WO2016167729A1 - Dispersible tablets comprising deferasirox - Google Patents
Dispersible tablets comprising deferasirox Download PDFInfo
- Publication number
- WO2016167729A1 WO2016167729A1 PCT/TR2015/000154 TR2015000154W WO2016167729A1 WO 2016167729 A1 WO2016167729 A1 WO 2016167729A1 TR 2015000154 W TR2015000154 W TR 2015000154W WO 2016167729 A1 WO2016167729 A1 WO 2016167729A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- deferasirox
- dispersible tablet
- weight
- tablet according
- dispersible
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
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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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Definitions
- PCT application WO2007/045445 (Novartis AG) is related to dispersible tablet dosage form comprising deferasirox 42% to 65% by weight and specific amounts of tablet excipients. Equivalent EP 1940360 was deemed to be withdrawn.
- the dispersible tablet formulation comprises excipients in ratios given below:
- At least one surfactant 0.5% to 1.5% by weight
- the lubricant may be selected among talc, magnesium stearate, PEG 6000, sodium chloride, silicon dioxide, stearic acid, sodium stearyl fumarate and/or a combination thereof.
- binder may be selected among polyvinylpyrrolidone, polyethyleneglycol, hydroxypropyl cellulose.
- Step II Granulation of at least one filler and deferasirox with the granulation solution of Step I (Step II)
- Step III • Mixing of granules obtained in Step II with at least one pharmaceutically available excipient in order to obtain a mixture
- Test formulations are produced with the process below.
- Granules are dried in fluidized bed drier or drying oven.
- Crospovidone, sodium chloride present in the outer phase are mixed by adding aerosol 200.
- test formulations and reference products have shown similar dissolution results and since more than 85% of them have dissolved in the dissolution medium (pH 6.8 phosphate buffer comprising 0.5% Tween 20), they are accepted as compatible without the requirement of f 2 calculation according to CPMP/QWP/EWP/ 1401/98.
- dissolution medium pH 6.8 phosphate buffer comprising 0.5% Tween 20
- the results obtained above in line with the 500 mg tablet, also the 250 mg and 125 mg dispersible tablet formulations were studied and results similar to the ones obtained with high dosage products were obtained.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (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)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention is related to a dispersible tablet formulation which comprises 42% to 50% deferasirox or pharmaceutically acceptable salt thereof in weight based on the total weight of the tablet and at least one disintegrant, whose tablet hardness is between 20N and 200N and friability value is less than 0.6%.
Description
DISPERSIBLE TABLETS COMPRISING DEFERASIROX
Technical Field
This invention is related to dispersible tablet formulation comprising deferasirox.
Prior Art
Deferasirox is an oral iron chelating agent used for the treatment of excessive iron accumulation. Chemical name is 4-[3,5-Bis (2-hydroxyphenyl)-lH-l,2,4-triazole-l-yl]benzoic acid (Formula I).
Formula I
Dispersible tablets of deferasirox are commercially available in America, Europe and many other countries under the brand name EXJADE®. Its free acid form, salts and crystallized forms are described in PCT application W097/49395.
The molecular formula of deferasirox is C21H15N3O4 and its molecular weight is 373.36 mg/mol. Deferasirox does not dissolve in water. It has a high lipophilicity, thus it has a good permeability. According to the Biopharmaceutical Classification System (BCS), deferasirox molecule is a Class 2 molecule. Namely it has a low solubility and high permeability. Although deferasirox does not dissolve in water, its solubility is high in mediums with high pH.
The deferasirox molecule which does not practically dissolve in water and aqueous mediums generally shows a low dissolution profile and low bioavailability. There is need for a preparation whose dissolution profile and physical features such as hardness and friability are improved and which comprises deferasirox drug substance with high absorption.
PCT application WO2004/035026 (Novartis AG) is related to dispersible tablet dosage form comprising 5% to 40% deferasirox by weight. Equivalent EP 1556013 Bl covers 5% to 40% deferasirox and 10% to 35% disintegrant by weight.
PCT application WO2007/045445 (Novartis AG) is related to dispersible tablet dosage form comprising deferasirox 42% to 65% by weight and specific amounts of tablet excipients. Equivalent EP 1940360 was deemed to be withdrawn.
PCT application WO2005/097062 (Novartis AG) is related to dispersible tablet dosage form comprising 42% to 65% deferasirox by weight. Equivalent EP 1734924 was deemed to be withdrawn.
PCT application WO2009/067557 (Teva Pharmaceutical Industries Ltd) is related to the pharmaceutical preparation prepared by grinding at least two excipients which are surfactant and another excipient with deferasirox.
Description of the Invention
The present invention is related to the pharmaceutical formulation of dispersible tablet of deferasirox.
The present invention comprises 42% - 50% deferasirox or pharmaceutically acceptable salt thereof in weight based on the total weight of the tablet and at least one disintegrant. Dispersible tablet comprises preferably 44% to 46% and more preferably 45% deferasirox or pharmaceutically acceptable salt thereof.
