yet another embodiment of the present invention, 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. resins (strong cationic exchangers based upon polystyrenesulphonic acid with variable crosslinking (1-12% divinylbenzene)), Tulsion^® 335 - (Polacrilex/{Polacirilex S), Tulsion^® 339 (Polacrilin potassium USP), Tulsion^® 344 (Sodium polystyrene sulfonate BP), Indion^® 204 (crosslinked polyacrylic acid), Indion^® 214 (crosslinked polyacrylic acid), Indion^® 234 (crosslinked polyacrylic acid), Indion^® 234S (crosslinked polyacrylic acid), Indion^® 294 (crosslinked polyacrylic acid), Purolite^® C115 HMR (carboxylic acid functional group), Purolite^® C1 5 E (carboxylic acid functional group), Purolite^® C100 HMR (sulfonic acid functional group), Purolite^® 100 MR (sulfonic acid functional group) or cation exchange resins having phosphonic functioned groups and the like or any combinations thereof. In one embodiment, 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.

In another embodiment, the taste-masking agent employed in the compositions of the present invention is a carbomer or a derivative thereof. In one embodiment, 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. These complexes can be prepared by mixing, blending or slurrying PDE5 inhibitor and carbomer together to allow the desired complex formation. In another embodiment, 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.

In yet another embodiment, 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. 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.

In one 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 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.

In one embodiment 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. In one embodiment 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.

In an embodiment, taste-masked PDE-5 inhibitor formulation of the present invention is in the form of orally disintegrating tablets. In one embodiment, 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. The 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. Examples of 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. Examples of suitable 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. Examples of 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. Examples of the lubricant 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. Examples of 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. The compositions of the present invention may also include stabilizers -such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like. Examples of 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. The 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. Further, the 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.

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. In one embodiment of the present invention, 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.

In an aspect of the present invention, 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. In another embodiment, 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.

In an embodiment of the present invention, 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.

Examples of 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 such as pregelatinized starch, acrylic acid and methacrylic acid polymers, and esters thereof, maleic anhydride polymers; polymaleic acid; poly(acrylamides); poly(olefinic alcoholjs; poly(N-vinyl lactams); polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; povidone vinylpyrrolidone/vinyl acetate copolymer and polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone, chitin, - cyclodextrin, gelatin, chitosan, and combinations thereof. 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.

The terms "tablet" 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.

In a still another embodiment of the present invention, 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. In such a formulation, 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.

In another embodiment of the present invention, 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, as discussed above 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; alginates, such as alginic acid and sodium alginate; and fatty acid derivatives, such as glyceryl monostearate and glyceryl palmitostearate. These 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;

(b) blending the taste-masked PDE-5 inhibitor of step (a) with other excipients, except lubricant, to form a uniform powder mix;

(c) lubricating the powder mix of step (b); and -

(d) compressing the powder mix of step (c) into a orally disintegrating tablet composition,

wherein 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:

(a) physically mixing PDE-5 inhibitor with at least one taste-masking agent;

(b) blending the mix of step (a) with other excipients, except lubricant, to form a^~ uniform powder mix;

(c) lubricating the powder mix of step (b); and

wherein 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:

(a) complexing PDE-5 inhibitor with at least one taste-masking agent to form a taste-masked PDE-5 inhibitor;

(c) lubricating the powder mix of step (b); and

wherein 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:

(a) adsorbing PDE-5 inhibitor with at least one taste-masking agent to form a taste-masked PDE-5 inhibitor;

(c) lubricating the powder mix of step (b); and

(d) compressing the powder mix of step (c) into an orally disintegrating tablet composition,

wherein 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. In another embodiment, there is provided use of the 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. In a still further embodiment of the present invention 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. In another embodiment of the present invention 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.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Details of the present invention, including its objects and advantages, are provided in the non-limiting exemplary illustrations below.

