WO2014016371A1 - Aléglitazar micronisé - Google Patents

Aléglitazar micronisé Download PDF

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Publication number
WO2014016371A1
WO2014016371A1 PCT/EP2013/065701 EP2013065701W WO2014016371A1 WO 2014016371 A1 WO2014016371 A1 WO 2014016371A1 EP 2013065701 W EP2013065701 W EP 2013065701W WO 2014016371 A1 WO2014016371 A1 WO 2014016371A1
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WO
WIPO (PCT)
Prior art keywords
aleglitazar
dosage form
composition
micronized
hydrophilizing agent
Prior art date
Application number
PCT/EP2013/065701
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English (en)
Inventor
Dominique Meergans
Original Assignee
Ratiopharm Gmbh
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 Ratiopharm Gmbh filed Critical Ratiopharm Gmbh
Publication of WO2014016371A1 publication Critical patent/WO2014016371A1/fr

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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
    • A61K9/14—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
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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

Definitions

  • the present invention relates to micronized aleglitazar, preferably in the form of a composition together with a hydrophilizing agent.
  • the invention further relates to a method of preparing dosage forms containing micronized aleglitazar.
  • Aleglitazar is reported to be the INN name o (S)-2-methoxy-3-[4-[2-(5-methyl- 2-phenyloxazol-4-yl )ethoxy]benzo[b]thiophen-7-yl] propionic acid and is characterized by the following chemical formula (I):
  • PPARs Peroxisome Proliferator- Activated Receptor agonists
  • PPARs Peroxisome Proliferator- Activated Receptor agonists
  • PPARa Peroxisome Proliferator- Activated Receptor agonists
  • PPARy nuclear receptor proteins
  • they can play different roles in the regulation of cellular differentiation, development, metabolism and tumorigenesis.
  • Aleglitazar exhibits dual acting activity and thus it can show affinity to PPARa as well as to PPARy.
  • PPARa-activation increasing HDL, lowering LDL and triglycerides, lipoproteins
  • PPARy-activation insulin resistance and glucose levels are decreased. Due to its positive therapeutic effects to multiple symptoms, aleglitazar might be a medical drug.
  • Aleglitazar for example aleglitazar sodium, may form primary pin-like particles of 1 to 5 ⁇ . However, these primary particles tap into agglomerates of over 100 ⁇ . These resulting agglomerates are reported to involve some difficulties in view of their processability. For example, the processability of aleglitazar agglomerates and/or the pharmaceutical formulations containing the respective aleglitazar agglomerates may be improved, especially when prepared on a large scale. As one option, a spray granulation process is reported to handle the above- mentioned problem. Reference can be made to WO 2010/084066. However, said process is regarded to be still improvable, in particular in view of content uniformity, especially when small amounts of active agent are used. Moreover, the processability, e.g. the flowability and/or compressibility, appears to be increasable, in particular, if the ideal process conditions are not exactly met. Further, said process is time consuming and not advantageous in view of cost efficiency.
  • aleglitazar free acid has a very low solubility in highly acidic media potentially leading to precipitation of the drug in the stomach, thus leading to a lower resorption of the active ingredient.
  • a further object of the invention was to avoid solvents, in particular organic solvents.
  • the formulations should show advantageous processability (e.g. superior flowability). Consequently, it was an object of the invention to provide the active agent in a form which possesses superior processability and compressibility. If compressed, the resulting dosage form should exhibit a high level of hardness and low friability.
  • the resulting dosage form should have a particularly even distribution of active agent (content uniformity) even with a low content of active agent.
  • the above objectives are achieved by using a specific form of aleglitazar, namely micronized aleglitazar. More specifically, the drawbacks of the above-mentioned known aleglitazar-containing preparations can be overcome by using compositions containing micronized aleglitazar for processing dosage forms.
  • the subject of the present invention is micronized aleglitazar.
  • the subject of the invention is a composition comprising micronized aleglitazar (a), a hydrophilizing agent (b) and optionally one or more further excipients (c).
  • micronized aleglitazar or the composition of the invention possesses desirable properties and overcomes the drawbacks of the prior art.
  • the subject of the invention also relates to methods of preparing micronized aleglitazar or hydrophilized micronized aleglitazar in the form of the composition of the invention. Further, it was found that the composition of the invention as well as the corresponding dosage forms can be very stable over a long period. This is important since aleglitazar is applied in low doses and even little degradation of the active agent can lower its beneficial effects.
