OA16372A - Reclaimer machine. - Google Patents

Reclaimer machine. Download PDF

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Publication number
OA16372A
OA16372A OA1201300141 OA16372A OA 16372 A OA16372 A OA 16372A OA 1201300141 OA1201300141 OA 1201300141 OA 16372 A OA16372 A OA 16372A
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OA
OAPI
Prior art keywords
pharmaceutical composition
deferasirox
composition according
inhibitor
sodium
Prior art date
Application number
OA1201300141
Inventor
Marcelo Menezes Cruz
Original Assignee
Vale S.A.
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Publication of OA16372A publication Critical patent/OA16372A/en

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Abstract

This document describes a reclaimer machine (100) for reclaiming and homogenizing materials such as ore, coal and others, stock-piled in yards. The reclaimer machine (100) comprising a bucket wheel (1) which includes a series of buckets (8) rotating a shaft (2), a conveyor belt (3) connected to the bucket wheel (1) and to a transfer chute (5), the conveyor belt (3) being supported by a mobile upper platform (4) which moves laterally to a pile on tracks attached to a mobile lower platform (7), wherein a first end of the conveyor belt (21) structure is connected to the bucket wheel (1) and another end of the conveyor belt structure (3) is connected to a counterweight' (6) which maintains the balance of the reclaimer machine (100) and supports the bucket wheel (1), upper platform (4) and lower platform (7) movements.

Description

The présent invention relates to a pharmaceutical composition comprising an iron chelating agent, and more particularly, relates to a pharmaceutical composition comprising deferasirox or a pharmaceutically acceptable sait thereof, a process for preparing such pharmaceutical composition, and its use in the treatment of chronic iron overload.
BACKGROUND AND PRIOR ART:
One of the major obstacles to the development of highly potent pharmaceutical formulations is the poor water solubility of many drugs. Approximately 40% of potentîal drugs identified by pharmaceutical companies are poorly soluble în water, which greatly hinders their clinical use. Low water solubility limits the bioavailability and absorption of these agents.
Deferasirox has the chemical name 4-[3, 5-bîs (2-hydroxyphenyl) - [1, 2, 4] triazol-l-yl] enzoic acid, and is reported to hâve the following chemical structure.
Deferasirox is an orally active iron chelator, and has been approved for the treatment of iron overload in transfusion dépendent anémias (transfusion hemosîderosis), in particular thalassemia major, thalassemia intermediate and in sickle cell disease to reduce iron-related morbidity and mortality, in patients having an âge of two years and older.
Chronic iron overload îs a resuit of regular blood transfusions used in the treatment of several conditions including β-thalassemia, sickle cell disease and myelodysplastic syndromes.
Each unit of blood contains iron and as the human body has no physiological mechanism to actively excrete excess iron, repeated blood transfusions resuit in excessive accumulation of iron.
This excess of iron deposited in body tissues can cause severe damage to organs such as liver, heart, endocrine organs. This may lead to many complications including cardiomyopathy, liver cirrhosis, diabètes mellitus and reduced life expectancy.
Deferasirox mobilizes tissue iron by forming soluble stable complexes that are then excreted in the feces. It Îs a tridentate iron chelator requiring two molécules of the drug to form a stable complex. Iron is chelated both from the réticuloendothélial cells (RE cells) as well as various parenchymal tissues. The chelated iron is cleared by the liver and excreted through the bile. It also has the ability to prevent the myocardial cell iron uptake by removing iron directly from myocardîal cells.
Deferasirox is highly water-insoluble and is highly lipid-soluble, and is also observed to possess good permeability. According to the Bio-pharmaceutics Classification System (BCS), it has been classified as a Class II drug, implying that it is a poorly soluble, and a highly permeable drug. Though deferasirox is highly water-insoluble, whatever limited solubility it has, that too exhibits a high pH-dependent solubility. Though it is practically insoluble in lower pH, even at a pH of 6.8, it still remains insoluble, untîl the buffer strength is altered to get optimal dissolution profile.
Deferasirox being practically insoluble in aqueous media exhibits a generally poor dissolution profile and hence consequently poor bioavailability.
Several strategies and formulations have been employed to overcome these limitations of solubility and poor bioavailability. Although existing strategies such as complexing drugs with cyclodextrins, conjugation to dendrimers, sait formation of îonizable drugs and the use of cosolvents have been shown to improve drug solubility, solubilization methods that can improve the absorption ofthe drug are still highly désirable.
