WO2014125343A1 - Composition de comprimé de tadalafil présentant un dosage réduit - Google Patents

Composition de comprimé de tadalafil présentant un dosage réduit Download PDF

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Publication number
WO2014125343A1
WO2014125343A1 PCT/IB2013/059747 IB2013059747W WO2014125343A1 WO 2014125343 A1 WO2014125343 A1 WO 2014125343A1 IB 2013059747 W IB2013059747 W IB 2013059747W WO 2014125343 A1 WO2014125343 A1 WO 2014125343A1
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Prior art keywords
tadalafil
tablet composition
tablet
pharmaceutical
composition
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PCT/IB2013/059747
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English (en)
Inventor
Veerababu TADURI
Chithambaram MUTHULINGAM
Sagar SETH
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Alembic Pharmaceuticals Limited
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Publication of WO2014125343A1 publication Critical patent/WO2014125343A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • Present invention relates to pharmaceutical tablet composition of 30 to 34 mg, 15 to 17 mg, 7.5 to 8.5 mg, 3.75 to 4.25 mg and 1.875 to 2.125 mg of tadalafil which is bioequivalent to 40 mg, 20 mg, 10 mg, 5 mg and 2.5 mg of tadalafil tablets (CIALIS®) respectively under fasted and fed condition.
  • the pharmaceutical tablet composition of present invention also exhibits minimum difference in C ma x and AUC between fed and fasted condition. Further the present invention also relates to process for preparing the said tablet composition.
  • Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) and chemically known as pyrazino[1 ',2': 1 ,6]pyrido[3,4-b]indole-1 ,4-dione, 6-(1 ,3-benzodioxol-5- yl)-2,3,6,7, 12,12ahexahydro-2-methyl-, (6R, 12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. In USA it is approved as CIALIS® for treating erectile dysfunction and ADCIRCA® for the treatment of pulmonary arterial hypertension.
  • cGMP cyclic guanosine monophosphate
  • PDE5 phosphodiesterase type 5
  • CIALIS® is available as almond-shaped tablets for oral administration as 2.5, 5, 10 and 20 mg strengths and contains inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
  • US5859006 discloses a class of ⁇ -carboline compound including tadalafil and also describes pharmaceutical compositions thereof which are useful in the treatment of conditions which required the inhibition of PDE5.
  • US5985326 discloses solid dispersion in the form of co-precipitates of poorly water soluble drugs like selective inhibitors of cGMP specific PDE5, process for preparing the same and their use in the pharmaceutical composition.
  • US6821975 discloses tadalafil in the form of free drug wherein at least 90% of the particles have a particle size of less than about 40 microns and pharmaceutical composition of the same with pharmaceutically acceptable carriers, diluents or excipients.
  • US7417044 describes particulate tadalafil having particle size distribution such that at least 90% of the particles, by volume, have a particle size of about 200 to about 600 microns.
  • US20080009502 discloses pharmaceutical composites for making pharmaceutical formulation for oral administration that provides rapid dissolution of the PDE5 inhibitor tadalafil wherein the tadalafil is in the form of solid solution.
  • US200909821 1 discloses compressed solid dosage form of tadalafil with starch wherein weight ratio of starch to tadalafil is about 4:5:1 or more and tadalafil has a particle size distribution such that d(0.9) is greater than or equal to 40 microns.
  • US201 1263606 describes buccal and/or sublingual oral film dosage form and process for preparing the same using solubility enhancer for better absorption and improved bioavailability.
  • US20120189694 relates to a co-precipitate comprising a phosphodiesterase-5 inhibitor (PDE-5-inhibitor) and a pharmaceutically compatible copolymer carrier comprising 2 or more different acrylic acid derivatives, a method for production thereof and a medication comprising the co-precipitate.
  • PDE-5-inhibitor phosphodiesterase-5 inhibitor
  • a pharmaceutically compatible copolymer carrier comprising 2 or more different acrylic acid derivatives
  • US20120088774 relates to dosage forms comprising active pharmaceutical ingredients (API) such as tadalafil, simvastatin, fenofibrate and lovastatin that are practically insoluble in water, adsorbed on a carrier. Further it relates to an adsorbate comprising API being practically insoluble in water and to a process for the preparation of said adsorbate with non-polar solvent (s) such as chlorinated hydrocarbon, diisopropylethes and hexane and process for the preparation of the dosage form, as well as to the use of the adsorbate for the preparation of the dosage form.