  • Micronized aleglitazar of the invention or a composition of the invention can be processed into dosage forms.
  • a further subject of the invention relates to a dosage form comprising micronized aleglitazar according to the invention or a composition comprising micronized aleglitazar and hydrophilizing agent.
  • the dosage form of the present invention can reproducibly exhibit required content uniformity.
  • the subject of the invention relates to a method of producing said dosage forms comprising the steps of providing the composition of the invention containing aleglitazar (a) in micronized form;
  • step (i) optionally granulating the composition of step (i);
  • step (i) mixing the composition of step (i) or the granulates of step (ii) with optionally one or more excipient(s) (c);
  • step (iii) optionally granulating the mixture from step (iii); and processing the mixture of step (iii) or the granulates from step (iv) into a dosage form.
  • the subject of the invention relates to PPAR-modulator in a micronized form for the use as a drug treating patients with diabetes mellitus type II.
  • PPAR-modulator in a micronized form for the use as a drug treating patients with diabetes mellitus type II.
  • the term “aleglitazar” refers to ( S )-2-methoxy-3- [4-[2-( -methyl-2-phenyloxazol-4-yl )ethoxy]benzo[b]thiophen-7-y I ] propionic acid in accordance with formula (I) above.
  • the term “aleglitazar” as used in the present application can refer to aleglitazar in the form of the free acid as well as to its pharmaceutically acceptable salts, hydrates, solvates, polymorphs and mixtures thereof.
  • the pharmaceutically acceptable salts can be obtained by reaction, preferably with an inorganic base.
  • the carboxylic hydrogen atom of aleglitazar can be replaced by a metal atom, for example an alkali metal atom.
  • aleglitazar is used in the form of its sodium salt.
  • micronized aleglitazar can be used in the context of this invention to designate aleglitazar in particulate form which can have an average particle diameter (D50) of 0.1 to 75 ⁇ , preferably 0.5 to 50 ⁇ , more preferably 1 to 20 ⁇ , particularly preferably 1.5 to 15 ⁇ and especially 2 ⁇ to 9 ⁇ .
  • D50 average particle diameter
  • average particle diameter can relate in the context of this invention to the D50 value of the average particle diameter determined by means of laser diffractometry.
  • a Malvern Instruments Mastersizer 2000 can be used to determine the diameter (preferably wet measurement with ultrasound 60 sec, 2,000 rpm, preferably shading 6%, preferably dispersed in liquid paraffin, the evaluation being performed according to the Fraunhofer model).
  • the average particle diameter which is also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter which corresponds to the D50 value. Similarly, 50% by volume of the particles have a larger diameter than the D50 value.
  • the D 10 value of the integral volume distribution is defined as the particle diameter at which 10% by volume of the particles have a smaller diameter than the diameter which corresponds to the D 10 value.
  • the Dio value of the integral volume distribution is from 0.01 to 7 ⁇ , preferably from 0.05 to 5 ⁇ , more preferably from 0.1 to 3.5 ⁇ and especially from 0.5 to 1.5 ⁇ .
  • the D90 value of the integral volume distribution is defined as the particle diameter at which 90% by volume of the particles have a smaller diameter than the diameter which corresponds to the D 90 value.
  • the D 90 value of the integral volume distribution is from 10 to 250 ⁇ , preferably from 15 to 175 ⁇ , more preferably from 20 to 150 ⁇ and especially from 25 to 100 ⁇ .
  • the ratio of the D 90 value to the D 10 value of the micronized aleglitazar is between 1 : 1 and 20 : 1, more preferably between 1.1 : 1 and 15 : 1 , even more preferably between 1.5 : 1 and 13 : 1 and especially between 2 : 1 and 5 : 1. It appears that a small ratio of the D 90 value to the D 10 value seems to be favourable for good distribution of the active agent within the composition and therefore assures that the above-mentioned objects are achieved.
  • the aleglitazar of the invention can be present in micronized and hydrophilized form, namely in the form of a composition containing micronized aleglitazar (a) and a hydrophilizing agent (b); and optionally further excipients (c).
  • composition of the present invention and the corresponding dosage form comprise aleglitazar as the sole pharmaceutical active agent.
  • composition of the present invention and the corresponding dosage form can comprise aleglitazar in combination with further pharmaceutical active agent(s).
  • the "hydrophilizing agent" (b) in the context of this invention can be a substance which is capable of accumulating on aleglitazar (chemically or physically) and increasing the hydrophilicity of the surface.