WO 2004035026 discloses a dispersîble tablet of deferasirox wherein the active ingrédient is présent in an amount of from 5% to 40% by weight based on total weight of the tablet.
WO 2005097062 discloses a dispersîble tablet of deferasirox wherein the active ingrédient îs présent in an amount of from 42% to 65% by weight based on total weight of the tablet.
WO 2007045445 discloses a dispersîble tablet of deferasirox or a pharmaceutically acceptable sait thereof présent in an amount of from 42% to 65% by weight based on total weight of the tablet and at least one pharmaceutically acceptable excipient suitable for the préparation of dispersible tablets and to process for making said dispersible tablet.
WO 2009067557 discloses a process of preparing deferasirox formulations having sufficiently high dissolution rate and good bioavailability wherein said process comprises co- milling deferasirox with at least two pharmaceutically acceptable excipients in the absence of any solvent.
WO 2010035282 discloses oral pharmaceutical composition comprising deferasirox in the form of a dispersible tablet wherein the active ingrédient has a mean particle size less than about lOOpm and is présent in an amount greater than 66% by weight based on total weight of the tablet.
Deferasirox is commercîally available as dispersible tablet (EXJADE®) for oral administration. EXJADE is supplied as a dispersible tablet containing 125 mg, 250 mg and 500 mg of deferasirox per tablet. This tablet is dispersed in a glass of water or any other suitable drink, and this resulting suspension is then administered to the patient.
Deferasirox is administered as a once daily oral iron chelator, which is prescribed as a dispersible tablet, i.e., a tablet which needs to be dispersed in an aqueous medium prior to administration,
Deferasirox îs typicalîy administered at an initial dose of about 20 mg/kg body weight, and the dose is adjusted up to a maximum of 30 mg/kg body weight.
Further, the recommended dosage of deferasirox is on the higher side in order to hâve a clinical benefit. Due to its high dosage, the overall tablet weight and its volume including its dimension makes it inconvénient to administer, in order to provide a pharmacologically active daily dosage amount of deferasirox.
Hence, there is a need for an oral dosage form having a high drug content which would be convenient for patient administration, which would exhibit acceptable dissolution and absorption which leads to better bioavailability.
OBJECT OF THE INVENTION:
The object of the présent invention is to provide a pharmaceutical composition comprising nanosized deferasirox having improved surface area and solubility.
Another object of the présent invention îs to provide a process for preparing the pharmaceutical composition comprising nanosized deferasirox.
Yet another object of the présent invention is to provide a method for treatment of chronic iron overload which comprises administering a pharmaceutical composition comprising nanosized deferasirox.
SUMMARY OF THE INVENTION:
According to one aspect of the présent invention there îs provided a composition comprising deferasirox in the form of particles, wherein substantially the particles hâve an average particle size of less than or equal to about 2000nm.
According to another aspect of the présent invention there is provided a pharmaceutical composition comprising deferasirox and at least one excipient.
According to another aspect of the présent invention there is provided a pharmaceutical composition comprising deferasirox and a pharmaceutically acceptable carrier.
According to another aspect of the présent invention there is provided a process for preparing a pharmaceutical composition, which process comprising the steps of: homogenizing deferasirox and at least one excipient to produce a homogenized dispersion of the deferasirox in the excipient; and milling said homogenized dispersion to produce a slurry of particles having an average particle size of less than or equal to about 2000nm.
According to another aspect of the présent invention there is provided the use of a composition according to présent invention in the manufacture of a médicament for treating chronic iron overload.
According to another aspect of the présent invention there is provided a method of treating chronic iron overload comprising administering a therapeutically effective amount of a composition having deferasirox according to the présent invention to a patient in need thereof.
According to another aspect of the présent invention there is provided a method of treating chronic iron overload comprising administering a therapeutically effective amount of deferasirox according to the présent invention to a patient in need thereof.
According to one aspect of the présent invention there is provided a pharmaceutical composition comprising deferasirox or pharmaceutically acceptable sait, solvaté, dérivatives, hydrate, enantiomer, polymorph, complex, or mixtures thereof.
According to another aspect of the présent invention there is provided a pharmaceutical composition comprising deferasirox or pharmaceutically acceptable sait, solvaté, dérivatives, hydrate, enantiomer, polymorph, complex or mixtures thereof wherein the deferasirox is in the nanosize range.
According to yet another aspect of the présent invention there is provided a process for preparing a pharmaceutical composition comprising deferasirox or pharmaceutically acceptable sait, solvaté, dérivatives, hydrate, enantiomer, polymorph, complex or mixtures thereof wherein the deferasirox is in the nanosize range.