  • API active pharmaceutical ingredients
  • s non-polar solvent
  • Starting dose of 2.5 mg of tadalafil may sometime not effective to treat the erectile dysfunction while highest dose of 20 mg is efficient to treat the erectile dysfunction of human being but associated with certain adverse effects like back pain, nasal congestion, myalgia, flushing, headache and dyspepsia.
  • erectile dysfunction patient population ranges in between 40 year to 70 years who are already suffering one or more diseases.
  • side effects of tadalafil may get exaggerated and may lead to fatal result.
  • tadalafil which exhibits similar efficacy to treat erectile dysfunction while reducing the severity or the proportion of side effects.
  • the tablet composition of tadalafil can be prepared using lower dose strength which exhibits bioequivalence with tadalafil tablets (CIALIS®) composition with reduced side effects and minimum difference of C ma x and AUC between fasted and fed condition.
  • CIALIS® tadalafil tablets
  • One aspect of the present invention is to provide a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 30 to 34 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 40 mg (2 tablets of 20 mg) tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C ma x and AUCo-t and AUCo-inf of fasted and fed condition is less than 7%.
  • One aspect of the present invention is to provide a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 15 to 17 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 20 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C max and AUC 0 -t and AUC 0 -inf of fasted and fed condition is less than 7%.
  • CIALIS® 20 mg tadalafil tablet
  • One more aspect of the present invention is to provide a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 7.5 to 8.5 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 10 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C ma x and AUCo-t and AUCo- inf of fasted and fed condition is less than 7%.
  • CIALIS® 10 mg tadalafil tablet
  • Yet another aspect of the present invention is to provide a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 3.75 to 4.25 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 5 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C ma x and AUCo-t and AUCo- inf of fasted and fed condition is less than 7%.
  • CIALIS® 5 mg tadalafil tablet
  • Yet another aspect of the present invention is to provide a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 1.875 to 2.125 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 2.5 mg tadalafil tablet (CIALIS®) composition under fasted and fed condition and the difference between C ma x and AUCo-t and AUCo-inf of fasted and fed condition is less than 7%.
  • CIALIS® 2.5 mg tadalafil tablet
  • Yet another aspect of the present invention is to provide process for preparing tadalafil tablet composition comprising the steps of:
  • step d) compressing the resulting blend of step d) into tablets
  • step e optionally coating the tablets of step e).
  • the present invention provides a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 30 to 34 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 40 mg (2 tablets of 20 mg) tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003, under fasted and fed condition.
  • the present invention provides a a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 15 to 17 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 20 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003, under fasted and fed condition.
  • CIALIS® bioequivalent to 20 mg tadalafil tablet
  • the present invention provides a a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 7.5 to 8.5 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 10 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 under fasted and fed condition.
  • CIALIS® bioequivalent to 10 mg tadalafil tablet
  • the present invention provides a pharmaceutical tablet composition comprising 3.75 to 4.25 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 5 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 under fasted and fed condition.
  • CIALIS® bioequivalent to 5 mg tadalafil tablet
  • the present invention provides a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising 1 .875 to 2.125 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 2.5 mg tadalafil tablet (CIALIS®) described in the U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 under fasted and fed condition.
  • tadalafil means the free base tadalafil and pharmaceutically acceptable salts, solvates and polymorphs thereof. In a preferred embodiment, tadalafil is in the form of free base.
  • the % of tadalafil in tablet composition of present invention is 0.2 to 10% w/w.
  • the % of tadalafil present in the tablet composition is 0.2 to 5% w/w.
  • a method of treating a patient in need of treatment erectile dysfunction comprises administering to the patient a tadalafil tablet composition of present invention.
  • the tablet composition comprising 15 to 17 mg of tadalafil is bioequivalent to the reference drug CIALIS® 20 mg.
  • Reference drug means a tadalafil product as described in U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 as provided in the U.S. Federal Food and Drug Administration's Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations.