EXAMPLES

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

Ingredients mg/tab

Tadalafil 2.5

Glyceryl behenate, USP 2.5

Directly compressible excipient comprising mannitol 59.0

and calcium silicate

Starch, USP 10.0

Microcrystalline cellulose, USP 6.0

Crospovidone, USP/NF 10.5

Aspartame, USP 4.0

Acesulfame K, Ph.Eur. 3.0

Colloidal silicon dioxide, USP 1.0

Magnesium stearate, USP 1.0

Flavor (Tutty Frutty) 0.5

Total 100 Procedure: 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:

Hardness (N) : 30-38 — Friability (%) 0.40

Disintegration time (sec) 10-15

Disintegration time in oral cavity (sec) 30-40

Example 2: Taste-masked tadaiafil bite- dispersion tablets

Table 2: Formulation of blend with microcrystalline cellulose

Procedure: The drug was blended with microcrystalline cellulose (1 :2 parts). 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

Procedure: The coated taste masked tadalafil granules were blended with other excipients lubricated using magnesium stearate. The blend was compressed to get a bite-dispersion tablet.

The tablets had pleasant and acceptable mouth feel along with desirable disintegration time.

Example 3: Taste-masked tadalafil orally disintegrating tablets

Table 5: Composition of orally disintegrating tablets

Ingredients mg/ tablet

Tadalafil 5.0

Basic butylated methacrylate copolymer, Ph. Eur. 10.0

Povidone, USP 24.0 Directly compressible excipient comprising mannitol and

74.0

calcium silicate

Starch, USP 18.0

Microcrystalline cellulose, USP 40.0

Crospovidone, USP/NF 18.0

Aspartame, USP 3.5

Acesulfame K, Ph.Eur. 3.0

Colloidal silicon dioxide, USP 1.5

Magnesium stearate, USP 2.0

Flavor (Tutty Frutty) 1.0

Total 200

Procedure: 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

Friability (%) 0.28

Disintegration time (sec) 10-18

Disintegration time in oral cavity (sec) 22-32

Orally disintegrating tablets of tadalafil with pleasant taste and acceptable wicking time were obtained.

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%.

Table 6: Composition of tadalafil dispersible tablet

Ingredients mg/unit

Taste masked tadalafil granules equivalent to 20 mg tadalafil 264.0 Microcrystalline cellulose, USP . 80.0

Hydroxy ethyl cellulose , USP 50.0

Crospovidone, USP/NF 42.0

Hydroxy propyl cellulose, USP 15.0

Mannitol, USP 17.0

Copovidone, Ph. Eur. 10.0

Aspartame, USP 10.0

Vanilla flavor, USP 3.0

Colloidal silicon dioxide, USP 4.0

Magnesium stearate, USP 5.0

Total 500

Procedure: All the ingredients were sifted and blended with taste-masked tadalafil. The blend was lubricated and compressed to form dispersible tablets. The dispersibje tablets had excellent palatability and passed the disintegration and dispersibility tests as per Ph. Eur. (4^th Edition). The dispersion produced in water with the tablets showed desired rate of sedimentation, with not more than 50% of the active settling in 5 minutes.

Example 5: Orally disintegrating tablets of taste-masked tadalafil

Table 7: Composition of orally disintegrating tadalafil tablets

Ingredients mg/ tablet

Tadalafil 5.0

Cationic ion exchange resin 10.0

Directly compressible excipient comprising mannitol and

52.0

calcium silicate

Starch, Ph. Eur. 8.0

Microcrystalline cellulose, USP 11.0

Crospovidone, USP 5.0

Aspartame, UP 3.0

Acesulfame K, Ph. Eur. 3.0

Colloidal silicon dioxide, USP 1.0 Grapes Flavor 1.0

Magnesium stearate, USP 1.0

Total 100.0

Procedure: 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:

Hardness (N) 20-40

Friability (%) 0.66 %

Disintegration time (sec) 8-12

Disintegration time in oral cavity (sec) 20-30

Tablets with desired taste masking, friability and disintegration time were obtained. Example 6: Bite dispersion tablets of tadalafii