The invention is characterized in that the hardness of the tablet is 20N-200N, preferably 100- 180N, and more preferably 140-160N and the friability test value is less than 0.6% in weight based on the total weight of the tablet, preferably less than 0.5% and more preferably less than 0.4% by weight. Tests are carried out in accordance with USP.
The dispersible tablet formulation comprises excipients in ratios given below:
At least one filler 10% to 20% by weight,
At least one disintegrant 5% to 35% by weight.
At least one surfactant 0.5% to 1.5% by weight,
At least one binder 1% to 5% by weight,
At least one glidant 0% to 1.5% by weight,
At least one lubricant 1% to 10% by weight.
By decreasing the amounts of excipients which will be used in the formulation according to the present invention, a tablet with lower weight, suitable hardness and friability values, which disperse faster and dissolves in water is obtained.
Pharmaceutical formulations according to the present invention may comprise 125 mg, 250 mg or 500 mg deferasirox or its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof. In terms of polymorphic structure, deferasirox may be in the form of crystal, amorphous or combinations thereof.
Pharmaceutical formulations according to the invention comprise at least one excipient selected among filler, disintegrant, surfactant, binder, glidant and lubricant groups.
According to the invention the filler may be selected among calcium carbonate, dibasic caicium phosphate, microcrystalline cellulose, dextrose, fructose, iactitol, lactose, magnesium carbonate, maltose, mannitol, sorbitol, sodium caseinate, potassium casemate, calcium caseinate.
According to the invention, the disintegrant may be selected among carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crosscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate.
According to the invention the surfactant may be selected among sodium lauryl sulphate, sodium tripolyphosphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
According to the invention the lubricant may be selected among talc, magnesium stearate, PEG 6000, sodium chloride, silicon dioxide, stearic acid, sodium stearyl fumarate and/or a combination thereof.
According to the invention glidant may be selected among magnesium carbonate, calcium silicate, colloidal silicon dioxide, talc or mixtures thereof.
According to the invention binder may be selected among polyvinylpyrrolidone, polyethyleneglycol, hydroxypropyl cellulose.
According to the invention dispersible tablets are obtained by the implementation of the production process below:
• Preparation of granulation solution which comprises at least one binder and at least one surfactant (Step I)
• Granulation of at least one filler and deferasirox with the granulation solution of Step I (Step II)
• Mixing of granules obtained in Step II with at least one pharmaceutically available excipient in order to obtain a mixture (Step III)
• Compression of the mixture of Step III with a suitable punch (Step IV) Examples
Dispersible tablet dosage forms are shown in Table 1.
1. 1/4 of PVP K30 and all of Sodium lauryl sulphate are mixed in distilled water until they are entirely dissolved.
2. The rest of the mannitol, microcrystalline cellulose, deferasirox and polyvinylpyrrolidone are mixed in the granulator.
3. The granulation process is carried out by adding the granulation solution prepared in the first step onto the powder mixture in the granulator.
4. Granules are dried in fluidized bed drier or drying oven.
5. The dried granules are sieved through a suitable mesh.
6. Crospovidone, sodium chloride present in the outer phase are mixed by adding aerosol 200.
7. Finally, it is lubricated by the addition of magnesium stearate.
8. Tablets are compressed with a suitable punch.
Dissolution
Reference products (Exjade® 125 mg, 250 mg and 500 mg dispersible tablet) and all formulations are tested in the dissolution conditions (pH 6.8 phosphate buffer comprising 0.5% Tween 20, paddle method, 50 rpm, 900 ml sampling times, 5, 10, 15, 20, 30, 45 minute) provided by FDA. Test results are given in Table 2.
Table 2: Dissolution test results
As can be seen in the table, the test formulations and reference products have shown similar dissolution results and since more than 85% of them have dissolved in the dissolution medium (pH 6.8 phosphate buffer comprising 0.5% Tween 20), they are accepted as compatible without the requirement of f2 calculation according to CPMP/QWP/EWP/ 1401/98.
In accordance with the results obtained above, in line with the 500 mg tablet, also the 250 mg and 125 mg dispersible tablet formulations were studied and results similar to the ones obtained with high dosage products were obtained.
Hardness and Friability
Reference products (Exjade® 125 mg, 250 mg and 500 mg dispersible tablet) and all formulations are tested for hardness and friability. Test results are given in Table 3.
Table 3
Description of the Figures
Figure 1. Dissolution profiles of 500 mg Formula 1 and Formula II with 500 mg original product (Dissolution medium: pH 6.8 phosphate buffer comprising 0.5% Tween 20)
Claims
1) A dispersible tablet characterized in that it comprises 42% to 50% deferasirox or pharmaceutically acceptable salt thereof in weight based on the total weight of the tablet and at least one disintegrant, wherein its hardness value is between 20N and 200N and friability value is less than 0.6% in weight based on the total weight of the tablet.
