WO2023227185A1 - Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation - Google Patents

Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation Download PDF

Info

Publication number
WO2023227185A1
WO2023227185A1 PCT/EP2022/000049 EP2022000049W WO2023227185A1 WO 2023227185 A1 WO2023227185 A1 WO 2023227185A1 EP 2022000049 W EP2022000049 W EP 2022000049W WO 2023227185 A1 WO2023227185 A1 WO 2023227185A1
Authority
WO
WIPO (PCT)
Prior art keywords
tadalafil
active ingredient
agents
appropriate
sieve
Prior art date
Application number
PCT/EP2022/000049
Other languages
English (en)
Inventor
Agni GRYPIOTI
George Papandreou
Panagiotis TSITSAS
Original Assignee
Rontis Hellas S.A.
Pharos Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rontis Hellas S.A., Pharos Ltd. filed Critical Rontis Hellas S.A.
Priority to PCT/EP2022/000049 priority Critical patent/WO2023227185A1/fr
Publication of WO2023227185A1 publication Critical patent/WO2023227185A1/fr

Links

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to an improved pharmaceutical composition for oral administration, and in particular to a chewable pharmaceutical composition comprising a therapeutically effective quantity of tadalafil or a pharmaceutically acceptable salt or derivative thereof, as an active ingredient, having an improved solubility, bioavailability and onset of action. Furthermore, the present invention relates to a nanomilling process for the preparation of said pharmaceutical composition.
  • Erectile dysfunction can have a range of causes, both physical and psychological. Possible physical causes include heart disease, diabetes, high blood pressure (hypertension) and hormonal problems. Possible psychological causes include stress, anxiety, depression, and relationship problems. ED is treatable at any age, and awareness of this fact has been growing.
  • PDE-5 inhibitors have become the preferred first-line treatment for erectile dysfunction worldwide.
  • PDE-5 inhibitors are competitive inhibitors of phosphodiesterase type 5 (PDE-5), an enzyme that breaks down cyclic guanosine monophosphate (cGMP) in various tissues, the second messenger of Nitric Oxide (NO).
  • PDE-5 inhibitors enhance the vasodilatory effect of NO and restore the ability to achieve an erection in patients with erectile dysfunction.
  • Tadalafil is a potent and selective PDE-5 inhibitor, a secondary messenger for the smooth muscle relaxing effects of NO, which plays an important role in the vasodilation of erectile tissues.
  • Tadalafil s chemical name is pyrazino[l', 2': l,6]pyrido[3,4-b]indole-l, 4-dione, 6-(l,3- benzodioxol-5-yl)-2,3,6,7,12,12a- hexahydro-2-methyl-, (6R,12aR).
  • Tadalafil is a crystalline solid, practically insoluble in water and very slightly soluble in ethanol.
  • Tadalafil is commercially available under the brand name Cialis® (a film-coated, almond-shaped tablet for oral administration). Each tablet contains 2.5mg, 5mg, lOmg, or 20 mg of Tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
  • Tadalafil is well absorbed after oral administration with a mean maximum observed plasma concentration (Cmax) of 378 ng/mL after oral administration of the 20-mg tablet. Cmax is achieved at a mean time of 2 hours after dosing. Tadalafil mean volume of distribution is approximately 63 L, with a mean half-life of 17.5 hours in healthy subjects.
  • CONFIRMATION COPY EP-B-0828479 relates to a solid dispersion comprising Tadalafil and a carrier or excipient thereof and a manufacturing process comprising the co-precipitating of the poorly water soluble drug and the carrier or excipient.
  • EP-A- 1200090 refers to a pharmaceutical formulation comprising Tadalafil in “free drug” (not intimately embedded in a polymeric co-precipitate) form in a mixture with a diluent, lubricant, a hydrophilic binder, and a disintegrant.
  • EP-B- 1200092 claims a pharmaceutical composition
  • a pharmaceutical composition comprising a free drug form of Tadalafil, salts and solvates thereof and at least one carrier, diluent or excipient, in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate and wherein at least 90 % of the particles have a particle size of ⁇ 40 microns
  • an object of the present invention to provide an improved solid pharmaceutical composition for oral administration comprising Tadalafil as an active ingredient, which is bioavailable, with sufficient self-life and good pharmacotechnical properties.
  • Another aspect of the present invention is to achieve a solid immediate release formulation for oral administration comprising Tadalafil as an active ingredient, with improved solubility and bioavailability characteristics which further may exhibit a faster therapeutic onset compared to the commercially available product Cialis® (reference product).
  • a cost effective and simple process for manufacturing a solid pharmaceutical composition for oral administration containing Tadalafil as an active ingredient, thereby offering a pharmacotechnical linearity and used in the treatment of erectile dysfunction.
  • Said process comprises the use of nanomilling as a dissolution enhancing process which facilitates drug release and increases the bioavailability of the active ingredient.