  • CIALIS® is a tadalafil tablet product at a strength of 2.5 to 20 mg.
  • CIALIS® 20 mg strength is the "reference listed drug" under 21 CFR 314.94(a)(3)), i.e., the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its AN DA.
  • Bioequivalence is defined as: “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. " In one embodiment, bioequivalence is any definition thereof as promulgated by the U.S. Food and Drug Administration or any successor agency thereof.
  • bioequivalence is determined according to the Federal Drug Administration's (FDA) guidelines and criteria, including "GUIDANCE FOR INDUSTRY BIOAVAILABILITY AND BIOEQUVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS-GENERAL CONSIDERATIONS" available from the U.S. Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) March 2003 Revision 1 ; and "GUIDANCE FOR INDUSTRY STATISTICAL APPROACHES TO ESTABLISHI NG BIOEQUIVALENCE” DHHS, FDA, CDER, January 2001 , both of which are incorporated herein in their entirety.
  • FDA Federal Drug Administration's
  • the pharmaceutical table composition of present invention used lower dosage of tadalafil and exhibits bioequivalent to higher dosage strength of CIALIS® which means the tablet composition of present invention that is 30 to 34 mg, 15 to 17 mg, 7.5 to 8.5 mg, 3.75 to 4.25 mg and 1.875 to 2.125 mg is bioequivalent to 40 mg, 20 mg, 10 mg, 5 mg and 2.5 mg tadalafil tablet (CIALIS®) respectively under fasted and fed condition. Further as the amount of tadalafil is reduced without affecting the efficacy, may lead to reduction in the side effects or adverse effects associated with the higher amount of tadalafil.
  • the present invention provides a process for preparing tadalafil tablet composition comprising the steps of:
  • step b) granulating step a) with binder solution, c) drying the granules of step b),
  • step d) compressing the resulting blend of step d) into tablets
  • step f) optionally coating the tablets of step e).
  • a tadalafil tablet composition of present invention comprises tadalafil, wherein the tablet composition is bioequivalent to a tadalafil tablet (CIALIS®) according to NDA 021368, wherein the tablet composition contains less amount of tadalafil than the tadalafil tablets according to NDA 021368.
  • CIALIS® a tadalafil tablet
  • Cmax is a term refers to the maximum (or peak) concentration that a drug achieves in tested area after the drug has been administrated and prior to the administration of a second dose.
  • AUC Absolute under the curve
  • AUCo-t means area under the plasma concentration-time curve from time zero to the last measurable concentration.
  • AUCo-inf means area under the plasma concentration-time curve from time zero to infinity.
  • the difference is less than 10% or is insignificant.
  • the tablet composition of present invention can be taken with or without food and food does not affect the pharmacokinetic parameter of the tadalafil from the tablet composition of present invention.
  • the tablet composition of present invention can be prepared by any known techniques like direct compression, wet granulation, dry granulation, spray drying and solid dispersion.
  • preparation of solid dispersion of drug and at least a carrier is preferred which is further mixed with one or more pharmaceutically acceptable carrier and compressed in to tablets.
  • Solid dispersions of the present invention can be prepared by any of the below mentioned techniques;
  • solvent method drug and carrier is dissolved in a common solvent, which is then evaporated by any known means to get solvent free film or powder.
  • the drug-carrier solution can also be spray dried alone or over any suitable pharmaceutically acceptable carrier.
  • the main advantage of the solvent method is thermal decomposition of drugs or carriers can be prevented because of the relatively low temperatures required for the evaporation of organic solvents.
  • This method involves preparation of solid dispersions by dissolving the drug in a suitable liquid solvent and then incorporating the solution directly into the melt of any suitable polymer like polyethylene glycol, which is then evaporated until a clear, solvent free powder or film is obtained.
  • a suitable liquid solvent for incorporating the solution directly into the melt of any suitable polymer like polyethylene glycol, which is then evaporated until a clear, solvent free powder or film is obtained.
  • the 5 -10% (w/w) of liquid compounds can be incorporated into polyethylene glycol 6000 without significant loss of its solid property. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. Also the liquid solvent used may affect the polymorphic form of the drug, which precipitates as the solid dispersion.