  • the hydrophilizing agent (b) may be a hydrophilic polymer, which means a polymer with hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, amino, carboxy, sulphonate.
  • a hydrophilic polymer suitable for preparing a composition according the invention may have a weight-average molecular weight of 1,000 to 500,000 g/mol, more preferably 2,000 to 250,000 g/mol, even more preferably 2,500 to 100,000 g/mol.
  • the resulting solution preferably can have a viscosity of 1 to 20 mPas, more preferably 1 to 5 mPas, even more preferably 2 to 4 mPas, measured at 25° C and determined in accordance with Ph. Eur., 6.0, chapter 2.2.10.
  • the weight average molecular weight is determined by gel permeation chromatography.
  • hydrophilizing agent (b) can also encompass solid, non-polymeric compounds which preferably contain polar side groups. Examples of these can be sugar alcohols or di saccharides. The term "sugar alcohols" in this context can also include monosaccharide.
  • composition of the invention may, for example, comprise the following hydrophilizing agents (b): polysaccharides, such as hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC, especially sodium and calcium salts), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers (such as Kollidon ® VA64, BASF), polyoxyethylene/polyoxypropylene block polymer (Poloxamer ® ), gelatine, polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, mannitol, sorbitol, meglumin, xylitol, is
  • hydrophilizing agent is a combination comprising mannitol and meglumin.
  • hydrophilizing agents (b) can generally be classified with regard to the change in the shape of the particles under compression pressure (compaction). 'Plastic' hydrophilizing agents are characterized by showing plastic deformation of the particles upon exertion of a compressive force, whereas particles of 'brittle' hydrophilizing agents, when compressive force is exerted, tend to break into smaller particles. Brittle behaviour on the part of the hydrophilizing agent (b) can be quantified by the increase in the surface area in a compressed part.
  • the “yield pressure” can preferably be calculated using the reciprocal of the gradient of the Heckel plot, as described in York, P., Drug Dev. Ind. Pharm. 18, 677 (1992).
  • the measurement in this case can preferably be made according to the "ejected tablet” method at 25° C and a deformation rate of 0.1 mm/s.
  • the hydrophilizing agent can have a "yield pressure" of at least 80 MPa, preferably 90 to 300 MPa.
  • Examples of preferred hydrophilizing agents (b) having the above-described "yield pressure” can be microcrystalline cellulose, sucrose and lactose. Especially lactose is preferred.
  • the composition of the invention can contain micronized aleglitazar (a) and hydrophilizing agent (b), the weight ratio of micronized aleglitazar to hydrophilizing agent being 1 : 1 to 1 : 250 , preferably 1 : 2 to 1 :200, more preferably 1 : 3 to 1 : 150, even more preferably 1 : 4 to 1 : 100, especially 1 : 5 to 1 : 50.
  • the type and amount of the hydrophilizing agent (b) can be selected such that at least 80% of the surface of the resulting composition particles can be covered with hydrophilizing agent, more preferably at least 90% of the surface, particularly preferably at least 95% of the surface, especially at least 99% of the surface.
  • the subject of the invention can be a method of preparing the micronized aleglitazar of the invention or the composition of the invention.
  • Micronized aleglitazar in accordance with the invention is preferably obtainable by milling.
  • the milling can be performed in conventional milling apparatuses, as non limiting examples such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder, rotor mill.
  • a planetary mill is preferably used.
  • An air jet mill is most preferably used.
  • the invention relates to a process for preparing the composition of the invention, comprising the steps of (gl) providing aleglitazar (a) and hydrophilizing agent (b) and optionally one or more excipients (c) and
  • step (g2) of providing aleglitazar (a) and hydrophilizing agent (b) can comprise mixing the compounds (a) and (b) and optionally one or more excipients (c).
  • step (g2) of micronizing the mixture from step (gl) can preferably be carried out by milling. The mixing may take place before or even during the milling, i.e. steps (gl) and (g2) may be performed simultaneously.
  • the milling conditions can be selected such that at least 80% of the surface of the resulting composition particles is covered with hydrophilizing agent, more preferably at least 90% of the surface, particularly preferably at least 95% of the surface, especially at least 99% of the surface.
  • the milling is generally performed in conventional milling apparatuses, such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder, rotor mill.
  • a planetary mill is preferably used.
  • An air jet mill is most preferably used.