According to a further aspect of the présent invention there is provided a method of treatment of chronic iron overload using a pharmaceutical composition comprising deferasirox or pharmaceutically acceptable sait, solvaté, dérivatives, hydrate, enantiomer, polymorph, complex or mixtures thereof wherein deferasirox is în the nanosize range.
DETAILED DESCRIPTION OF THE INVENTION:
In iron chélation therapy, a chelating drug binds with free or “labile” iron in the blood and organs, which allows for removal of excess iron from the body. Thus if more of deferasirox is available for chélation, there will be better removal of excess iron from the body.
Also, where multiple transfusions are repeatedly needed and phlebotomy is not possible, the chélation therapy provides a means of controlling the iron overload. The bioavailability (the percentage of the drug absorbed compared to its initial dosage) is Iimited by însolubility.
Dissolution rate is a function of the surface area of the particles and solubility. Dissolution rate is a direct function of total surface area for a dispersed phase.
The recommended dosage of deferasirox is on the higher side, i.e., an initial dose of about 20mg/kg body weight, and this dose is adjusted up to a maximum of 30mg/kg body weight. Further, deferasirox has been classified as a Class II drug which exhibits poor solubility.
Therefore, formulating a suitable formulation of deferasirox with désirable advantages such as, easy to manufacture as well as which possess advantages such as patient compliance is a challenge.
The inventors of the présent invention hâve found that, the solubility properties of deferasirox were improved by using nanosîzed deferasirox and thus leading to better bioavailability of the drug.
Nanonization of hydrophobie or poorly water-soluble drugs generally învolves the production of drug nanocrystals through either chemical précipitation (bottom-up technology) or disintegration ( top-do wn technology). Different methods may be utilized to reduce the particle size of the hydrophobie or poorly water soluble drugs. [Huabing Chen et al., discusses the various methods to develop nanoformulations in “Nanonization strategies for poorly water-soluble drugs,” Drug Discovery Today, Volume 00, Number 00, March 2010].
The term “nanosizing” as used herein refers to the réduction of deferasirox particle size to the sub-micron range. By submicron range, this suitably means having an average particle size of less than or equal to about 2000nm.
Nanosizing leads to increase in the exposure of surface area of deferasirox particles leading to an increase in the rate of dissolution.
The présent invention thus provides a pharmaceutical composition comprising deferasirox wherein deferasirox is in the nanosize range.
The term “nanosize” as used herein refers to deferasirox particles having an average particle size of less than or equal to about 2000nm, preferably less than or equal to about lOOOnm. The average particle size may, for example, be measured using laser based particle size analyzer.
Preferably, substantially ail particles hâve a particle size of less than or equal to about 2000 nm, preferably less than or equal to about 1000 nm.
The term “particles” as used herein refers to individual particle of deferasirox, or particles of deferasirox or deferasirox granules or deferasirox compositions and/or mixtures thereof.
The average particle size of the deferasirox is preferably above l nanometre.
The term “Deferasirox” is used in broad sense to include not only “Deferasirox” per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable dérivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
The nanoparticles of the présent invention can be obtained by any of the process such as but not limited to milling, précipitation and homogenization.
According to one embodiment of the présent invention, the process of milling comprises dispersing deferasirox particles in a liquid dispersion medium in which deferasirox is poorly soluble, followed by applying mechanical means in the presence of grinding media like milling pearls to reduce the particle size of deferasirox to the desired average particle size.
According to another embodiment of the présent invention, the process of précipitation involves the formation of crystalline or semi-crystalline deferasirox nanoparticles by nucléation and the growth of drug crystals. In a typical procedure, drug molécules are first dissolved in an appropriate organic solvent such as acetone, tetrahydrofuran or N-methyl-2-pyrrolidone at a super saturation concentration to allow for the nucléation of drug seeds. Drug nanocrystals are then formed by adding the organic mixture to an antisolvent like water in the presence of stabîlizers such as Tween 80, Poloxamer 188 or lecithin. The choice of solvents and stabilizers and the mixing process are key factors to control the size and stability of the drug nanocrystals.
According to one another embodiment of the présent invention, the process of homogenization in volves passing a suspension of crystalline deferasirox and stabilizers through the narrow gap of a homogenizer at high pressure (for eg- 500-2000 bar). The pressure créâtes powerful disruptive forces such as cavitation, collision and shearing, which disintegrate coarse particles to nanoparticles.