  • the drug-carrier mixture is processed with a twin-screw extruder.
  • the drug-carrier mixture is simultaneously melted, homogenized and then extruded and shaped as tablets, granules, pellets, sheets, sticks or powder.
  • the intermediates can then be further processed into conventional tablets.
  • An important advantage of the hot melt extrusion method is that the drug-carrier mixture is only subjected to an elevated temperature for about 1 min, which enables drugs that are somewhat thermo labile to be processed.
  • Lyophilisation or freeze-drying method involves transfer of heat and mass to and from the product under preparation. This technique was proposed as an alternative technique to solvent evaporation. Lyophilisation has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion.
  • solid dispersion(s) are prepared either by heating binder, drug and carrier to a temperature above the melting point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the heated carrier (spray-on procedure) by using a high shear mixer.
  • a rotary processor has been shown to be alternative equipment for melt agglomeration. The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates.
  • the effect of binder type, method of manufacturing and particle size are critical parameters in preparation of solid dispersion(s) by melt agglomeration.
  • surfactants in solubilization of poorly soluble drugs is well known. Adsorption of surfactant on solid surface can modify their hydrophobisity, surface charge, and other key properties that govern interfacial processes such as flocculation/dispersion, floatation, wetting and solubilization. Surfactants have also been reported to cause solvation/plasticization, manifesting in reduction of melting the active pharmaceutical ingredients, glass transition temperature and the combined glass transition temperature of solid dispersions. Because of these unique properties, surfactants have attracted the attention of investigators for preparation of solid dispersions.
  • Electrospinning is a method in which solid fibers are produced from a polymeric fluid stream solution or melt delivered through a millimeter- scale nozzle. This process involves the application of a strong electrostatic field over a conductive capillary attaching to a reservoir containing a polymer solution or melt and a conductive collection screen. Upon increasing the electrostatic field strength up to but not exceeding a critical value, charge species accumulated on the surface of a pendant drop destabilize the hemispherical shape into a conical shape. Beyond the critical value, a charged polymer jet is ejected from the apex of the cone (as a way of relieving the charge built-up on the surface of the pendant drop).
  • the ejected charged jet is then carried to the collection screen via the electrostatic force.
  • the coulombic repulsion force is responsible for the thinning of the charged jet during its trajectory to the collection screen.
  • the thinning down of the charged jet is limited by the viscosity increase, as the charged jet is dried.
  • the supercritical anti-solvent (SAS) process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing concurrently use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer; it poses no danger to the patient.
  • the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature.
  • supercritical fluids are used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component).
  • the solvent method is used for the preparation of solid dispersion of present invention wherein the tadalafil and a carrier is dissolved in a solvent system followed by spray drying the solution over the pharmaceutically acceptable carrier followed by drying which is further mixed with one or more pharmaceutically acceptable carrier and compressed to a tablet using suitable punch tooling.
  • the pharmaceutically acceptable carrier as used herein can be selected from the group consisting of diluent, binder, disintegrant, lubricant, anti- adherent and/or wetting agent.
  • Suitable diluents in a tablet composition of the present invention may be one or more compounds which are capable of providing bulk to obtain a desired tablet mass.
  • the suitable diluents may be water soluble or water insoluble or mixture thereof.
  • Suitable diluents include inorganic phosphates such as dibasic calcium phosphate; sugars such as lactose monohydrate, lactose anhydrous, mannitol, sorbitol, sucrose, dextrose; and cellulose or cellulose derivatives such as microcrystalline cellulose and the like.
  • the diluent can be added intragranularly and optionally extragranularly.
  • a water soluble diluent is to be used.
  • lactose monohydrate having surface area in the range of 0.4648 m 2 /g to 0.8632 m 2 /g is to be used.
  • the diluent can be present in a suitable amount from about 20-90 % w/w, preferably 40-80 % w/w of the total composition.
  • Suitable solvents used for dissolving tadalafil can be selected from acetone, isopropanol, methanol, ethanol, ethyl acetate and dichloromethane and the like or mixtures thereof.
  • Suitable binder in a tablet composition of the present invention may be one or more compounds which are capable of facilitating granulation of tadalafil into aggregates and/or more free-flowing particles and include cellulose, carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyl propyl methylcellulose, methylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch, alginic acid, sodium alginate, gelatin and the like.
