WO2019108157A1 - Formulation de comprimé entaillé sous une forme dispersible comprenant du déférasirox - Google Patents

Formulation de comprimé entaillé sous une forme dispersible comprenant du déférasirox Download PDF

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Publication number
WO2019108157A1
WO2019108157A1 PCT/TR2018/050657 TR2018050657W WO2019108157A1 WO 2019108157 A1 WO2019108157 A1 WO 2019108157A1 TR 2018050657 W TR2018050657 W TR 2018050657W WO 2019108157 A1 WO2019108157 A1 WO 2019108157A1
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WO
WIPO (PCT)
Prior art keywords
deferasirox
weight
oral formulation
formulation according
pharmaceutical oral
Prior art date
Application number
PCT/TR2018/050657
Other languages
English (en)
Inventor
Umit Cifter
Urun Kandemirer
Gulnur YAZICI
Original Assignee
Biofarma Ilac Sanayi Ve Ticaret A.S.
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 Biofarma Ilac Sanayi Ve Ticaret A.S. filed Critical Biofarma Ilac Sanayi Ve Ticaret A.S.
Publication of WO2019108157A1 publication Critical patent/WO2019108157A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention is related to the formulation of a scored tablet in a dispersible form comprising deferasirox or a pharmaceutically acceptable salt of deferasirox.
  • Deferasirox is the first of a new group iron chelatagents in the form of tridentate, which is used by oral route in the treatment of chronic iron overload and which is named with 4-[3,5- Bis(2-hydroxyphenyl)-lH-l,2,4-triazole-l-yl]benzoic acid chemical formula; and characterized by the formula- 1 indicated below.
  • Deferasirox is the first medicine approved for iron overload treatment which is an approved molecule in 2005 by FDA (Food and Drug Administration).
  • Iron is important for the formation of new red blood cells.
  • excessive iron by taken into the body with various reasons causes iron accumulation in several tissues, this also causes many health problems.
  • iron overload There are a lot of reasons which can result in iron overload in the body.
  • One of the reasons for the accumulation of excess iron in the body is also hereditary hemochromatosis. It is known that this disease results from a mutation in gene which regulates how much iron the body needs for iron absorption.
  • hereditary anemia disease in patient, high iron problem may occur due to the treatment. When anemia occurs in case of the body cannot produce enough amount of blood cell, the body starts to absorb high amount of iron and the problem of iron overload occurs.
  • deferasirox is indicated in the treatment of chronical iron loading (transfusional hemosiderosis) due to blood transfusion in children aged 2 and above and in grown-ups, also is indicated in treatment of chronical iron loading in patients aged 10 and above who have thalassemia symptoms not dependent on transfusion.
  • Deferasirox is a molecule which is known as an alternative to deferoxamine which is a standard treatment option that is used via parenteral route in treatment of iron overload. It is found out that, chelation treatment is effective for removing iron quickly, reducing iron stores to a low level, inhibiting heart and other organ damage that results from iron overload and effective for prolonging survival in patients who have chronical iron poisoning. Deferasirox has been prepared in tablet form for oral suspension which is taken once a day. It is considered that it is a molecule which is more suitable for long term use and thereby enhances to manage chronical iron poisoning. In addition to this, it may enhance significantly the life quality of patients who have to get iron chelation treatment during all their lifetimes.
  • EP0914118B1 deferasirox is being described wherein the usage of it is disclosed for treatment of diseases that cause iron overload.
  • a tablet comprising 200 mg of active agent, a coated tablet comprising 400 mg of active agent, hard gelatin capsules comprising 500 mg of active agent, oral suspension powder comprising 300 mg of active agent is disclosed.
  • the amounts of excipients used in addition to the 500 mg of deferasirox active agent disclosed in the document are different from the amounts of excipients used in invention.
  • a dividable- scored dispersible tablet form of deferasirox is not disclosed in the said document.
  • EP1734924 pertains to a formulation comprising deferasirox or a pharmaceutically acceptable salt thereof in an amount of from 42% to 65% by weight based on the total tablet weight. It is mentioned that 125 mg and 1000 mg deferasirox dispersible tablet in the document. However, the amounts of some excipients (filler, disintegrant and lubricant) used in the document beside of deferasirox active agent are different from amount used in the invention. Furthermore, a dispersible scored tablet form of deferasirox is not disclosed in the said document.
  • EP1940360 pertains to a dispersible tablet form wherein deferasirox or a pharmaceutically acceptable salt thereof in an amount of from 42% to 65% by weight based on the total tablet weight.
  • a dispersible tablet having a total weight of 2000 mg ⁇ 5%, comprising deferasirox in an amount of 1000 mg ⁇ 5%, is disclosed.
  • a dispersible tablet comprising 800 mg deferasirox, is disclosed.
  • the amounts of some excipients (filler, disintegrant and lubricant) used in the document beside of deferasirox active agent are different from the amounts of excipients which used in the invention.
  • a dispersible scored tablet form of deferasirox is not disclosed in said document.
