Classifications

• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
  • A61K33/08—Oxides; Hydroxides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

• the present invention relates to a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of a non-purine selective inhibitor of xanthine oxidase such as Febuxostat in complex with magnesium oxide (MgO) and a method for the preparation thereof.
• a non-purine selective inhibitor of xanthine oxidase such as Febuxostat in complex with magnesium oxide (MgO)
• Uric acid is formed from the breakdown of certain chemicals (purines) in the body. Hyperuricemia occurs when the body produces more uric acid than it can eliminate. The uric acid forms crystals in joints (gouty arthritis) and tissues, causing inflammation and pain. Elevated blood uric acid levels also can cause kidney disease and kidney stones. Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine to xanthine to uric acid. Both steps in the above transformations are catalyzed by xanthine oxidase (XO).
• XO xanthine oxidase
• Febuxostat is a 2- arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat has been shown to inhibit both the oxidised and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism.
• Febuxostat 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-l,3- thiazole-5 -carboxylic acid.
• the molecular formula is C16H16N2O3S corresponding to a molecular weight of 316.374. It is a white crystalline powder.
• Febuxostat is practically insoluble in water, sparingly soluble in ethanol, soluble in dimethylsulfoxide and freely soluble in dimethylformamide. Febuxostat exhibits polymorphism.
• Crystal forms of Febuxostat disclosed in EP 1020454 namely anhydrate A, anhydrate B, anhydrate C, hydrate G, a solvate with methanol (Form D) and anhydrated form K are the most known crystalline forms.
• Crystalline form A is the thermodynamically most stable form. Even though the present invention does not make use of such most stable form, it achieves enhanced stability profile through an innovative technology.
• WO-A-2012/153313 discloses an immediate-release Febuxostat composition
• an inert carrier covered with at least one layer containing Febuxostat in a micronized form, a hydrophilic polymer and, optionally, a surfactant.
• WO-A-2014/125504 discloses an immediate release tablet comprising Febuxostat and an acid component in an amount of from 0.05% to 2% by weight of the tablet.
• thermodynamically stable and efficient product comprising a salt complex of a non-purine selective inhibitor of xanthine oxidase such as Febuxostat suitable for oral administration.
• the present invention aims at developing a formulation that not only matches the physical and chemical attributes of the reference product but also overcomes the disadvantages associated with the prior art compositions through the application of an innovative technology.
• a major object of the present invention is to provide a film-coated tablet comprising Febuxostat MgO complex, which is bioavailable and with sufficient self-life.
• Further object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients, the effective drug substance particle size distribution and the method of preparation of final product in order to achieve the appropriate dissolution profile and stability for the finished dosage form.
• Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient.
• a further approach of the present invention is to provide a tablet composition for oral administration comprising Febuxostat MgO complex which is manufactured through a fast, simple and cost-effective process.
• a process for the preparation of a solid dosage form for oral administration, containing Febuxostat as an active ingredient and an effective amount of a specific alkalizing agent in order to be formed a complex ensuring enhanced API solubility is provided, which comprises the following steps:
• a pharmaceutical composition comprising an active ingredient is considered to be“stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
• the main object of the present invention is to provide a stable pharmaceutical composition of Febuxostat for oral administration that is simple to manufacture, bioavailable, cost effective and possesses good pharmacotechnical properties.
• Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, XRPD spectrum and IR-spectrum. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up; however, they may have distinct advantageous physical properties which can have a direct effect on the ability to process and/or manufacture the drug substance as well as on drug product stability, dissolution, and bioavailability. These distinct physical properties of different polymorphs of the same compound can render different polymorphs more or less useful for a particular purpose, such as for pharmaceutical formulation.
• Febuxostat crystalline forms generally exhibit problems related to polymorphic conversion during preparation and/or typical formulation conditions and storage.
• Solubility the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response.
• Febuxostat belongs to class II according to the Biopharmaceutical Classification System. It is permeable but relatively insoluble, and is considered not such good clinical candidate without the use of enhanced formulation techniques aimed at increasing solubility or rate of dissolution. Solubility enhancement is a major challenge for formulation development. Any drug to be absorbed must be present in the form of solution at the site of absorption.
• solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.
• Febuxostat solubility is pH dependent; in alkalic media the solubility is higher. Therefore, an alkalizing agent may enhance dissolution rate.
• the alkalizer is used to create a microenvironment in the formulation to optimize drug release after the formulation is in a hydrated media.
• the alkalizers used in the present invention are capable of raising the pH of the micro-environment of the hydrated formulation to a pH greater of the starting pH of the media.
• Alkalizing agents used in the present invention include, for example, magnesium oxide, dibasic calcium phosphate, tricalcium phosphate, calcium carbonate and are used in an amount 3-10% (w/w).
• magnesium oxide is used in the present invention.
• the innovative technology as elaborated in the present invention overcomes problems associated with poor solubility of Febuxostat and instability of its crystalline forms.
• the formation of Febuxostat MgO complex results in the loss of the initial crystalline form that was responsible for poor API solubility.
• Such complex provides enhanced API solubility without compromising the stability profile of the preferred composition of the present invention.
• a ratio by weight of Febuxostat base to alkalizing agent of about 3:1 gave the best results in terms of enhanced solubility.
• the ratio by weight of Febuxostat base to alkalizing agent can be from 4:1 to 2:1.
• only in combination with MgO was formed a stable complex according to the purposes of the present invention.
• the particle size of the API is a critical parameter that can affect the solubility of low solubility API’s such as Febuxostat.
• the specific surface area is increased with decreasing particle size of the drug, resulting in an increase in dissolution rate.
• the dissolution rate of poorly soluble drugs is strongly related to the particle size distribution and thus the dissolution profile of the final product.
• the first step in that process is the disintegration of the dosage form followed by dissolution of the active ingredient.
• One way to increase dissolution rate of poorly soluble drugs such as Febuxostat is to increase the surface available for dissolution by reducing particle size. It has been surprisingly found that the objects of the present invention are achieved when the formulation is prepared using Febuxostat with specific particle size, in particular wherein D90 ⁇ 30pm.
• the pharmaceutical compositions of the present invention may also contain one or more additional formulation excipients such as diluents, disintegrants, binders, lubricants, provided that they are compatible with the active ingredient of the composition, so that they do not interfere with it in the composition and in order to increase the stability of the drug and the self-life of the pharmaceutical product.
• Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form easier for the patient and care giver to handle.
• Diluents for solid compositions include, for example, microcrystalline cellulose (MCC), dextrose, fructose, mannitol, maltodextrin, maltitol, lactose.
• the dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach may be increased by the addition of a disintegrant to the composition.
• Disintegrants include sodium starch glycolate, alginic acid, carboxymethylcellulose sodium, croscarmelose sodium, colloidal silicon dioxide (aerosil).
• Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose function include helping to bind the active ingredient and other excipients together after compression.
• Binders for solid pharmaceutical compositions include hydroxyethyl cellulose, methylcellulose, hydroxypropyl cellulose (HPC), polydextrose, polyethylene oxide, povidone.
• a dosage form such as a tablet
• the composition is subjected to pressure from a punch and dye.
• Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause surface irregularities to the product.
• a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
• Lubricants include talc, magnesium stearate, calcium stearate, glyceryl behenate.
• compositions 1-4 The manufacturing process of Compositions 1-4 includes a wet granulation of internal phase ingredients. The preparation steps followed are presented below:
• compositions 1-4 were tested for their dissolution rate.
• Composition 1 with magnesium oxide as alkalizing agent gave the best dissolution profile.
• the effective amount of alkalizing agent is set to be in the range of 5-10%.
• particle size of the active ingredient has an effect on dissolution properties and most particular on the early stages of the dissolution rate.
• the PSD reduction enhances the dissolution rate above the target of 85% release for this time interval.
• the effective particle size is set to be in the range of D90: 5-30 mm.
• Tablets of Composition 1 were placed in chambers under normal (25°C / 60% RH), and accelerated conditions (40°C/ 75% RH) and were examined in appropriate time points in order to control their stability.
• X-ray powder diffraction (XRD) analysis is a rapid analytical technique primarily used for phase identification of a crystalline material and can provide information on unit cell dimensions.