  • the binder can be present in a suitable amount from 0.5-10 % w/w of the total composition. Binder may be present either in the dry form or in the solution in appropriate solvent.
  • Suitable disintegrant in a tablet composition of the present invention may be one or more compounds which are capable of facilitating the break up of a tablet prepared from the composition when placed in contact with an aqueous medium and include cellulose, carboxymethylcellulose sodium, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, pregelatinized starch, low substituted hydroxypropylcellulose, sodium starch glycolate, starch and the like.
  • the disintegrant can be present in a suitable amount from 1 -20 % w/w, preferably 5-18 % w/w of the total composition.
  • Suitable antiadherent in a tablet composition of the present invention may be one or more compounds capable of prevent sticking to punch faces such as colloidal silicon dioxide, magnesium trisilicate, talc and the like.
  • the antiadherent can be present in a suitable amount from 0.02-7 % w/w, preferably 0.05-5 % w/w, more preferably 0.1-2 % w/w of the total composition.
  • Suitable lubricant in a tablet composition of the present invention may be one or more compounds capable to decrease friction at the interface between the tablet surface and the die wall during ejection and include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, talc and the like.
  • the lubricant can be present in a suitable amount from 0.02-7 % w/w, preferably 0.05-5 % w/w, more preferably 0.1-2 % w/w of the total composition.
  • Suitable wetting agent in a composition of the present invention can be selected from the group consisting of anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride and benzethonium chloride.
  • the wetting agent can be present in a suitable amount from 0.01-2 % w/w or 0.05-1 % w/w of the total composition.
  • Suitable coloring agent in a suitable amount in a composition of the present invention may be one or more compounds which impart a desired color to a tablet prepared from the composition and include FDA approved colors for oral use such as ferric oxides.
  • a coating can be applied using the materials and methods known to a person skilled in the art.
  • film coating material includes Opadry® which is Colorcon's customized, one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate.
  • the film coating can be applied in an amount up to about 5% w/w of the formulation.
  • Suitable solvents for coating can be selected from solvents such as water, isopropanol, ethanol, dichloromethane and the like.
  • the coating solutions may be applied using techniques, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating as known to person skilled in the art.
  • the pharmaceutical tablet of present invention is bioequivalent to Cilias® (tadalafil) tablets which means that the tablet of present invention is effective to treat the erectile dysfunction and further as the % of tadalafil is reduced in the tablet, it will lead to reduction in the side effects of tadalafil comparatively.
  • Lactose monohydrate (Granulac 200) and Low-substituted hydroxypropylcellulose (LH-31 ) were sifted through 30# sieve.
  • step 1 Material of step 1 ) was granulated with solution of step 2) by top spray process.
  • step 4) was further granulated with solution of step 3).
  • step 5 Granules of step 5 were dried and sifted through 30# sieve. 7. Low-substituted hydroxypropylcellulose (LH-31 ), croscarmellose sodium and colloidal silicone dioxide were sifted through 40 # and mixed with dried granules of step 6).
  • LH-31 Low-substituted hydroxypropylcellulose
  • croscarmellose sodium and colloidal silicone dioxide were sifted through 40 # and mixed with dried granules of step 6).
  • Magnesium stearate was sifted through 40# and blend of step 7) was lubricated with sifted magnesium stearate.
  • step 10 Compressed tablets of step 9) were coated using the Opadry Yellow 03F520005 dispersion prepared in purified water.
  • a pharmaceutical tablet composition comprising 30 to 34 mg, 15 to 17 mg, 7.5 to 8.5 mg, 3.75 to 4.25 mg and 1.875 to 2.125 mg of tadalafil wherein the composition comprises of 0.2 to 10 %w/w of tadalafil, 20 to 90% w/w of diluent, 0.5 to 10% w/w of binder, 1 to 20 % w/w of disintegrant and 0.01 to 2% w/w of wetting agent wherein said tadalafil tablet composition is bioequivalent to 40 mg, 20 mg, 10 mg, 5 mg and 2.5 mg tadalafil tablet (CIALIS ® ) respectively under fasted and fed condition and wherein the difference between C ma x, AUCo-t and AUCo-inf of tablet composition under fasted and fed condition is less than 7%.