  • the dose of the deferasirox to be administered to the patient is dependent on several factors like patient’s age, weight, the level of iron accumulation, interaction with the other used drugs if any.
  • the doses to be administered (as mg/kg) are calculated by checking the clinical monitoring indications and applied by adapting them to the closest tablet dose.
  • Recommended initial dose in treatment is 20 mg/kg; it is 30 mg/kg in the grownups who gets erythrocyte transfusion and whose iron load is aimed to be reduced, and 10 mg/kg in the grownups who gets erythrocyte suspension and whose iron load is aimed to be continued at the same level.
  • dispersible tablet formulations 125 mg, 250 mg and 500 mg, comprising deferasirox active ingredient of Novartis.
  • dispersible scored pharmaceutical product which provides three dosage on the same tablet and no suitable formulation to obtain this product in the state of the art.
  • the drugs comprising deferasirox are substantially expensive.
  • the present drug dose alternatives checked there is no option in the market for using the individual’s required dose in a single package.
  • the dose of the drug may desired to reduce by the doctor.
  • the doctor may not know the side effects of the pharmaceutical product on the patient. Therefore, he may prescribe the drug having the lowest dose initially.
  • the doctor may desire to increase this dose. This causes the patient to have to take a new dose and therefore have difficulties in prescribing.
  • all solid-dosage pharmaceutical products manufactured in the state of the art comprise at least one active ingredient.
  • the active ingredient or components must be produced with at least one excipient.
  • the excipients which are indispensable to many solid dosage forms and provide a functionality to the product can be binders, diluents, disintegrants, coloring agents (or colourants), coaters; but not limited to these listed in pharmaceutical products.
  • the appropriate selection of excipients to be used in addition to the active ingredient is very important in order to increase the patient's comfort of solid dosage form pharmaceutical product.
  • deferasirox formulations need to be developed to increase the effectiveness, bioavailability, properties and efficiency of the deferasirox molecule used for deferasirox formulations. Therefore, for improving deferasirox oral tablet formulations, it is necessary to select appropriate excipient to be used in addition to deferasirox. In addition, similarly, the amount of excipients must also be appropriate.
  • the aim of the invention is to provide a formulation comprising deferasirox or a pharmaceutically acceptable salt of deferasirox in the dispersible scored tablet form.
  • the product manufactured by disclosed formulation is in the form of a dispersible scored tablet and can be divided at least into two.
  • the number of dose is preferably three for formulation of dispersible tablet form.
  • these doses in the invention are 125 mg, 250 mg, 500 mg in a dispersible scored tablet.
  • the user is able to supply the different dose recommended by the doctor without purchasing another commercial dose form. Thereby, the user can take any one of these three doses as recommended by the doctor. Therefore, with the disclosed scored pharmaceutical product, also patient comfort is going to increase.
  • At least one excipient is used in a proper amount with deferasirox in the invention.
  • Patients who have difficulty swallowing can use the medication more easily because the tablet is dispersible in liquid, for example in water. In this way, for patients using dispersible tablet forms patient comfort is more than patients using another tablet forms.
  • absorption of the active ingredient in stomach and therefore its therapeutic effect is increasing.
  • a pharmaceutical product is developed in a form which is easier to produce than the prior art and dispersible, using the different ratio of deferasirox and /or at least one suitable selected excipient according to this ratio.
  • Figure 1 Schematic top view of pharmaceutical product subject to the invention.
  • Figure 2 Schematic side view of pharmaceutical product subject to the invention.
  • the present invention is related to formulation of a scored (11) tablet in dispersible form, comprising deferasirox which is known that 4-[3,5-Bis(2- hydroxyphenyl )-lH-l,2,4-triazole- l-yl]benzoic acid as chemical name or a pharmaceutically acceptable salt of deferasirox for the treatment of situations occurring with excessive amounts of iron accumulation in the body.
  • dividable scored (11) tablet forms are disclosed for doses of 125 mg, 250 mg ve 500 mg; and also 90 mg, 180 mg and 360 mg of deferasirox or a pharmaceutically acceptable salt of deferasirox.
  • Deferasirox or a pharmaceutically acceptable salt of deferasirox used as the active agent (active ingredient or active substance) in the invention is an iron chelating agent.
  • the disclosed pharmaceutical formulation comprises one active agent and at least one excipient.
  • the excipients to be used in the formulation of the invention and amounts thereof are selected in accordance with the active substance.
  • the active agent in the invention is deferasirox or a pharmaceutically acceptable salt of deferasirox.
  • the pharmaceutical formulation comprises excipients; at least one filler and/or at least one disintegrant and/or at least one binder and/or at least one surfactant and/or at least one glidant and/or at least one lubricant, but are not limited to the described herein.