According to one more embodiment of the présent invention, the process of spray-freeze drying involves the atomîzation of an aqueous deferasiorx solution into a spray chamber filled with a cryogénie liquid (liquid nitrogen) or halocarbon réfrigérant such as chlorofluorocarbon or fluorocarbon. The water is removed by sublimation after the liquid droplets solidify.
According to a still another embodiment of the présent invention, the process of supercritical fluid technology involves controlled crystallization of deferasiorx from dispersion in supercritical fluids, carbon dioxide.
According to another embodiment of the présent invention, the process of double emulsion/solvent évaporation technique involves préparation of oil/water (o/w) émulsions with subséquent removal of the organic phase through évaporation. The émulsions are prepared by emulsifying an organic phase containing deferasirox, polymer and organic solvent in an aqueous solution containing emulsifier. The organic solvent diffuses out of the polymer phase and into the aqueous phase, and is then evaporated, forming deferasirox-loaded polymeric nanoparticles.
According to a further embodiment of the présent invention, the process of PRINT (Particle réplication in non-wetting templates) involves utilization of a low surface energy fluoropolymeric mold that enables high-resolution imprint lithography, to fabricate a variety of organic particles. PRINT can precisely manipulate particle size of deferasirox ranging from 20 nm to more than 100 pm.
According to one further embodiment of the présent invention, the process of thermal condensation involves use of capillary aérosol generator (CAG) to produce high concentration condensation submicron to micron sized aérosols from a deferasirox solution.
According to still further embodiment of the présent invention, the process of ultrasonication may be used for nano-sizing deferasirox. The process of ultrasonication involves application of ultrasound during particle synthesis or précipitation, which leads to smaller particles of deferasirox and increased size uniformity.
According to another embodiment of the présent invention, the nano-sized deferasirox may be prepared by spray drying. The process of spray drying involves supplying a feed solution at room température and pumping it through the nozzle where it is atomized by a nozzle gas. The atomized solution is then dried by preheated drying gas in a spécial chamber to remove moisture from the system, thus forming dry particles of deferasirox.
According to a preferred embodiment of the présent invention, the nanomilled deferasirox may be obtained by nanomilling of deferasirox with at least one surface stabilizer, at least one viscosity building agent and at least one polymer.
The présent invention thus provides a pharmaceutical composition comprising nanosîzed deferasirox particles, prefereably in the form of granules. The granules may comprise at least one excipient. The excipient may comprise at least one of the following, but not limited to, at least one surface stabilizers, at least one viscosity building agent and at least one polymer and optionally other pharmaceutically acceptable carriers.
Surface stabilizer, according to the présent inventions, means surfactants that are capable of stabilizing the increased surfaced charge of the nanomilled drug. Suîtable amphoteric, non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the pharmaceutical composition of the présent invention.
According to the présent invention, surfactants may comprise one or more, but not limited to Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trîmethyl ammonium bromide (CTAB) Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N-dimethyldodecylamineN-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphénol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonîum chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated naturel oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & ît's ethoxylated dérivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensâtes, Polyoxyethylene fatty acid amides, Quatemary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, Ν,Ν,Ν,Ν tetrakis substituted ethylenediamines 2alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium sait, N-tallow 3 ίο iminodipropionate disodium sait, N-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium sait etc.
Viscosity builders means, excipients that are capable of stabilizing the nanoparticles by increasing the viscosity of the composition and thus preventing physical interaction of nanoparticles under the operating conditions employed.
According to the présent invention, viscosity builders, may comprise one or more, but not limited to dérivatives of sugars, such as lactose, saccharose, hydrolyzed starch (maltodextrin) etc or mixtures thereof.
Polymers or polymers blends, according to the présent invention, may comprise one or more hydrophilic polymers, but not limited to cellulose dérivâtes like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleîc anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and algînates, carboxypolymethylene, bentonîte, magnésium aluminum silicate, polysaccharides, modified starch dérivatives and copolymers..
The deferasirox composition having nanosized partîcles of the invention can be formulated into any suitable dosage form, including but not limited to liquid dispersions, gels, aérosols, oîntments, créants, controlled release formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immédiate release and controlled release formulations along with pharmaceutically acceptable carriers.
Solid oral dosage forms for administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent îs admixed with at least one of the following carriers: (a) one or more inert excipients (or carriers) (b) fillers or extenders (c) binders (d) humectants (e) disintegrating agents (f) solution retarders (g) absorption accelerators (h) wetting agents (i) adsorbents and (j) lubricants. For capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
The granules comprising nanosized deferasirox, according to the présent invention, may either be encapsulated in capsules or be compressed to form tablets or may be provided as sachets or be provided as powders for reconstitution.