  • the milling time is usually 0.5 minutes to 1 week, preferably 2 minutes to 50 hours, more preferably 15 minutes to 24 hours.
  • the process conditions in this embodiment are preferably selected such that the resulting composition particles can have an average particle diameter (D50) of 0.1 to 200 ⁇ , preferably 0.5 to 50 ⁇ , more preferably 1 to 25 ⁇ , particularly preferably 1.5 to 25 ⁇ and especially 2 ⁇ to 15 ⁇ .
  • D50 average particle diameter
  • An alternatively preferred process for preparing the composition of the invention comprises the steps of
  • step (h2) micronizing the mixture from step (hi); (h3) adding a further part of hydrophilizing agent (b) and micronizing said mixture and one or more excipients (c) ;
  • step (h4) optionally repeating step (h3) one to five times.
  • step (hi) of providing aleglitazar (a) and a first part of hydrophilizing agent (b) and optionally one or more excipients (c) can comprise mixing the compounds (a) and (b).
  • crystalline (non- micronized) aleglitazar (a) and hydrophilizing agent (b) and optionally one or more excipients (c) can be mixed in step (hi).
  • Step (h2) of micronizing the mixture from step (hi) can preferably be carried out by milling.
  • the mixing may take place before or even during the milling, i.e. steps (hi) and (h2) may be performed simultaneously.
  • the milling conditions can be selected such that at least 80% of the surface of the resulting composition particles is covered with hydrophilizing agent, more preferably at least 90% of the surface, particularly preferably at least 95% of the surface, especially at least 99% of the surface.
  • the milling can be performed in conventional milling apparatuses, as non limiting examples such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder, rotor mill.
  • a planetary mill is preferably used.
  • An air jet mill is most preferably used.
  • the milling time is usually 0.5 minutes to 1 week, preferably 2 minutes to 50 hours, more preferably 15 minutes to 24 hours.
  • the process conditions in this embodiment can preferably be selected such that the resulting composition particles can have an average particle diameter (D50) of 0.1 to 100 ⁇ , preferably 0.5 to 500 ⁇ , more preferably 1 to 25 ⁇ , particularly preferably 1.5 to 20 ⁇ and especially 2 ⁇ to 15 ⁇ .
  • step (h3) of adding a further part of hydrophilizing agent (b) and optionally one or more excipients (c) can preferably be performed by an accompanying mixing step.
  • Step (h4) of optionally repeating step (h3) one to five times may depend on the number of parts into which the initial hydrophilizing agent (b) is divided.
  • composition of the invention containing micronized aleglitazar and hydrophilizing agent and optionally one or more excipients (c).
  • the subject of the invention therefore can relate to compositions obtainable by this method.
  • the one or more excipient(s) (c) optionally used in the composition according to the invention can be preferably selected from the excipients described below. More preferably, the optionally one or more excipient(s) (c) used in the above process can be preferably selected from surfactants and fillers, in particular from sodium lauryl sulfate and disodium phosphate as well as sodium dihydrogen phosphate. Further, it is preferred that composition of the present invention additionally comprises basic components, preferably basic buffer salts. Basic buffer salts can be present in an amount of 1 to 30 wt.-%, based on the weight of the composition.
  • the micronized aleglitazar of the invention and the composition of the invention i.e. the hydrophilized and micronized aleglitazar of the invention
  • a subject of the invention can be a dosage form containing micronized aleglitazar of the invention or a composition of the invention as well as one or more pharmaceutical excipient(s) (c).
  • excipients (c) with which the person skilled in the art is familiar, such as those described in the European Pharmacopoeia.
  • the application refers to "Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende füre", edited by H. P. Fiedler, 4 th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H.
  • excipients (c) used to prepare the dosage form of the invention can preferably be disintegrants (cl), anti-sticking agents (c2), surfactants (c3), fillers (c4), glidants (c5), binders (c6) and/or lubricants (c7).
  • Disintegrants are reported to be compounds which can enhance the ability of the dosage form to break into smaller fragments when in contact with a liquid, preferably water.
  • Suitable disintegrants can be, for example, organic disintegrants such as crosslinked PVP, carrageenan, croscarmellose, starch, sodium carboxymethyl starch and crospovidone.
  • Alkaline disintegrants can preferably be used.
  • alkaline disintegrants means disintegrants which, when dissolved in water, produce a pH level of more than 7.0.
  • inorganic alkaline disintegrants can be used, especially salts of alkali metals and alkaline earth metals.