  • the disclosed formulation comprises preferably lactose monohydrate and preferably microcrystalline cellulose (Type 102) as filler, preferably crospovidone as disintegrant, preferably povidone K30 as binder, preferably sodium lauryl sulfate (SLS) as surfactant, preferably colloidal silicon dioxide as glidant, preferably magnesium stearate as lubricant but are not limited to the described in the invention.
  • SLS sodium lauryl sulfate
  • the formulation comprises deferasirox or pharmaceutically acceptable salt of deferasirox at a rate of 5% to 65 % by weight, preferably 40.9% to 45.3% by weight, more preferably 43.1% by weight based on the total tablet weight.
  • it comprises from 5% to 10% by weight, preferably 5.1% by weight lactose monohydrate and/or from 5% to 10 % by weight, preferably 5.2% by weight based on the total tablet weight microcrystalline cellulose (Type 102) as filler and/or from 36% to 50% by weight, preferably 40.0% by weight based on the total tablet weight crospovidone as disintegrant and/or from 1% to 5% by weight , preferably 3.4% by weight based on the total tablet weight povidon K30 as binder and/or from 0.1% to 5% by weight, preferably 0.5% by weight based on the total tablet weight sodium lauryl sulfate (SLS) as surfactant and / or from 0.1% to 5% by weight,
  • SLS sodium lau
  • the lubricants used in the formulation are used to prevent the components from sticking to the printing device during the process.
  • the tablet printing is greatly easy during the production stage.
  • the binders used in the formulation are used to hold the components together in the formulation. The binders directly affect dissolution, hardness, brittleness and dispersion of tablets.
  • povidone K30 is used as the binder.
  • the filler is used to bring the tablets to suitable size for using easily and to compress the tablets easily.
  • both lactose monohydrate and microcrystalline cellulose are used as filler material.
  • the disintegrants allow the tablets to disperse in the stomach or intestinal environment.
  • crospovidone is used as the disintegrant.
  • the surfactants are used to facilitate dissolution by increasing the wettability of the active agent.
  • sodium lauryl sulfate is used as the surfactant.
  • the glidants facilitate the flow of powders by reducing friction between powders and granules.
  • colloidal silicon dioxide is used as the glidant. colloidal silicon dioxide used in the invention prevents the electrification between the powder and the surface of the print machine.
  • the pharmaceutical product (1) having the formulation of the invention comprises at least one unit dose (10) which is divisible and at least one score (11) providing divisibility.
  • the pharmaceutical product (1) produced by the formulation of the present invention is in the form of Figure-l and preferably comprises 4 part unit doses (10) in the preferred embodiment of the invention.
  • a unit dose (10) comprises deferasirox or pharmaceutically acceptable salt of deferasirox.
  • Said score (11) is in the form of“+” but not limited to this and when the patient holds a part of the product (1) and applies force to one of the unit doses (10) in the another part of the product (1), unit dose (10) can be broken easily from the score (11).
  • the product (1) can be divided into two from the score (11).
  • the product (1) can be divided to two or three or four parts from the score (11) easily.
  • different unit doses (10) can be provided from one product (1) by score (11). Therefore, dose flexibility can be provided with the invention.
  • Every dividable unit dose (10) is equivalent to each other as amount of dose and in one embodiment the amount of deferasirox or a pharmaceutically acceptable salt thereof at each unit dose (10) is minimum 125 mg.
  • the product (1) obtained from the pharmaceutical formulation is in a pharmaceutical form which the user can use quite easily.
  • the pharmaceutical product (1) is a dispersible tablet. The absorption of dispersible tablets in the body is very fast.
  • the total amount of deferasirox or a pharmaceutically acceptable salt thereof in the pharmaceutical product (1) is 500 mg.
  • the doctor can easily adjust the dose according to the need of patient at the initial and continuation of the treatment.
  • a patient who uses a dose form of 500 mg can take the dose recommended by the doctor from the same package, without purchasing a commercial dose comprising another dose form.
  • the user can reach a dose of 125 mg of the active ingredient via dividing the 500 mg pharmaceutical product (1) into four unit dose (10) by its score (11) and a dose of 250 mg of the active ingredient via dividing the 500 mg pharmaceutical product (1) into two unit dose (10) by its score (11).
  • the user starting from a high dose can achieve to a low dose (for example 125 mg) via dividing the pharmaceutical product (1) from its score (11).
  • a high dose for example 500 mg
  • a low dose for example 125 mg
  • the most important factor that provides divisibility of the product (1) is the score (11).
  • Another physical factor that provides the divisibility of the scored product (1) in a unit dose (10) is hardness.
  • the pharmaceutical product (1) is compressed with the predetermined pressure force (for instance in the hardness of 18 to 25 kp).
  • the product (1) can be divided easily by the user via applying pressure to the score (11).