The solid dosage form, according to the présent invention, may also optionally be coated. More preferably, the formulation may be seal coated and then film coated.
According to an embodiment of the présent invention, pharmaceutical composition may be film coated with but not limited to Ready colour mix Systems (such as Opadry colour mix Systems) and Kollicoat® Protect.
According to the présent invention, the seal coat comprises film forming polymeric materials, such as but not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolîdone, methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatîn to increase adhérence and cohérence of the seal coat.
In one aspect of the présent invention there is provided a pharmaceutical composition comprising deferasirox in the form of dispersible tablet, wherein deferasirox is in the nanosize range.
In another aspect of the présent invention there is provided a pharmaceutical composition comprising deferasirox in the form of dispersible tablet, wherein deferasirox îs in the nanosize range of less than or equal to about 2000nm, preferably less than or equal to about lOOOnm.
The term “dispersible tablet” as used herein refers to a tablet which normally disperses in aqueous phase, e.g. in water, with or without external agitation.
Suitable carriers may be used for formulating the various dosage forms according to the présent invention.
According to the présent invention, pharmaceutically acceptable opacifier for use in the pharmaceutical composition of the présent invention may comprise one or more, but is not limited to titanium dioxide.
According to the présent invention, pharmaceutically acceptable diluents or fillers for use în the pharmaceutical composition of the présent invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, β-lactose) lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avîcel), hydroxypropylcellulose, Lhydroxypropyl cellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose dérivatives, starches or modified starches (including potato starch, com starch, maize starch and rice starch) and mixtures thereof.
According to the présent invention, glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical composition of the présent invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnésium stéarate, calcium stéarate, sodium stearyl fumarate or other metallic stéarate), talc, waxes (for example, microcrystalline waxes) and glycerides, light minerai oil, PEG, silica acid or a dérivative or sait thereof (for example, silicates, silicon dioxide, colloïdal silicon dioxide and polymers thereof, crospovidone, magnésium aluminosilicate and/ or magnésium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil), or mixtures thereof.
According to the présent invention, suitable binders may also be présent in the pharmaceutical composition of the présent invention, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose dérivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrîn, gelatin, gum arable, guar gum, tragacanth, sodium alginate, or mixtures thereof or any other suitable binder.
According to the présent invention, suitable disintegrants may also be présent in the pharmaceutical composition of the présent invention, which may comprise one or more, but not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate; alginic acid or a sait thereof, such as sodium alginate or their équivalents and mixtures thereof.
Further, the pharmaceutical composition according to the présent invention may further comprise at least one additional active ingrédient such as but not limited to leukotriene, probenecid, indomethacin, penicillin G, ritonavir, indinavir, saquinavir, furosemide, methotrexate, sulfinpyrazone, interferon, ribavirin, viramidine, valopicitabine, aromatase inhibitor, antiestrogen, anti-androgen, gonadorelin agonist, topoisomerase I inhibitor, topoisomerase II inhibitor, microtubule active agent, alkylating agent, anti-neoplastic, anti-metabolite, platin compound, anti-angiogenic compound, cyclooxygenase inhibitor, bisphosphonate, heparanase inhibitor, telomerase inhibitor, protease inhibitor, matrix metalloproteinase inhibitor, protéasome inhibitor, somatostatin receptor antagonist, anti-leukemic compound, ribonucleotide reductase inhibitor, S-adenosylmethionine decarboxylase inhibitor; ACE inhibitor, antibiotics such as gentamicin, amikacîn, tobramycin, ciprofloxacin, levofloxacin, ceftazidime, cefepime, cefpîrome, piperacillin, ticarcillin, meropenem, imipenem, polymyxîn B, colistin and aztreonam; cyclosporin A, cyclosporin G, rapamycin.
There îs also provided a process for preparing the pharmaceutical composition of the présent invention, which process comprises homogenizing deferasirox and at least one excipient to produce a homogenîzed dispersion of the deferasirox in the excipient; and milling said homogenized dispersion to produce a slurry of deferasirox particles having an average particle size of less than or equal to about 2000 nm.