  • Preferred examples here are sodium, potassium, magnesium and calcium.
  • carbonate, hydrogen carbonate, phosphate, hydrogen phosphate and dihydrogen phosphate can preferably be used. Examples are sodium hydrogen carbonate, calcium hydrogen carbonate.
  • Crospovidone and/or croscarmellose can particularly preferably be used as disintegrants.
  • Disintegrants (cl) can be used from 0.5 to 15% by weight, preferably 1.0 to 10% by weight, more preferably 1.5 to 7% by weight, based on the total weight of the dosage form.
  • Anti-sticking agents (c2) are reported to be substances which reduce agglomeration in the core bed. Examples are talcum, silica gel, polyethylene glycol (preferably with 2,000 to 10,000 g/mol weight-average molecular weight) and/or glycerol monostearate. Examples of preferred anti-sticking agents are talcum and polyethylene glycol (Mg 3,000-6,000 g/mol), carrageenan. Preferably, an anti- sticking agent (c2) can be used when micronized aleglitazar is used in the dosage form.
  • Anti-sticking agents (c2) can be used in an amount of 0.1 to 5% by weight, more preferably 0.5 to 3% by weight, based on the total weight of the dosage form.
  • Surfactants (c3) are reported to be substances lowering the interfacial tension between two phases, thus enabling or supporting the formation of dispersions or working as a solubilizer.
  • preferred surfactants include but are not limited to alkyl sulfates (for example sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates and the like.
  • Sodium lauryl sulfate can particularly be used as a surfactant.
  • Surfactants (c3) can preferably be used in an amount from 0.1 to 5% by weight, more preferably from 0.3 to 3% by weight even more preferably from 0.5 to 2% by weight, based on the total weight of the dosage form.
  • Fillers (c4) or diluents can be used to increase the bulk volume and weight of a low-dose drug to a limit at which a pharmaceutical dosage form can be formed. Therefore, the normal purpose of fillers is to obtain a suitable tablet size. Fillers may fulfil several requirements, such as being chemically inert, non-hygroscopic, biocompatible, easily processable and possessing good biopharmaceutical properties.
  • Examples of preferred fillers are lactose, lactose derivatives, microcrystalline cellulose, starch, starch derivatives, treated starch, talcum, chitin, cellulose and derivatives thereof, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and/or potassium chloride.
  • Prosolv ® Rettenmaier & Sonne, Germany
  • Fillers are normally used in an amount of 1 to 80% by weight, more preferably 30 to 60% by weight, based on the total weight of the dosage form.
  • Glidants can be used to improve the flowability.
  • talc was used as glidant, but it is nowadays nearly fully replaced by colloidal silica (for example Aerosil ® ).
  • the silica has a specific surface area of 50 to 400 m 2 /g, more preferably 150-250 m /g, measured by gas adsorption according to Ph. Eur., 6.0, Chapter 2.9.26, multipoint method, volumetric determination.
  • Glidants (c5) can be used in an amount of 0.1 to 3% by weight, preferably 0.2 to 2.0% by weight, based on the total weight of the dosage form.
  • Binders (c6) or adhesives are reported to be substances that ensure that granulates or tablets can be formed with the required mechanical strength.
  • Binders can be, for example, starch, sucrose, gelatine, polyvinylpyrrolidone, cellulose derivates, preferably hydroxypropyl methylcellulose and microcrystalline cellulose.
  • Binders (c6) can be used in an amount of 0.1 to 15% by weight, preferably 2- 10% by weight, based on the total weight of the dosage form.
  • Lubricants (c7) can be used in order to reduce sliding friction.
  • the intention is to reduce the sliding friction occurring during tablet pressing between the die and the die wall, on the one hand, and between the edge of the tablet and the die wall, on the other hand.
  • the lubricant can be preferably a stearate or fatty acid, more preferably an earth alkali metal stearate, such as magnesium stearate.
  • the lubricant can be suitably present in an amount of 0 to 3 wt.%, preferably about 0.1 to 1.0 wt.% of the total weight of the dosage form.
  • Lubricants are generally used in an amount of 0.1 to 3% by weight, based on the total weight of the dosage form.
  • microcrystalline cellulose may act both as hydrophilizing agent (b) and as filler (c4).
  • one and the same pharmaceutical compound can only function as one of the compounds (b) or (cl) to (c7).