  • a further aspect of the present invention is to afford a method for the preparation of a solid pharmaceutical composition for oral administration which overcomes the difficulties encountered in pharmaceutical production because of the low solubility of Tadalafil.
  • a manufacturing process for the preparation of a pharmaceutical dosage form for oral administration comprising a therapeutically effective quantity of Tadalafil or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, wherein said process comprises nanomilling.
  • Said process further comprises the following steps:
  • Nanomilling Pass the suspension from step B through nanomill.
  • Nano and micro Suspension mixing Mix the intermediate nanosuspension obtained from step C and the microsuspension obtained from step E for appropriate time and under appropriate temperature.
  • Preparation of slurry Mix the suspension obtained from step F and the sucrose solution obtained from step H for appropriate time and under appropriate temperature.
  • step J The granules obtained from step J are dried in fluid bed dryer to appropriate loss on drying (LOD).
  • LOD loss on drying
  • Lubrication Weight individually Magnesium Stearate, sieve it through appropriate sieve and mix it with the blend obtained from step N for appropriate time.
  • an immediate release oral solid dosage form preferably chewable pharmaceutical nanoparticulate composition for oral administration, comprising a therapeutically effective quantity of tadalafil or a pharmaceutically acceptable salt, or derivative thereof, as an active ingredient wherein the particle size of Tadalafil active ingredient is effectively reduced by employing the nanomilling process of the present invention.
  • Fig. 1 Comparative dissolution profiles of composition 2 of the present invention prepared by nanomilling process and composition 2a prepared without the application of nanomilling process.
  • Fig. 2 Comparative XRD of pure Tadalafil API, placebo of composition 2 and Tadalafil in the composition 2 of the present invention produced by nanomilling process.
  • Fig. 3 Comparative dissolution profiles of composition 2 of the present invention and reference product at 50 rpm in water containing surfactant to provide sink condition.
  • Fig. 4 Comparative dissolution profiles of composition 2 of the present invention and reference product at 50 rpm and under FED conditions.
  • Fig. 5 Comparative mean plasma concentrations of composition 2 (Test product) of the present invention and reference product under FAST conditions for the whole sampling period.
  • Fig. 6 Comparative mean plasma concentrations of composition 2 (Test product) of the present invention and reference product for the first 4 hrs sampling points.
  • a pharmaceutical composition comprising Tadalafil is considered to be improved if said composition achieves increased solubility, bioavailability and earlier therapeutically effective drug concentration than the known pharmaceutical formulations of Tadalafil.
  • a major object of the present invention is to provide a solid immediate release formulation of Tadalafil which is simple to manufacture, cost effective, posses good pharmacotechnical properties and linearity.
  • Another aspect of the present invention is to provide an immediate release dosage form in the form of a chewable tablet , which reaches the minimum effective drug concentration in plasma in a shorter period than the commercially available product Cialis® (hereafter referred to as reference product).
  • the object of the present invention is achieved by employing nanomilling, microdispersion and subsequently common wet granulation process.
  • nanomilling which employs common excipients and practices, combines mechanical energy to physically break down large coarse particles of Tadalafil.
  • nanomilling process has major impact on the present composition as by increasing the surface area of the active ingredient, enhances the solubility and subsequently its bioavailability.
  • aqueous solubility of an active ingredient is one of the most important physicochemical properties as low aqueous solubility and low dissolution rate can reduce the active ingredient absorption in the gastro-intestinal tract.
  • Low active ingredient solubility also directs to decreased bioavailability, increased chance of food effect, more frequent incomplete release from the dosage form and higher interpatient variability.
  • Poorly water soluble active ingredients consist a large majority of the pharmaceutical active ingredients, thereby limiting their potential uses and increasing the difficulty of formulating bioavailable pharmaceutical products.
  • Tadalafil belongs to this category of active ingredients. Poorly soluble active ingredients have stimulated the development of active ingredient delivery technologies to overcome the obstacles to their solubilization through either chemical or mechanical modification of the environment surrounding the active ingredient molecule, or physically altering the macromolecular characteristics of aggregated active ingredient particles.