According to one embodiment the pharmaceutical composition of the présent invention, may be prepared by a process which comprises (a) preparing a dispersion of deferasirox with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose in purified water under stirring conditions;
(b) homogenizing the dispersion of step (a) and then nanomilling the homogenized dispersion;
(c) adsorbing the nanomilled drug by spraying the nanomilled slurry on lactose monohydrate, microcrystalline cellulose and crospovidone mixture în fluidized bed granulator; (d) drying and blending the granules obtained in step (c). The granules may be lubricated and finally compressed into tablets. The tablets obtained may be seal coated and then film coated.
The présent invention further provides a method for treating chronic iron overload which method comprises administering a therapeutically effective amount of a pharmaceutical composition according to the présent invention.
Furthcrmore. the présent invention provides pharmaceutical compositions comprising deferasirox for use in the treatment of chronic iron overload.
The following examples are for the purpose of illustration of the invention only and are not 10 intended in any way to limit the scope of the présent invention.
Example 1
Sr. No. Ingrédients Qty mg/tablet
Binder Solution
I. Deferasirox 500.00
2. Docusate Sodium IP 5.00
3. Hydroxypropylmethylcellulo.se 3cps IP 100.00
4. Sodium lauryl sulphate IP 14.00
5. Sucrose IP 150.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 175.00
8. Microcrystalline Cellulose IP (Avicel PH 101) 152.00
9. Crospovidone IP 50.00
Lubrication
10. Crospovidone IP 36.00
11. Magnésium Stéarate IP 6.00
Total 1188.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps IP 12.00
13. Isopropyl Alcohol IP q.s
14. Dichloromethane BP q.s
Total 1200.00
Film Coating
15. Opadry AMB White OY-B-28920 INH 25.00
16. Purified Water q.S.
Total 1225.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in water under stirring conditions.
2. Deferasirox was dispersed in the solution obtained in step (l).
3. Above dispersion was homogenîzed and then nanomilled .
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator.
5. Granules obtained were sized and lubricated.
6. Lubricated granules were finally compressed into tablets.
7. The tablets obtained were seal coated and then film coated.
Example 2
Sr. No. Ingrédients Qty mg/tablet
Binder Solution
1. Deferasirox 500.00
2. Docusate Sodium IP 5.00
3. H ydroxypropylmethyl cellulose 3cps IP 100.00
4. Sodium lauryl sulphate IP 14.00
5. Sucrose IP 150.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 175.00
8. Microcrystalline Cellulose IP (Avicel PH 101) 152.00
9. Crospovidone IP 50.00
Lubrication
10. Crospovidone IP 36.00
11. Magnésium Stéarate IP 6.00
Total 1188.00
Seal Coating
12. Hydroxypropyl methylcellulose 3cps IP 12.00
13. Isopropyl Alcohol IP q.s
14. Dichloromethane BP q.s
Total 1200.00
Film Coating
15. Kollîcoat Protect 15.00
16. Talc IP 60.25
17. Titanium dioxide IP 3.75
18. Purifîed Water IP q.s.
19. Isopropyl Alcohol IP q.s.
Total 1225.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in water under stirring conditions;
2. Deferasirox was dispersed in the solution obtained in step (1);
3. Above dispersion was homogenized and then nanomilled. 4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated;
6. Lubricated granules were finally compressed into tablets; and
7. The tablets obtained were seal coated and then film coated.
Example 3
Sr.No. Ingrédients Qty mg/tablet
Binder Solution
1. Deferasirox 250.00
2. Docusate Sodium 5.00
3. Hydroxypropylmethyl cellulose 15.00
4. Sodium lauryl sulphate 13.80
5. Sucrose 25.00
6. Purifîed water q.s.
Dry Mix
7. Lactose Monohydrate (200 mesh) 154.70
9. Crospovidone 50.00
Imbrication
10. Silicified Microcrystalline Cellulose 50.00
11. Crospovidone 40.00
12.
13.
14.
Croscannellose Sodium
Magnésium Stéarate
Total
20.00
1.50
625.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in water under stirring conditions;
2. Deferasirox was dispersed în the solution obtained în step (1);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were finally compressed into tablets.
Example 4
Sr.No. Ingrédients
Binder Solution
1. Deferasirox
2. Docusate Sodium
3. Hydroxypropylmethylcellulose
4. Sodium lauryl sulphate
5. Sucrose
Qty mg/tablet
500.00
10.00
30.00
27.6
50.00
6. Purified water
q.s
Dry Mix
7. Lactose Monohydrate (200 mesh)
309.40
9. Crospovidone
100.00
Lubrication
11. Crospovidone
80.00
12. Croscannellose Sodium
40.00
13. Magnésium Stéarate
3.00
Total
1250.00
10. Silicified Microcrystalline Cellulose
100.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in water under stirring conditions;
2. Deferasirox was dispersed în the solution obtained în step (l);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and crospovidone mixture in a fluîdized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were finally compressed into tablets.