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

Abstract

L'invention concerne une formulation pharmaceutique comprenant du déférasirox ou un sel pharmaceutiquement acceptable de déférasirox dans une forme de comprimé entaillé dispersible (11) destinée à être utilisée dans le traitement de situations se produisant dans le corps avec une accumulation excessive de fer.
PCT/TR2018/050657 2017-11-28 2018-11-05 Formulation de comprimé entaillé sous une forme dispersible comprenant du déférasirox WO2019108157A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201718944 2017-11-28
TR2017/18944 2017-11-28

Publications (1)

Publication Number Publication Date
WO2019108157A1 true WO2019108157A1 (fr) 2019-06-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022240279A1 (fr) * 2021-05-10 2022-11-17 Garcia Perez Miguel Angel Comprimé dispersible contenant du déférasirox sous forme de dispersion solide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1556013A1 (fr) * 2002-10-15 2005-07-27 Novartis AG Comprimes solubles de deferasirox
US20080311194A1 (en) * 2005-10-19 2008-12-18 Florian Battung Dispersible Tablets Comprising Deferasirox

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1556013A1 (fr) * 2002-10-15 2005-07-27 Novartis AG Comprimes solubles de deferasirox
US20080311194A1 (en) * 2005-10-19 2008-12-18 Florian Battung Dispersible Tablets Comprising Deferasirox

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022240279A1 (fr) * 2021-05-10 2022-11-17 Garcia Perez Miguel Angel Comprimé dispersible contenant du déférasirox sous forme de dispersion solide

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