  • Nanomilling has been applied as a process by which the particle size of Tadalafil is reduced in a liquid vehicle (typically aqueous) via grinding using polymeric or ceramic milling media. Decreasing the particle size has a tremendous increase in surface area which directly correlates to an increase in dissolution rate.
  • Nanomilling is a “top-down” approach to turning large, coarse particles into smaller, finer particles. It entails the application of mechanical energy to physically break down Tadalafil particles.
  • the main technique used for milling Tadalafil is high energy media milling. This technique relies on milling media beads of 0.2-1 pm diameter size, beads that are made from ceramics or highly crosslinked polystyrene. The beads shear and collide with the active ingredient particles during the milling process, reducing their particle size.
  • Tadalafil is suspended in a solution containing water and at least one stabilizer to prevent reaggregation of particles over time.
  • the Tadalafil suspension is then pumped from a holding tank through the milling chamber, where the agitator rapidly rotates and creates turbulence in the media. As the suspension enters the milling chamber the shear forces and impaction with milling media break down large coarse particles into smaller particles.
  • the Tadalafil suspension exits the milling chamber through a screen that keeps the suspension separate from the milling media.
  • a coolant is pumped around the milling chamber to maintain a desired temperature. This is important for active ingredients that are thermally sensitive, as the milling process generates a significant amount of heat.
  • the nanomilling process generates an intermediate consisting of nanoparticles suspended in an aqueous vehicle. This is often referred to as a nanoparticulate suspension (or nanosuspension).
  • the obtained Tadalafil nanosuspension is subsequently used as a granulation liquid in wet granulation step. Decreasing the particle size has a tremendous increase in surface area which directly correlates to an increase in dissolution rate and bioavailability which is the greatest contribution to the object of the present invention.
  • compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions (tablet/capsule compositions).
  • Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, glidants, lubricants, flavors, water scavengers, colorants, sweetener, coating agents and preservatives.
  • the optional excipients must be compatible with Tadalafil or salt, or derivative thereof so that it does not interfere with it in the composition.
  • any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of these substances, and in order to increase the solubility of the drug and the self-life of the pharmaceutical product and provide a product exhibiting excellent bioavailability and palatability.
  • composition of the present invention may include further additives (alone or in a combination) such as absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH control agents, plasticizers, retarding agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers etc.
  • Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 10-90 weight % of the total weight of the composition.
  • Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide,, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1-40 weight % of the total weight of the composition.
  • Disintegrants may be selected from alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 0.1 - 25 weight % of the total weight of the composition.
  • Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.
  • Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.01-2 weight % of the total weight of the composition.
  • Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame and the like.
  • Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavor, peppermint flavor and the like.
  • Solubilizers may be selected from sodium lauryl sulphate or complex forming agents such as cyclodextrins, ion exchange resins, crown ethers and the like.
  • the manufacturing process used for the preparation of a pharmaceutical dosage form for oral administration comprising a therapeutically effective quantity of Tadalafil or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, comprises the following steps:
  • Tadalafil suspension phase for nanomilling Dilute in water the quantity of Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate and add the active ingredient Tadalafil.
  • Nanomilling Pass the suspension from step B through nanomill.
  • Nano and micro Suspension mixing Mix the intermediate nanosuspension obtained from step C and the microsuspension obtained from step E for appropriate time and under appropriate temperature.
  • Preparation of slurry Mix the suspension obtained from step F and the sucrose solution obtained from step H for appropriate time and under appropriate temperature.
  • step J The granules obtained from step J are dried in fluid bed dryer to appropriate loss on drying (LOD).
  • LOD loss on drying
  • Lubrication Weight individually Magnesium Stearate, sieve it through appropriate sieve and mix it with the blend obtained from step N for appropriate time.
  • P. Compression Compress the homogeneous powder obtained from step O in tablets in a rotary tabletting machine using appropriate punches.