Example 5
Sr.No. Ingrédients
Binder Solution
1. Deferasirox
2. Docusate Sodium
3. Polyvinylpyrrolidone
4. Sodium lauryl sulphate
5. Sucrose
Qty mg/tablet
250.00
5.00
15.00
13.80
25.00
6. Purified water
q.s.
Dry Mix
7. Lactose Monohydrate (200 mesh)
154.70
9. Crospovidone
50.00
Lubrication
10. Silicified Microcrystalline Cellulose 50.00
11. Crospovidone
40.00
12. Croscarmellose Sodium
20.00
13. Magnésium Stéarate
1.50
Total
625.00
Process:
1. Docusate sodium, PVP, sodium lauryl sulphate and sucrose were solubalized in water under stirring conditions;
2. Deferasirox was dispersed in the solution obtained in step (l);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were finally compressed into tablets.
Ëxample 6
Sr.No. Ingrédients Binder Solution Qty mg/tablet
L Deferasirox 500.00
2. Docusate Sodium 10.00
3. Polyvinylpyrrolidone 30.00
4. Sodium lauryl sulphate 27.6
5. Sucrose 50.00
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate (200 mesh) 309.40
9. Crospovidone 100.00
Lubrication
10. Silicified Microcrystalline Cellulose 100.00
11. Crospovidone 80.00
12. Croscarmellose Sodium 40.00
13. Magnésium Stéarate 3.00
Total 1250.00
Process:
1. Docusate sodium, PVP, sodium lauryl sulphate and sucrose were solubalized in purified water under stirring conditions;
2. Deferasirox was dispersed in the solution obtained în step (1);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were final ly compressed into tablets.
It will be readîly apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the présent invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limîting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and équivalents thereof as well as additional items.
It must be noted that, as used in this spécification and the appended claims, the singular forms a, an and the include plural référencés unless the context clearly dictâtes otherwise. Thus, for example, reference to a propellant includes a single propellant as well as two or more different propellants; reference to a cosolvent refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

Claims (18)

  1. CLAIMS:
    1. A pharmaceutical composition comprising deferasirox in the form of particles, wherein the particles hâve an average particle size of less than or equal to about 2000 nm.
  2. 2. A pharmaceutical composition according to claim 1, wherein the particles hâve an average particle size of less than or equal to about 1000 nm.
  3. 3. A pharmaceutical composition according to claim 1 or 2, comprising at least one excipient, which is selected from the group comprising at least one surface stabilizer, viscosîty building agent and polymer.
  4. 4. A pharmaceutical composition according to any one of claims 3, wherein the surface stabilizer is a surfactant, which is an amphoteric, non-ionic, cationic or anionic or combinations thereof.
  5. 5. A pharmaceutical composition according to claim 4, wherein the surfactant comprises one or more of polysorbates; sodium dodecyl sulfate (sodium lauryl sulfate); lauryl dimethyl amine oxide; docusate sodium; cetyl trimethyl ammonium bromide (CTAB); a polyethoxylated alcohol; a polyoxyethylene sorbitan; Octoxynol; N,N-dimethyldodecylamine-N-oxide; hexadecyltrimethylammonium bromide, polyoxyl 10 lauryl ether, brij, a bile sait, such as sodium deoxycholate or sodium cholate; a polyoxyl castor oil; nonylphenol ethoxylate; a Cyclodextrin; lecithin; methylbenzethonium chloride; a carboxylate; a sulphonate; a petroleum sulphonate; an alkylbenzenesulphonates; a naphthalenesulphonate; and olefin sulphonate; a sulphate surfactant; an alkyl sulphate; a sulphated natural oil or fat; a sulphated ester; a sulphated alkanolamide; an alkylphenol, optionally ethoxylated and sulphated; an ethoxylated aliphatiç alcohol; polyoxyethylene; a carboxylic ester; a polyethylene glycol esters; an anhydrosorbitol ester or an ethoxylated dérivative therof; a glycol ester of a fatty acid; a carboxylic amide; a monoalkanolamine condensate; a polyoxyethylene fatty acid amide; a quaternary ammonium sait; an amine with amide linkages; a polyoxyethylene alkyl amine; a polyoxyethylene alicyclic amine; a N,N,N,N tetrakis substituted ethylenediamine; a 2-alkyl-l-hydroxyethyl-2-imidazoline; N-coco-3-aminopropionic acid or a sodium sait thereof; N-tallow-3-iminodipropionate disodium sait; N-carboxymethyl-n-dimethyl-n-9 octadecenyl ammonium hydroxide; n-cocoamidethyl-nhydroxyethylglycine sodium sait; or mixtures thereof.