  • lactose is added as hydrophilizing agent (b), it cannot additionally be added as filler (c4).
  • the active agent is present in an mount of 0.01 to 50 o by weight, preferably from 0.1 to 5 c, more preferably 0.2 to 1.5 o, by weight, based on the total weight of the dosage form.
  • the dosage form is a solid oral dosage form, preferably a tablet or a capsule, more preferably a tablet.
  • the oral dosage form can have a content uniformity wherein the acceptance value is at most 15, preferably 0.1 - 10, more preferably 1 - 7.5, in particular at most 2 - 6.5.
  • the acceptance value of the content uniformity is determined by assaying 10 individual dosage forms and calculating the corresponding acceptance value in accordance with Ph. Eur., 5.3, Chapter 2.9.40.
  • Another subject of the present invention is a method of producing a dosage form comprising the steps of (i) providing the composition of the present invention containing aleglitazar (a) in a micronized form;
  • step (ii) optionally granulating the composition of step (i); (iii) mixing the composition of step (i) or the granulates of step (ii) with optionally one or more excipient(s) (c);
  • step (iv) optionally granulating the mixture from step (iii), ;
  • step (v) processing the mixture of step iii) or the granulates from step (iv) into a dosage form.
  • step (i) a composition of the present invention containing micronized aleglitazar (a) is provided.
  • This composition can be prepared by the above- mentioned process for preparing a composition according to the invention.
  • micronized aleglitazar can be provided in step (i).
  • Step (ii) of optionally granulating the composition from step (i) can be performed, for example, by "slugging", using a large heavy-duty rotary press to compact the composition to slugs and afterwards breaking up the slugs to granulates with a hammer mill or by roller compaction, using for example roller compactors by Powtec or Alexanderwerk.
  • step (iii) can be characterized by mixing the composition of step (i) or the granulates of step (ii) with one or more excipient(s) (c).
  • the mixing (iii) can be carried out with conventional mixing devices. In order to ensure an even distribution, mixing in intensive mixers is preferable. Suitable mixing devices can preferably be compulsory mixers or free fall mixer, for example like Turbula ® T 10B (Bachofen AG, Switzerland). Mixing can be carried out for example for 1 minute to 1 hour, preferably for 5 to 30 minutes.
  • the excipient(s) (c) used in step (iii) can preferably be selected from disintegrants (cl), anti-sticking agents (c2), surfactants (c3), fillers (c4), glidants (c5), binders (c6) and/or lubricants (c7).
  • crosslinked PVP used as disintegrant
  • sodium lauryl sulfate used as surfactant
  • lactose and microcrystalline cellulose used as fillers
  • povidone used as binder
  • sodium stearyl fumarate used as lubricant
  • microcrystalline cellulose and lactose used as filler
  • mixing (iii) can be conducted such that the composition of step (i) or the granulates of step (ii) can be mixed with only a part of the excipient(s) in a mixing device, for example in a high shear or tumbler mixer. After this first mixing step a next part of the excipient(s) can be added, which may be followed by a next mixing step. This procedure can be repeated until the last part of the excipient(s) is used, preferably one to five times. This kind of mixing can assure an even distribution of active agent and provide a mass for further processing in step (iv), for example for a tabletting process.
  • the composition of step (i) or the granulates of step (ii) initially can be mixed with only a part of the excipient(s) (for example 25 to 95%).
  • This mixture can preferably be granulated in step (iv).
  • a next part of the excipient(s) can be added and a next mixing (iii) and/or granulation step (iv) can be performed.
  • the excipients should preferably be mixed in before the first granulation step, between multiple granulation steps or after the last granulation step.
  • the procedure can be repeated as many times as the number of parts the initial amount of excipient(s) was divided in. This specific combination of mixing and granulating step can assure an even distribution of active agent. It is preferred that if step (iv) is carried out, the granulation is performed in the absence of solvents, especially in the absence of organic solvents.
  • step (iv) comprises a compaction sub-step and a subsequent granulation sub -step.
  • the compacting conditions in steps (ii) and/or (iv) can preferably be selected such that the slugs have a density of 0.75- 1.1 g/cm .
  • the term "density” here preferably relates to the "pure density” (i.e. not to the bulk density or compacted density).
  • the pure density can be determined with a gas pycnometer.
  • the gas pycnometer is preferably a helium pycnometer; in particular, the AccuPyc 1340 helium pycnometer from the manufacturer Micromeritics, Germany, is used.