  • compositions of the present invention may optionally be prepared by fluid bed granulation.
  • the immediate release pharmaceutical composition of the present invention comprising Tadalafil as an active ingredient has been compared to reference product Cialis® consisting of Tadalafil with the following excipients croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
  • compositions according to the present invention are characterized by excellent pharmacotechnical properties, such as homogeneity, flowability and compressibility. Thanks to these properties, the solid dosage forms prepared by the process according to the present invention exhibit excellent technical characteristics including dissolution rate, hardness, stability, taste and bioavailability.
  • Dissolution test One of the most critical pharmacotechnical tests is the Dissolution test as it is strongly correlated with the bioavailability of the product.
  • a Paddle Apparatus was used at rotation speed 50rpm, in aqueous dissolution medium with 0.4% SLS.
  • composition 2 The following table illustrates the results of the solubility studies of composition 2 and the reference product dissolved in aqueous medium with 0.4 SLS.
  • composition 2 according to the present invention has dissolution rate similar to reference product, thereby providing an in vitro release of Tadalafil as depicted in Fig. 3.
  • composition 2 was exposed to normal and accelerated stability studies according to the current ICH guidelines. The results showed that the stability of the present invention was good (e.g. total impurities were not increased throughout normal and accelerated conditions).
  • the tablets may be chewable, film coated with functional or non-functional coating.
  • Example 1 Tadalafil composition 1 according to the present invention
  • Composition 1 of the present invention is illustrated in TABLE 2 below
  • Tadalafil as active ingredient was weighted individually and passed through appropriate sieve. Hydroxypropyl Cellulose-SL as binder/ Stabilizing agent and Sodium Lauryl Sulfate as surfactant were weighted and passed through the appropriate sieve. Hydroxypropyl Cellulose-SL and SLS were diluted in appropriate quantity of water. The sieved Tadalafil was added in the above solution and mixed for appropriate time. The suspension was passed through nanomill (nanosuspension).
  • Sucrose as re-suspending Agent was weighted and diluted to appropriate quantity of water and then the solution was added in the nanosuspension and mixed for adequate time and appropriate temperature. The resulting slurry was used as a granulation liquid.
  • Lactose Monohydrate and Microcrystalline Cellulose as diluents were weighted, sieved, and transferred in a high shear mixer granulator and granulated by adding slurry. The obtained granules were dried in fluid bed dryer to appropriate loss on drying (LOD) and subsequently passed through an appropriate sieve.
  • Croscarmellose Sodium as disintegrant, Aspartame as sweetener and Flavor Peppermint as flavor were weighted sieved and mixed with dried granules for appropriate time until complete homogeneity.
  • Magnesium stearate as lubricant was weighted sieved and mixed the obtained mixture from previous steps. The resulting powder was compressed in tablets in a rotary tabletting machine using appropriate punches.
  • Example 2 A preferred composition 2 according to the present invention is illustrated in Table 3 below.
  • Composition 2 comprises nanosuspension Tadalafil and microsuspension Tadalafil.
  • the mixture as intermediate step and with the addition of sucrose solution will be the granulation liquid wherein the weight ratio of nanosuspension Tadalafil to microsuspension Tadalafil is 60:40.
  • composition 2 according to the present invention were prepared according to the following manufacturing process:
  • Tadalafil active ingredient was weighted individually and passed through appropriate sieve.
  • Hydroxypropyl Cellulose-SL as binder/ Stabilizing agent and Sodium Lauryl Sulfate as surfactant were weighted and passed through the appropriate sieve.
  • Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate (SLS) were diluted in appropriate quantity of water.
  • the sieved Tadalafil was added in the above solution and mixed for appropriate time. The suspension was passed through nanomill (nanosuspension).
  • Tadalafil suspension without passing through nanomill was prepare.
  • Tadalafil active ingredient was weighted individually and passed through appropriate sieve.
  • Hydroxypropyl Cellulose-SL and Sodium Lauryl Sulfate were weighted and passed through the appropriate sieve.
  • Hydroxypropyl Cellulose-SL and SLS were diluted in appropriate quantity of water.
  • the sieved Tadalafil was added in the above solution and mixed for appropriate time (microsuspension). Nanosuspension and microsuspension in a weight ratio 60:40 were mixed for adequate time and under appropriate temperature.
  • Sucrose as re-suspending Agent was weighted and diluted to appropriate quantity of water and then the solution was added in the nano/micro suspension and mixed for adequate time and appropriate temperature. The resulting slurry was used as a granulation liquid.