  • pharmaceutical acceptable carrier is selected from group consisting of diluent, binder, disintegrant, lubricant, anti adherent and wetting agent.
  • anionic and cationic surfactants such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride and benzethonium chloride.
  • a process for preparing tadalafil tablet composition according to claim 1 comprises the steps of:
  • step d) mixing the dried granules with at least one pharmaceutically acceptable carrier and e) compressing the resulting blend of step d) into tablets and
  • step f) optionally coating the tablets of step e).
  • the pharmaceutical tablet composition according to claim 1 wherein the tablet composition is useful for the treatment of erectile dysfunction.
  • a method of treating a patient in need of treatment erectile dysfunction comprises administering to the patient a tadalafil tablet composition of claim 1.

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Abstract

La présente invention concerne une composition pharmaceutique pour comprimé de tadalafil qui présente un dosage réduit et qui est bio-équivalente au produit en comprimés de tadalafil (CIALIS ®), comme stipulé dans la nouvelle réglementation relative aux médicaments de L'Agence américaine des produits alimentaires et médicamenteux (FDA) No. 021368 approuvée le 21 novembre 2003. En outre, la présente invention concerne également un procédé de préparation de ladite composition sous forme de comprimés.
PCT/IB2013/059747 2013-02-12 2013-10-29 Composition de comprimé de tadalafil présentant un dosage réduit WO2014125343A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019065006A (ja) * 2017-09-29 2019-04-25 ハンミ ファーマシューティカルズ カンパニー リミテッド 生産性及び均一性が改善されたタダラフィルを含む固形製剤、及びその製造方法
CN110664766A (zh) * 2019-10-10 2020-01-10 甘肃普安制药股份有限公司 一种他达拉非片剂及其制备方法

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Publication number Priority date Publication date Assignee Title
WO2001008686A1 (fr) * 1999-08-03 2001-02-08 Lilly Icos Llc Compositions pharmaceutiques a base de beta-carboline
WO2005013937A2 (fr) * 2003-07-23 2005-02-17 Elan Pharma International Ltd. Nouvelles compositions de base libre de sildenafil
WO2007002125A1 (fr) * 2005-06-23 2007-01-04 Schering Corporation Formulations orales à absorption rapide d'inhibiteurs de la pde5
WO2007033239A2 (fr) * 2005-09-13 2007-03-22 Elan Pharma International, Limited Formulations nanoparticulaires de tadalafil
EP1985310A1 (fr) * 2007-04-25 2008-10-29 Teva Pharmaceutical Industries Ltd. Formes de dosage solide
WO2012085927A2 (fr) * 2010-12-02 2012-06-28 Mylan Laboratories, Limited Compositions de tadalafil

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Publication number Priority date Publication date Assignee Title
WO2001008686A1 (fr) * 1999-08-03 2001-02-08 Lilly Icos Llc Compositions pharmaceutiques a base de beta-carboline
WO2005013937A2 (fr) * 2003-07-23 2005-02-17 Elan Pharma International Ltd. Nouvelles compositions de base libre de sildenafil
WO2007002125A1 (fr) * 2005-06-23 2007-01-04 Schering Corporation Formulations orales à absorption rapide d'inhibiteurs de la pde5
WO2007033239A2 (fr) * 2005-09-13 2007-03-22 Elan Pharma International, Limited Formulations nanoparticulaires de tadalafil
EP1985310A1 (fr) * 2007-04-25 2008-10-29 Teva Pharmaceutical Industries Ltd. Formes de dosage solide
WO2012085927A2 (fr) * 2010-12-02 2012-06-28 Mylan Laboratories, Limited Compositions de tadalafil

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019065006A (ja) * 2017-09-29 2019-04-25 ハンミ ファーマシューティカルズ カンパニー リミテッド 生産性及び均一性が改善されたタダラフィルを含む固形製剤、及びその製造方法
CN110664766A (zh) * 2019-10-10 2020-01-10 甘肃普安制药股份有限公司 一种他达拉非片剂及其制备方法

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