  • the compaction sub-step can preferably be carried out in a roll granulator.
  • the rolling force can be preferably 2 to 50 kN/cm, more preferably 4 to 30 kN/cm, especially 10 to 25 kN/cm.
  • the gap width of the roll granulator can be, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, especially 1.8 to 2.8 mm.
  • the compacting apparatus used can preferably have a cooling means.
  • the cooling can be such that the temperature of the compacted material does not exceed 50°C, especially 40°C.
  • the granulation conditions are selected such that the resulting particles (granulates) have an average particle diameter (D50) of 50 to 600 ⁇ , more preferably 100 to 500 ⁇ , even more preferably 150 to 400 ⁇ , especially 200 to 350 ⁇ .
  • D50 average particle diameter
  • the granulation conditions are preferably selected such that the resulting granulates have a bulk density of 0.2 to 0.85 g/ml, more preferably 0.3 to 0.8 g/ml, especially 0.4 to 0.7 g/ml.
  • the Hausner factor is usually in the range from 1.03 to 1.3, more preferably from 1.04 to 1.20 and especially from 1.04 to 1.15.
  • the "Hausner factor" in this context means the ratio of compacted density to bulk density.
  • the granulation is performed in a screen mill.
  • the mesh width of the screen insert is usually 0.1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, especially 0.8 to 1.8 mm.
  • the mixture resulting from step (iii) or the granulates of step (iv) can be further processed into an oral dosage form.
  • Step (v) can preferably comprise compressing the mixture resulting from step (iii) or the granulates of step (iv) into tablets or filling the mixture resulting from step (iii) or the granulates of step (iv) into devices like sachets, stick-packs or capsules.
  • step (v) of processing the mixture resulting from step (iii) or the granulates of step (iv) into an oral dosage form can include compressing the mixture resulting from step (iii) or the granulates of step (iv) into tablets.
  • the compression step (v), preferably a direct compression step, is preferably carried out on a rotary press, e.g. on a Fette ® 102i (Fette GmbH, Germany) or a Riva ® piccola (Riva, Argentina).
  • excipient(s) added in step (ii) or (iii) can depend on the type of tablet to be produced and the amount of excipient(s) already added.
  • the additives to improve powder flowability described above and the lubricants described above can preferably be used.
  • Compression force can for example range from 1 to 50kN, preferably 3 to 40kN.
  • the tabletting conditions are preferably selected such that the resulting tablets have a ratio of tablet height to weight of 0.005 to 0.3 mm/mg, particularly preferably 0.05 to 0.2 mm/mg.
  • the resulting tablets preferably have a hardness of 30 to 400 N, more preferably 50 to 250 N. The hardness is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.8.
  • the resulting tablets preferably have a friability of less than 10%, more preferably less than 8%, particularly preferably less than 5%. The friability is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.7.
  • the tablets produced by the method of the invention may be tablets which can be swallowed unchewed (non-film-coated or preferably film-coated). They may likewise be chewable tablets or dispersible tablets. "Dispersible tablet” here means a tablet to be used for producing an aqueous suspension for swallowing.
  • macromolecular substances are preferably used, such as modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and/or shellack.
  • HPMC is preferably used, especially HPMC with a number- average molecular weight of 10,000 to 150,000 g/mol and/or an average degree of substitution of - OCH 3 groups of 1.2 to 2.0.
  • the thickness of the coating is preferably 1 to 100 ⁇ , more preferably 10 to 80 ⁇ .
  • step (v) dependent dosing systems for example an auger
  • independent dosing systems for example MG2, Matic (IMA)
  • IMA independent dosing systems
  • Another preferred embodiment of the invention can be a micronized PPAR- modulator with dual acting activity (i.e. affinity to PPARa as well as to PPARy) for treating patients with diabetes mellitus type II having a value of triglyceride of 200-600 mg/dl. A triglyceride value of more than 200 mg/dl is reported to be harmful for a normal person.
  • Example 2a Dosage form prepared by Co-milling of Aleglitazar Aleglitzar, sodium lauryl sulfate, disodium phosphate and sodium dihydrogen phosphate and a quarter of mannitol were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125 ⁇ mesh size. Afterwards another quarter of mannitol was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125 ⁇ mesh size.