• the X-ray diffraction pattern of the following samples was recorded to evaluate the physical form stability of Febuxostat drug substance in the preferred composition of the present invention, i.e. Composition 1.
• Composition 1 6 months under Long-term storage conditions (25°C/60% RH)
• Composition 1 6 months under Accelerated storage conditions (40°C/75%
• the XRD pattern of aforementioned samples was recorded up to 50° diffraction angle with a scanning diffraction rate 0.05°.
• Table 5 XRD characteristic peaks of Adenuric®, Febuxostat Crystalline Form, Placebo & Febuxostat MgO complex
• Table 6 XRD characteristic peaks of Febuxostat Composition 1 Zero Time, 6 months at 25°C & 40°C.
• the enhanced in-vitro drug release profile recorded on Composition 1 with Magnesium Oxide as alkalizing agent is the result of the innovative technology presented in the present invention. More particularly, the following formulation Trials were prepared and analysed to investigate the impact of Magnesium Oxide on drug release profile of Febuxostat API. Intentionally, the requested API amount was dispensed either within the Wet granulation step or on the external phase to alter the API-Mg Oxide ratio included in the Wet granulation step along the manufacturing process of finished product. The Formulation Trials are listed in the table below along with the critical differences among the relevant formulas. Table 7: Formulation Trials of Febuxostat f.c. tabs prepared for Dissolution discriminative study.
• Attenuated total reflection is a sampling technique used in conjunction with infrared spectroscopy which enables samples to be examined directly in the solid state without further preparation.
• ATR uses a property of total internal reflection resulting in an evanescent wave.
• a beam of infrared light is passed through the ATR crystal in such a way that it reflects at least once off the internal surface in contact with the sample.
• composition 1 6 months under Long-term storage conditions (25°C/60% RH)
• Composition 1 6 months under Accelerated storage conditions (40°C/75% RH)
• ATR spectroscopy employs a single reflection diamond element.
• the samples spectra were measured at 4 cm 1 resolution as averages of 100 scans in triplicate.
• the 2 nd derivative of ATR spectra of samples are stated in comparative mode in Table 9.
• Table 9 2 nd Derivative ATR Characteristic peaks (in cm 1 ) of Febuxostat samples.
• the Febuxostat samples do not display the vibrational signature of the Febuxostat Crystalline Form neither at Zero 5 time nor at the stability phase (Long-term & accelerated storage conditions) since a few characteristic peaks have been either shifted or nearly disappeared.
• the same notification can be recorded for Febuxostat MgO complex.
• a remarkable feature of these samples is the decrease of the relative intensity (or near disappearance) of the characteristic peak at -1700 cm 1 .
• ATR band which is attributed definitely to the 10 carboxylic acid group (-COOH) on the thiazole ring of API molecule.
• NIR Near-infrared spectroscopy
• NIR spectra were collected by a diffuse reflectance optical fiber bundle (8cm 1 resolution, 100 scans) in triplicate.
• the Composition 1 does not display the characteristic vibrational signature of the API Crystalline Form (eg. at 6058cm 1 , 5437cm 1 , 5033cm 1 etc) neither at Zero time nor at the stability phase (Long-term & accelerated storage conditions).
• the same notice can be stated for Febuxostat MgO complex.
• the reference product Adenuric® (Menarini) with Febuxostat API Form A exhibits a different vibrational signature which is primarily attributed to the API polymorph A (eg. characteristic peak at 6038cm-l).
• the different salt of an active substance shall be considered to be the same active substance if they contribute to improved stability, solubility profiles and/or bulk physical properties, unless they differ significantly in properties with regard to safety and/or efficacy.
• the bioequivalence among the preferred composition of the present invention and Adenuric® (Menarini) was proved through an open label, randomized, two-treatment, two-sequence, two-period, crossover, single-dose, oral bioequivalence study of in healthy, adult, human subjects under fasting conditions.

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• 2018
  • 2018-09-07 GR GR20180100414A patent/GR1009659B/el active IP Right Grant
• 2019
  • 2019-09-06 WO PCT/EP2019/025297 patent/WO2020048641A1/en unknown
  • 2019-09-06 EP EP19768715.5A patent/EP3846785A1/de active Pending

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