Classifications

• • 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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0007—Effervescent
• • 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

Definitions

• the present invention relates to pharmaceutical formulations comprising tadalafil that shall be used in the treatment of erectile dysfunction. Said formulations are characterized by being in effervescent form.
• Tadalafil was first disclosed in the application numbered W09519978. In said document, it has been disclosed that tadalafil is effective in the treatment of erectile dysfunction.
• Tadalafil is available in 5 mg, 10 mg and 20 mg tablet forms on the market.
• suspension forms are mostly not preferred due to the reasons that they carry the possibility of uncontrolled dose intake, their production costs are high, they have physical and chemical instability problems, they pose problems during use and carrying phases.
• suspension forms have higher bioavailability values as compared to solid dosage forms, it is seen that they are more inconvenient than solid dosage forms when evaluated in terms of stability and shelf-life.
• the pharmaceutical compositions comprising tadalafil have been prepared in tablet and suspension forms.
• use of tablet dosage forms causes problems for people who have swallowing difficulties such as children, elderly and disabled people or for those who do not want to swallow tablets and capsules.
• Solution dosage forms are not preferred since they complicate compliance of the patients with the treatment as they carry the possibility of uncontrolled dose intake, have bad taste and are not user-friendly and since they have shorter shelf life than solid dosage forms due to their low stability.
• the present invention relates to the pharmaceutical formulations which comprise tadalafil and are characterized by being in effervescent form that shall be used in the treatment of erectile dysfunction.
• the formulations of the present invention are characterized in that they are in the form of effervescent powder, tablet and granule which have the advantages of both tablet and suspension forms together and they remove the problems encountered in said dosage forms. Effervescent dosage forms are useful especially for patients who have swallowing difficulties.
• the pharmaceutical formulations of the present invention comprise effervescent oral dosage forms comprising at least one pharmaceutically acceptable excipient in addition to tadalafil and effervescent couple or comprising only tadalafil and effervescent couple.
• the present invention relates to effervescent oral dosage forms comprising the active agent tadalafil, effervescent couple and at least one pharmaceutically acceptable excipient.
• Tadalafil comprised in the formulations of the present invention can be in the form of pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; in amorphous form or crystalline form or a combination thereof in terms of polymorphic structure.
• the amount of tadalafil comprised in the formulations is in the range of 1% to 90% by weight, preferably in the range of 1% to 85% by weight, more preferably in the range of 1% to 80% by weight.
• effervescent formulations of the present invention are in effervescent powder, tablet and granule forms.
• the characteristic feature of the effervescent formulations of the present invention is that; - said formulations are in effervescent powder, tablet and granule forms and
• the amount of tadalafil comprised in the formulations is in the range of 1% to 90% by weight, preferably in the range of 1% to 85% by weight, more preferably in the range of 1% to 80% by weight.
• the effervescent formulations of the present invention are preferably used as dissolved in a glass of water or in another suitable liquid. At this point, it is clear that water solubility of the formulation is a very important parameter in order to provide an effective treatment and therefore bioavailability.
• the inventors have found that the highest solubility is obtained with the formulations wherein the average particle size of tadalafil is less than 50 ⁇ in the effervescent formulations comprising tadalafil as the active agent.
• one characteristic feature of the effervescent formulations of the present invention is to comprise tadalafil having an average particle size less than 50 ⁇ as the active agent.
• another characteristic feature of the effervescent formulations of the present invention is to comprise tadalafil having an average particle size in the range of 1 ⁇ to 50 ⁇ as the active agent.
• another characteristic feature of the effervescent formulations of the present invention is to comprise tadalafil having an average particle size in the range of 1 ⁇ to 45 ⁇ as the active agent.
• formulations are in effervescent powder, tablet and granule forms
• the amount of tadalafil comprised in the formulations is in the range of 1% to 90% by weight, preferably in the range of 1% to 85% by weight, more preferably in the range of 1% to 80% by weight and - the average particle size of tadalafil comprised in the formulations is less than 50 ⁇ , preferably in the range of 1 ⁇ to 50 ⁇ and more preferably in the range of 1 ⁇ to 45 ⁇ .
• average particle size refers to average particle size by volume and is shown with d 50 in short.
• d 0 signifies that half of the said substance by volume has a particle size over the value stated with d 50 and the other half of the substance by volume has a particle size below the value stated with d 50 .
• D 5 o value can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
• effervescent formulations of the present invention comprise at least one pharmaceutically acceptable excipient along with tadalafil and effervescent couple.
• excipients that can be comprised in the effervescent formulations of the present invention can be selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, surfactants, stabilizing agents, oiling agent, lubricants, diluents, glidants, wetting agents, oiling agent, pH regulators, effervescent acids, effervescent bases, gelling agents, flavoring agent, sweeteners, taste regulating agents, emulsifying agents, antifoaming agents, antioxidants, preservative agents, solvent or solvent mixtures, coloring agents and complexing agents or combinations thereof.
• excipients that can be comprised in the effervescent formulations of the present invention can be selected from a group comprising effervescent acid, effervescent base, binder, sweetener and/or taste regulating agent, flavoring agent, solvent, coloring agent, antifoaming agent, lubricant and/or combinations thereof.
• the disintegrant that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
• the diluent that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
• the oiling agent that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
• the binder that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
• the effervescent acids that can be used in the effervescent formulations of the present invention comprising tadalafil are selected from a group comprising organic acids such as citric acid and acetic acid, tartaric acid, fumaric acid, adipic acid, malic acid or pharmaceutically acceptable hydrates, anhydrates thereof and similar forms or combinations thereof.
• the low solubility of tadalafil active agent and slow dissolution rate of the effervescent formulations comprising tadalafil is an important matter for both the patients and drug producers.
• the inventors have observed that when a combination of organic acid and its acceptable hydrate is used as effervescent acid, the effervescent formulations comprising tadalafil have higher solubility and a rapid dissolution can be provided resulting in a high bioavailability.