  • Example 2b Dosage form prepared by Co-milling of Aleglitazar Aleglitzar, sodium lauryl sulfate, disodium phosphate and sodium dihydrogen phosphate and a quarter of mannitol were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125 ⁇ mesh size. Afterwards another quarter of mannitol was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125 ⁇ mesh size. Then the remained part of mannitol was added to the blend and milling was continued for further 5 minutes at 150 rpm. Afterwards the blend was sieved through 125 ⁇ mesh size.
  • Example 2c Dosage form prepared by Co-milling of Aleglitazar
  • Example 3 Dosage form prepared by Co-milling of Aleglitazar
  • Aleglitzar, sodium lauryl sulfate, disodium phosphate and sodium dihydrogen phosphate and a quarter of lactose were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125 ⁇ mesh size. Afterwards another quarter of lactose was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125 ⁇ mesh size. Then the remained part of lactose was added to the blend and milling was continued for further 5 minutes at 150 rpm. Afterwards the blend was sieved through 125 ⁇ mesh size.
  • Aleglitzar, sodium lauryl sulfate, meglium and a quarter of mannitol were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125 ⁇ mesh size. Afterwards another quarter of mannitol was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125 ⁇ mesh size. Then the remained part of mannitol was added to the blend and milling was continued for further 5 minutes at 150 rpm. Afterwards the blend was sieved through 125 ⁇ mesh size.
  • the dosage form according to the present invention has a mean assay of 98.93% and the standard deviation is 2.25 %.
  • the dosage from according to W02010/084066 has a mean assay of 101.03 % and the standard deviation 2.93 %.
  • sample of the dosage form according to the present invention has a significantly lower acceptance value than the reference example as prepared by spray granulation.

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Abstract

La présente invention concerne l'aléglitazar micronisé, de préférence sous la forme d'une composition conjointement à un agent d'hydrophilisation. L'invention concerne en outre un procédé de préparation de formes galéniques contenant de l'aléglitazar micronisé.
PCT/EP2013/065701 2012-07-27 2013-07-25 Aléglitazar micronisé WO2014016371A1 (fr)

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US11749247B2 (en) 2018-04-25 2023-09-05 Massachusetts Institute Of Technology Energy efficient soundproofing window retrofits
US11851334B2 (en) 2016-02-24 2023-12-26 Massachusetts Institute Of Technology Solar thermal aerogel receiver and materials therefor

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US20070024984A1 (en) 2004-03-17 2007-02-01 Yoshito Iwasawa Zoom lens and imaging device using zoom lens
WO2009136884A2 (fr) * 2008-05-06 2009-11-12 Bilim Ilac Sanayi Ticaret A.S. Formulation de metformine-pioglitazone à effets antihyperglycémiques
WO2010084066A1 (fr) 2009-01-23 2010-07-29 F. Hoffmann-La Roche Ag Composition pharmaceutique comprenant de l'aleglitazar

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US20070024984A1 (en) 2004-03-17 2007-02-01 Yoshito Iwasawa Zoom lens and imaging device using zoom lens
WO2009136884A2 (fr) * 2008-05-06 2009-11-12 Bilim Ilac Sanayi Ticaret A.S. Formulation de metformine-pioglitazone à effets antihyperglycémiques
WO2010084066A1 (fr) 2009-01-23 2010-07-29 F. Hoffmann-La Roche Ag Composition pharmaceutique comprenant de l'aleglitazar

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A. QUIROGA ET AL: "DEVELOPMENT OF A DIRECT COMPRESSION ROBUST HYDROPHILIC MATRIX OF AN INSOLUBLE MICRONIZED ACTIVE USING NIFEDIPINE AS A MODEL DRUG", 1A REUNIÓN INTERNACIONAL DE CIENCIAS FARMACÉUTICAS 2010, 15 March 2011 (2011-03-15), pages 1 - 2, XP055042477, Retrieved from the Internet <URL:http://www.fbioyf.unr.edu.ar/ricifa/Resumenes2010/Tecnologia Farmaceutica/QUIROGA.pdf> [retrieved on 20121029] *
DUBERG, M.; NYSTR6M, C.: "Studies on direct compression of tablets VI. Evaluation of methods for the estimation of particle fragmentation during compaction", ACTA PHARM. SUEC., vol. 19, 1982, pages 421 - 436
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11851334B2 (en) 2016-02-24 2023-12-26 Massachusetts Institute Of Technology Solar thermal aerogel receiver and materials therefor
US11749247B2 (en) 2018-04-25 2023-09-05 Massachusetts Institute Of Technology Energy efficient soundproofing window retrofits

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