Table 8: Composition of tadalafii bite-dispersion tablet

Ingredients mg/tablet

Tadalafii 5.0

Stearoyl macrogol glycerides, USP 15.0

Directly compressible excipient comprising mannitol and 190.0 calcium silicate

Starch, USP 32.0

Microcrystalline cellulose, USP 25.0

Crospovidone, USP/NF 15.0

Acesulfame K, Ph. Eur. 10.0

Colloidal silicon dioxide, USP 3.0

Magnesium stearate, USP 3.0

Banana flavor 2.0

Total 300 Procedure: 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

Procedure: 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

Table 10: Formulation of blend with microcrystalline cellulose

Ingredients mg/tab

Vardenafil hydrochloride 10.0

Microcrystalline cellulose spheres 20.0 Table 11 : Composition of coating solution

Procedure: The drug was loaded onto the microcrystalline cellulose beads. Hydrogenated vegetable oil and glyceryl stearate were heated in a water bath at 70°C - 80°C. A part of the water was heated to 90°C and added to the molten waxy mass with constant stirring using a suitable laboratory stirrer to obtain a smooth emulsion. The emulsion was cooled to room temperature. Polyvinyl acetate dispersion 30% was mixed with the remaining quantity of water and added to the above emulsion under stirring to form a stable coating composition.

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

Ingredients mg/tab

Taste-masked coated vardenafil hydrochloride 39.0

Spray dried mannitol, USP 100.0

Microcrystalline cellulose, USP 63.0

Aspartame, USP 12.0

Sodium starch glycolate, USP 23.0

Citric acid , USP 15.0

Colloidal silicon dioxide , USP 11.0

Talc, USP 28.0

Orange Flavor 6.0

Magnesium stearate, USP 3.0

Total 300 Procedure: The coated taste masked granules of vardenafil hydrochloride were blended with other excipients and lubricated using magnesium stearate to form an orally disintegrating tablet.

Claims

1. A taste-masked pharmaceutical composition for oral administration comprising:

(a) at least one PDE-5 inhibitor;

(b) at least one taste-masking agent; and

(c) at least one pharmaceutically acceptable excipient.

2. The composition of claim 1 wherein said PDE-5 inhibitor is tadalafil^ sildenafil, vardenafil, avanafil, acetildenafil, udenafil, thiomethisosildenafil, lodenafil, mirodenafil or zaprinast.

3. The composition of claim 2 wherein said PDE-5 inhibitor is in the form of a free base, a pharmaceutically acceptable salt, a prodrug, an active metabolite, a polymorph, a solvate, a hydrate, an enantiomer, an optical isomer, a tautomer or a racemic mixture thereof.

4. The composition of claim 1 wherein said PDE-5 inhibitor is tadalafil.

5. The composition of claim 1 wherein said PDE-5 inhibitor is sildenafil citrate.

6. The composition of claim 1 herein said PDE-5 inhibitor is vardenafil hydrochloride.

7. The composition of claim 1 wherein said taste-masking agent is a non-polymeric pharmaceutically acceptable excipient, a polymeric pharmaceutically acceptable excipient, an adsorbent, a carbomer, an ion exchange resin, a sugar substitute, a cyclodextrin or a derivative thereof, or a combination thereof.

8. The composition of claim 7 wherein said non-polymeric pharmaceutically acceptable excipient is spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, mineral waxes, 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 tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides, stearoyl macrogolglycerides, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, cetyl alcohol, or stearyl alcohol, or a combination thereof.

9. The composition of claim 7 wherein said polymeric pharmaceutically acceptable excipient is a cellulose derivative, a saccharide or polysaccharide, a polyhydric alcohol, a poly(oxyethylene)-poly(oxypropylene) block copolymer, a vinyl derivative or polymer or copolymer thereof, or a acrylic acid derivative, or a combination thereof.

10. The composition of claim 9 wherein said cellulose derivative is ethyl cellulose, methylcellulose, hydroxyprdpylmethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxy ethylcellulose, carboxymethyl ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxy methyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, or ethylhydroxy ethylcellulose phthalate, or a combination thereof.