  6. 6. A pharmaceutical composition according to claim 3, 4, or 5, wherein the surfactant is docusate sodium and/or sodium lauryl sulphate.
  7. 7. A pharmaceutical composition according any one of claims 3, wherein the viscosîty building agent is lactose; sucrose; saccharose; a hydrolyzed starch, such as maltodextrin; or a mixture thereof.
  8. 8. A pharmaceutical composition according any one of claims 3, wherein the polymer is hydroxypropylcellulose; hydroxym ethyl cellulose; hydroxypropyl methylcellulose; a methylcellulose polymer; hydroxyethylcellulose; sodium carboxymethylcellulose; carboxymethylene hydroxyethylcellulose and/or carboxymethyl hydroxyethylcellulose; an acrylic polymer, such as acrylic acid, acrylamide, and maleic anhydride polymers and copolymers; or a mixture thereof.
  9. 9. A pharmaceutical composition according to any one of the preceding claims, wherein substantially ail the particles hâve an average particle size above 1 nm.
  10. 10. A pharmaceutical composition comprising a composition according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier, optionally the particles are adsorbed on the surface of the carrier.
  11. 11. A pharmaceutical composition according to claim 10, wherein the carrier comprises: one or more diluents or fïllers; one or more binders; one or more lubricauts; one or more glidants; one or more disintegrants; one or more preservatives; one or more humectants; one or more solution retarders; one or more absorption accelerators; one or more wetting agents; one or more adsorbents; one or more buffering agents; or a mixture thereof,
  12. 12. A pharmaceutical composition according to any one of claims 10 or 11, which is for oral administration, optionally in a solid oral dosage form.
  13. 13. A pharmaceutical composition according to claim 12, which is in a form of a tablet, optionally the tablet is a dispersible tablet.
  14. 14. A pharmaceutical composition according to any one of claims 1 to 13 for use in treating chronic iron overload.
  15. 15. A process for preparing a pharmaceutical composition, which process comprises the steps of:
    (1) homogenizing deferasirox and at least one excipient to produce a homogenized dispersion of the deferasirox; and (2) milling said homogenized dispersion to produce a slurry of deferasirox particles having an average particle size of less than or equal to about 2000 nm, optionally further comprising:
    (i) adsorbîng the milled slurry on a pharmaceutically acceptable carrier to form granules, which are optionally compressed to form tablets; or (ii) forming the slurring into a liquid dispersions, gels or aérosols.
  16. 16. A process according to any one of claim 15, wherein the excipient is as defined in any one of claims 3 to 8.
  17. 17. The use of a pharmaceutical composition according to any one of claims 1 to 13 in the manufacture of a médicament for treating chronic iron overload.
  18. 18. A pharmaceutical composition according to any one of claims 1 to 13 further comprising one or more actîve(s) selected from leukotriene, probenecid, indomethacin, penicillin G, ritonavir, indinavir, saquinavir, furosemide, methotrexate, sulfinpyrazone, interferon, ribavirin, viramidine, valopicitabine, aromatase inhibitor, antiestrogen, antî-androgen, gonadorelin agonist, topoisomerase I inhibitor, topoisomerase II inhibitor, microtubule active agent, alkylatîng agent, anti-neoplastîc, anti-metabolite, platin compound, antî-angiogenic compound, cyclooxygenase inhibitor, bisphosphonate, heparanase inhibitor, telomerase inhibitor, protease inhibitor, matrix metalloproteinase inhibitor, protéasome inhibitor, somatostatin receptor antagonîst, antileukemic compound, ribonucleotide reductase inhibitor, S-adenosylmethionine decarboxylase inhibitor; ACE inhibitor, antibiotics such as gentamicin, amikacin, tobramycîn, ciprofloxacin, levofloxacin, ceftazidime, cefepîme, cefpirome, piperacillin, tîcarcillin, meropenem, imipenem, polymyxin B, colistin and aztreonam; cyclosporin A, cyclosporin G, rapamycin or their pharmaceutically acceptable salts, solvatés, tautomers, dérivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
OA1201300141 2010-10-14 2011-08-14 Reclaimer machine. OA16372A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
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