  • Lactose Monohydrate and Microcrystalline Cellulose as diluents were weighted, sieved, and transferred in a high shear mixer granulator and granulated by adding slurry. The obtained granules were dried in fluid bed dryer to appropriate loss on drying (LOD) and subsequently passed through an appropriate sieve.
  • Croscarmellose Sodium as disintegrant, Aspartame as sweetener and Flavor Peppermint as flavor were weighted sieved and mixed with dried granules for appropriate time until complete homogeneity.
  • Magnesium stearate as lubricant was weighted sieved and mixed the obtained mixture from previous steps. The resulting powder was compressed in tablets in a rotary tabletting machine using appropriate punches.
  • Tadalafil composition 2 according to the present invention
  • the produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications.
  • composition 2 of the present invention indicates that the active ingredient Tadalafil remains stable and there is no conversion into amorphous state or another crystalline form (Fig. 2).
  • composition 2a comprising Tadalafil and the same excipients as composition 2 of the present invention is prepared by using dry blending process instead of nanomilling process on the active pharmaceutical ingredient.
  • the manufacturing process of composition 2a comprises the following steps: Mix Tadalafil and Microcrystalline Cellulose for appropriate time.
  • the obtained mixture is mixed with the following excipients: Lactose Monohydrate, Hydroxypropyl Cellulose-SL, Sodium Lauryl Sulfate, Croscarmellose Sodium, Aspartame and Flavour Peppermint for appropriate time.
  • the obtained blend is mixed with Magnesium Stearate for appropriate time and the final obtained homogeneous powder is compressed in tablets.
  • composition 2 of the present invention prepared by nanomilling process and composition 2a prepared by dry blending process are shown in Fig. 1.
  • the results indicate that the dissolution rate of Tadalafil is increased by using the nanomilling process. More than 90% is released within 10 min using nanomilling process while about 70% is released when a conventional process such as dry blending process is used.
  • composition 2 of the present invention was tested at several aqueous buffers and compared with the reference product. As it is shown in Fig. 3, composition 2 of the present invention and the reference product havesimilar dissolution profiles when tested with the same dissolution method which is also the Quality Control dissolution method, a methos adequate to distinguish the good from bad composition.
  • composition 2 and the reference product were tested at several dissolution conditions simulated those that could exist at the gastrointestinal tract. According to the dissolution results as shown in Fig. 4, the enhanced release profile of composition 2 compared to that of reference product is also confirmed at FED conditions.
  • composition 2 in the figures referred as test product
  • results as depicted in Figs. 5 and 6, indicate that composition 2 (in the figures referred as test product) of the present invention achieves an enhanced therapeutic onset and drug plasma concentration at earlier time after administration than the reference product.
  • Example 3 Composition 3 according to the present invention is illustrated in Table 4 below.
  • Composition 3 comprises nanosuspension Tadalafil and microsuspension Tadalafil.
  • the mixture as intermediate step and with the addition of sucrose solution will be the granulation liquid wherein the weight ratio of nanosuspension Tadalafil to microsuspension Tadalafil is 50:50.
  • composition 3 Tablets of the above composition 3 according to the present invention were prepared according to the same manufacturing process as in Example 2 of the present invention. However, the nanosuspension and microsuspension were mixed in a weight ratio of 50:50 for adequate time and under appropriate temperature. TABLE 4: Tadalafil composition 3
  • the produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications
  • compositions 1 , 2 and 3 of the present invention have been performed under the same conditions as in table 1.
  • TABLE 5 Comparative dissolution results of Compositions 1, 2 and 3 of the present invention and reference product
  • the dissolution profiles of the compositions according to the present invention in table 5 indicate that Tadalafil solid dosage formulations prepared with nanomilling process is rapidly dissolved and are similar with the dissolution profile of the reference product.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique améliorée comprenant une quantité thérapeutiquement efficace de tadalafil ou d'un sel ou d'un dérivé pharmaceutiquement acceptable de celui-ci, en tant que principe actif et l'application d'un procédé de nanobroyage pour réduire efficacement la taille de particule du tadalafil.
PCT/EP2022/000049 2022-05-27 2022-05-27 Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation WO2023227185A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2022/000049 WO2023227185A1 (fr) 2022-05-27 2022-05-27 Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2022/000049 WO2023227185A1 (fr) 2022-05-27 2022-05-27 Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation

Publications (1)

Publication Number Publication Date
WO2023227185A1 true WO2023227185A1 (fr) 2023-11-30

Family

ID=82258187

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/000049 WO2023227185A1 (fr) 2022-05-27 2022-05-27 Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation

Country Status (1)

Country Link
WO (1) WO2023227185A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001008688A2 (fr) * 1999-08-03 2001-02-08 Lilly Icos Llc PRODUITS DE MEDICAMENTS A BASE DE β-CARBOLINE
EP0828479B1 (fr) 1995-06-02 2001-10-24 Icos Corporation Procede de production d'une dispersion solide d'un medicament faiblement hydrosoluble
EP1200090A1 (fr) 1999-08-03 2002-05-02 Lilly Icos LLC Compositions pharmaceutiques a base de beta-carboline
WO2007033239A2 (fr) * 2005-09-13 2007-03-22 Elan Pharma International, Limited Formulations nanoparticulaires de tadalafil
WO2014209022A1 (fr) * 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Formule de comprimé à mâcher comprenant du tadalafil ou l'un de ses sels pharmaceutiquement acceptables
US20210137919A1 (en) * 2018-02-07 2021-05-13 Smawa Gmbh Pharmaceutical formulations, method for producing a pharmaceutical formulation, and medicament comprising same
CN113855639A (zh) * 2021-11-04 2021-12-31 昆明源瑞制药有限公司 一种他达拉非片剂及其制备方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0828479B1 (fr) 1995-06-02 2001-10-24 Icos Corporation Procede de production d'une dispersion solide d'un medicament faiblement hydrosoluble
WO2001008688A2 (fr) * 1999-08-03 2001-02-08 Lilly Icos Llc PRODUITS DE MEDICAMENTS A BASE DE β-CARBOLINE
EP1200090A1 (fr) 1999-08-03 2002-05-02 Lilly Icos LLC Compositions pharmaceutiques a base de beta-carboline
EP1200092B1 (fr) 1999-08-03 2004-04-21 Lilly Icos LLC Produits de medicaments a base de beta-carboline
WO2007033239A2 (fr) * 2005-09-13 2007-03-22 Elan Pharma International, Limited Formulations nanoparticulaires de tadalafil
WO2014209022A1 (fr) * 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Formule de comprimé à mâcher comprenant du tadalafil ou l'un de ses sels pharmaceutiquement acceptables
US20210137919A1 (en) * 2018-02-07 2021-05-13 Smawa Gmbh Pharmaceutical formulations, method for producing a pharmaceutical formulation, and medicament comprising same
CN113855639A (zh) * 2021-11-04 2021-12-31 昆明源瑞制药有限公司 一种他达拉非片剂及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KRUPA ANNA ET AL: "High-Energy Ball Milling as Green Process To Vitrify Tadalafil and Improve Bioavailability", MOLECULAR PHARMACEUTICS, vol. 13, no. 11, 23 September 2016 (2016-09-23), US, pages 3891 - 3902, XP093011393, ISSN: 1543-8384, DOI: 10.1021/acs.molpharmaceut.6b00688 *

Similar Documents

Publication Publication Date Title
TWI763881B (zh) 帕博西里之固態劑型
EP2180883B1 (fr) Composition pharmaceutique contenant un antagoniste des canaux calciques de type dihydropyridine et son procédé de préparation
JP5484910B2 (ja) レバプラザン含有の固体分散体及びその製造方法
US20160271124A1 (en) Formulations containing nalbuphine and uses thereof
KR102241643B1 (ko) 비정질 톨밥탄을 함유하는 경구 투여 현탁제
CA2599649C (fr) Formulations medicamenteuses ayant une biodisponibilite controlee
US20200061058A1 (en) Pharmaceutical formulation containing tadalafil
JP2010536798A (ja) 難溶性薬物の生体利用率を制御するための方法及び組成物
WO2023227185A1 (fr) Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation
JP2020502144A (ja) スボレキサントの医薬製剤
JP2019514898A (ja) アイバカフトールとルマカフトールの複合体製剤及びそれらの塩及び誘導体を含む医薬合剤組成物、それらの調製のための方法、並びにそれらを含有する医薬組成物
WO2017059877A1 (fr) Composition pharmaceutique contenant l'agomélatine et son procédé de préparation
WO2023232215A1 (fr) Composition pharmaceutique améliorée contenant du tadalafil et son procédé de préparation
WO2022042646A1 (fr) Composition de chlorhydrate de lurasidone et son procédé de préparation
WO1999020277A1 (fr) Composition medicamenteuse a dissolution rapide
AU2022355434A1 (en) Pharmaceutical composition comprising enavogliflozin
CA2709624A1 (fr) Forme posologique a liberation immediate de bosentan et procede de fabrication de ladite forme posologique
TW201831185A (zh) 含有他達拉非之藥物配製物
JP2019515029A (ja) アイバカフトールならびにアイバカフトールの塩及び誘導体の複合剤、その製造方法ならびにこれを含有する医薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22734111

Country of ref document: EP

Kind code of ref document: A1