11. The composition of claim 9 wherein said vinyl derivative or polymer or copolymer thereof is polyvinylacetate aqueous dispersion (Kollicoat® SR 30D), copolymers of vinyl pyrrolidone, polyvinyl alcohol phthalate, pol vinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, or polyvinylpyrrolidone, or a combination thereof.

12. The composition of claim 9 wherein said acrylic acid derivative is methacrylic acid, polymethacrylic acid, polyacrylate, or polymethacrylate, or a combination thereof, said polyacrylate being a) copolymer formed from monomers selected from the group consisting of methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters; b) copolymer formed from monomers selected from the group consisting of butyl methacrylate, (2-d^'imethylaminoethyl)methacrylate and methyl methacrylate; c) copolymer formed from monomers selected from the group consisting of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride; or d) copolymer of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose.

13. The composition of claim 7 wherein said adsorbent is activated granular carbon, active aluminum, clay, bentonite, kaolite, zeolite, sodium alginate, magnesium aluminium silicate, silica gel, or activated charcoal, or a combination thereof.

14. The composition of claim 7 wherein said carbomer is carbomer 934, carbomer 971 , or carbomer 974, or a combination thereof.

15. The composition of claim 7 wherein said ion exchange resin is a cationic ion exchange resin.

16. The composition of claim 7 wherein said cyclodextrin is a-cyclodextrin, β- cyclodextrin, γ-cyclodextrin, dimethyl^-cyclodextrin, trimethyl-p-cyclodextrin, hydroxymethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-β- cyclodextrin, β-cyclodextrin sulfate, β-cyclodextrin sulfonate, or β-cyclodextrin sulfobutyl ether, dihydroxypropyl- -cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-β- cyclodextrin, diglucosyl^-cyclodextrin, maltosyl-Y-cyclodextrin, maltosyl-γ- cyclodextrin, maltosyl-Y-cyclodextrin, maltotriosyl-β cyclodextrin, ma!totriosyl-γ- cyclodextrin, dimaltosyl- -cyclodextrin, maltosyl- -cyclodextrin/dimaltosyl-P- cyclodextrin, or a combination thereof.

17. The composition of claim 7 wherein said sugar substitute taste masks said PDE-5 inhibitor by salt formation, said sugar substitute being saccharin sodium, cyclamate, or acesulfame, or a mixture thereof.

18. The composition of claim 1 wherein said taste-masking agent is in the range of about 1% to about 95% by weight of the composition.

19. The composition of claim 1 wherein said taste-masking agent is in the range of about 2% to about 75% by weight of the composition.

20. The composition of claim 1 wherein said taste-masking agent is in the range of about 5% to about 60% by weight of the composition.

21. The composition of claim 1 wherein said PDE-5 inhibitor is taste-masked by physical mixing, coating, complexation, adsorption or salt formation using said taste-masking agent.

22. The composition of claim 1 wherein said excipient is a binder, disintegrant, superdisintegrant, diluent, salivating agent, surfactant, flavor, sweetener, colorant, souring agent, viscolizer, glidant, lubricant, solubilizer, or stabilizer.

23. The composition of claim 1 wherein said PDE-5 inhibitor is in the form of powder, granules, pellets, beads, minitablets, or a combination thereof.

24. The composition of claim 1 wherein said composition is in the form of an orally disintegrating tablet, chewable tablet, bite-dispersion tablet, effervescent tablet, dispersible tablet, sprinkle granules, dry suspension or dry syrup for reconstitution, quick melt wafers, lozenge, or chewing gum.

25. The composition of claim 1 further comprising an additional active agent.

26. The composition of claim 25 wherein said active agent is finasteride, dutasteride, izonsteride, idronoxil, epristeride, serenoa repens, PHL 00801 , atropine, fluvoxate, hyoscine, oxybutynin, darifenacin, tolterodine, (+)-N,N-diisopropyl-3-(2-hydroxy-5- hydroxymethylphenyl)-3-phenylpropylamine, propantheline, propiverine, trospium, solifenacin, fesoterodine, 3-alpha-androstanediol, ambrisentan, roflumilast, cilomilast.