• another aspect of the present invention is the formulations comprising tadalafil wherein said formulation comprises a combination of organic acid and its acceptable hydrate used as effervescent acid.
• the effervescent acid is preferably a combination comprising citric acid and monosodium citrate.
• another aspect of the present invention is the formulations comprising tadalafil wherein said formulation comprises a combination of citric acid and monosodium citrate used as effervescent acid.
• effervescent bases that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising alkaline or alkaline earth metal carbonates or bicarbonates or combinations thereof.
• Potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate and sodium bicarbonate or combinations thereof can be given as examples of the effervescent bases which are preferred in the formulations of the present invention.
• effervescent formulations of the present invention comprising tadalafil comprise an effervescent couple composed of at least one pharmaceutically acceptable effervescent acid and effervescent base in the range of 10% to 95%, preferably in the range of 15% to 95%, more preferably in the range of 20% to 95% in proportion to total weight of formulation.
• the term "effervescent couple” refers to the mixture of at least one effervescent acid and at least one effervescent base. Both or either of these agents can be in the form of combination of different types in the mixture of effervescent couple. For instance, an effervescent couple comprising two different effervescent acids and one effervescent base or two different effervescent acids and two different effervescent bases can be used.
• the ratio of at least one pharmaceutically acceptable effervescent acid to effervescent base comprised in the effervescent formulations of the present invention comprising tadalafil is in the range of 0.1 to 10 by weight.
• the antifoaming agent that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from polydimethylsiloxane, simethicone, other silicones, stearates, alcohols, glycols or combinations thereof.
• the pH regulating agent that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
• the surfactant that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from the agents sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and so forth.
• the stabilizing agents that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
• another aspect of the present invention is the formulations comprising tadalafil wherein said formulation comprises a combination comprising at least two, preferably three sweeteners and/or taste regulating agents.
• Another aspect of the present invention is the formulations comprising tadalafil wherein said formulation comprises a combination comprising the first taste regulating agent, second taste regulating agent and the third taste regulating agent.
• sweetener and/or taste regulating agents that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
• the inventors have also studied on the development of the taste of the effervescent formulations by using the different sweeteners and/or taste regulating agents. Based on the studies, they have observed that when the first taste regulating agent is sucralose, the second taste regulating agent is aspartame and the third taste regulating agent is sodium chloride, the effervescent formulation obtained has a favorable taste so that the patients have not difficulty while using the drug.
• another aspect of the present invention is the effervescent formulations comprising tadalafil wherein said formulation comprises a combination of three different taste regulating agents and wherein the first taste regulating agent is sucralose, the second taste regulating agent is aspartame and the third taste regulating agent is sodium chloride.
• flavouring agent that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from the flavors comprising menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and so forth.
• the lubricants that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.
• the solvent that can be used in the effervescent formulations of the present invention comprising tadalafil can be selected from deionized water, acetone, ethyl alcohol or a combination thereof.
• the effervescent formulations of the present invention comprising tadalafil can optionally comprise a second active agent in addition to tadalafil.
• the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant
• the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to tadalafil can be prepared in any of the dosage forms of effervescent tablet, effervescent granule, effervescent dry powder; in the case that the two active agents are comprised in different formulations but in the same dosage form, the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to tadalafil can be prepared in the dosage forms such as layered tablet, capsule; in the case that the two active agents are comprised in different formulations and in different dosage forms, the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to tadalafil can be prepared in a treatment package form wherein tadalafil is in any dosage forms of effervescent tablet, effervescent granule, effervescent dry powder, and the second active agent
• Preparation method of the formulations of the present invention comprises the steps of formulating the active agent with a suitable excipient composition and giving the said formulation the desired shape.
• formulations of the present invention can be produced according to any production methods given below;
• wet granulating the mixture which is obtained by mixing the active agent tadalafil and, if available, the second active agent with at least one pharmaceutically acceptable excipient homogeneously, with the granulation solution comprising at least one excipient; drying the granules obtained, optionally adding at least one pharmaceutically acceptable excipient into the dry granules and forming the granules obtained in a desired shape, 3.
• the effervescent formulations of the present invention are preferably in tablet form.
• the effervescent formulations of the present invention is preferably produced according to the following production method given below;
• Step II The granules obtained in Step II are dried and sieved.
• flavouring agent coloring agent, anti foaming agent, the taste regulating agent and lubricant are added into the granules obtained in Step III and the final mixture is obtained.
• the final mixture obtained in Step IV is compressed into tablet form.
• the inventors have seen that water solubility of the formulations is affected from tablet compression force in the case that these effervescent formulations are prepared in tablet dosage form.
• the characteristic feature of the effervescent formulations of the present invention comprising tadalafil is that the formulations are in effervescent form and the tablet compression force implemented during compressing said formulations in tablet form is in the range of 3 kN to 50 kN, preferably in the range of 4 kN to 45 kN, more preferably in the range of 4 kN to 40 kN.
• the pharmaceutical formulations of the present invention can be used in prevention and treatment of erectile dysfunction.
• effervescent formulation given above is produced according to any methods in the prior art explained in detail in the description and the formulation is presented for use in the dosage form required.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=48083586

Family Applications (2)

Family Applications Before (1)

Country Status (1)

Cited By (3)

Citations (5)

Family Cites Families (4)

• 2013
  • 2013-01-18 WO PCT/TR2013/000035 patent/WO2014092661A1/fr not_active Ceased
  • 2013-01-18 WO PCT/TR2013/000043 patent/WO2013109230A1/fr not_active Ceased

Patent Citations (5)

Also Published As

Similar Documents

Legal Events