2) A dispersible tablet according to Claim 1 wherein it comprises 44% to 46% deferasirox or pharmaceutically acceptable salt thereof by the total tablet weight.
3) A dispersible tablet according to Claim 2 wherein it comprises 45% deferasirox or pharmaceutically acceptable salt thereof by the total tablet weight.
4) A dispersible tablet according to Claim 1 wherein it comprises 5% to 35% disintegrant by the total tablet weight.
5) A dispersible tablet according to Claim 1 wherein its hardness is between 100N and 180N.
6) A dispersible tablet according to Claim 5 wherein its hardness is between 140N and 160N.
7) A dispersible tablet according to Claim 1 wherein its friability value is less than 0.5%.
8) A dispersible tablet according to Claim 7 wherein its friability value is less than 0.4%.
9) A dispersible tablet according to any of the previous claims wherein it comprises at least one lubricant selected among talc, magnesium stearate, sodium chloride, PEG 6000. silicon dioxide, stearic acid, sodium stearyl fumarate and/or a combination thereof.
10) A dispersible tablet according to any of the previous claims wherein it comprises 125 mg, 250 mg or 500 mg deferasirox or pharmaceutically acceptable salt thereof.
11) A dispersible tablet according to any of the previous claims; wherein it is obtained by the application of the production process below:
• Preparation of granulation solution which comprises at least one binder and at least one surfactant (Step I)
• Granulation of at least one filler and deferasirox with the granulation solution of Step I (Step II)
• Mixing of granules obtained in Step II with at least one pharmaceutically available exeipient in order to obtain a mixture (Step III)
• Compression of the mixture of Step III with a suitable punch (Step IV)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2015/000154 WO2016167729A1 (en) | 2015-04-16 | 2015-04-16 | Dispersible tablets comprising deferasirox |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2015/000154 WO2016167729A1 (en) | 2015-04-16 | 2015-04-16 | Dispersible tablets comprising deferasirox |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016167729A1 true WO2016167729A1 (en) | 2016-10-20 |
Family
ID=53277018
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2015/000154 Ceased WO2016167729A1 (en) | 2015-04-16 | 2015-04-16 | Dispersible tablets comprising deferasirox |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2016167729A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019151967A3 (en) * | 2017-12-29 | 2019-10-17 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Water-dispersible tablet formulations comprising deferasirox |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049395A1 (en) | 1996-06-25 | 1997-12-31 | Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
| WO2004035026A1 (en) | 2002-10-15 | 2004-04-29 | Novartis Ag | Deferacirox dispersible tablets |
| WO2005097062A1 (en) | 2004-04-08 | 2005-10-20 | Novartis Ag | deferasirox DISPERSIBLE TABLETS |
| WO2007045445A1 (en) | 2005-10-19 | 2007-04-26 | Novartis Ag | Dispersible tablets comprising deferasirox |
| EP2062572A1 (en) * | 2007-11-19 | 2009-05-27 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical compositions |
| WO2009106824A2 (en) * | 2008-02-25 | 2009-09-03 | Cipla Limited | Pharmaceutical formulations |
| WO2012003987A1 (en) * | 2010-07-08 | 2012-01-12 | Ratiopharm Gmbh | Oral dosage form of deferasirox |
| WO2014136079A1 (en) * | 2013-03-08 | 2014-09-12 | Novartis Ag | Oral formulations of deferasirox |
-
2015
- 2015-04-16 WO PCT/TR2015/000154 patent/WO2016167729A1/en not_active Ceased
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049395A1 (en) | 1996-06-25 | 1997-12-31 | Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
| WO2004035026A1 (en) | 2002-10-15 | 2004-04-29 | Novartis Ag | Deferacirox dispersible tablets |
| EP1556013B1 (en) | 2002-10-15 | 2009-05-13 | Novartis AG | Deferasirox dispersible tablets |
| WO2005097062A1 (en) | 2004-04-08 | 2005-10-20 | Novartis Ag | deferasirox DISPERSIBLE TABLETS |
| EP1734924A1 (en) | 2004-04-08 | 2006-12-27 | Novartis AG | Deferasirox dispersible tablets |
| WO2007045445A1 (en) | 2005-10-19 | 2007-04-26 | Novartis Ag | Dispersible tablets comprising deferasirox |
| EP1940360A1 (en) | 2005-10-19 | 2008-07-09 | Novartis AG | Dispersible tablets comprising deferasirox |
| EP2062572A1 (en) * | 2007-11-19 | 2009-05-27 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical compositions |
| WO2009067557A1 (en) | 2007-11-19 | 2009-05-28 | Teva Pharmaceutical Industries Ltd. | Deferasirox pharmaceutical compositions |
| WO2009106824A2 (en) * | 2008-02-25 | 2009-09-03 | Cipla Limited | Pharmaceutical formulations |
| WO2012003987A1 (en) * | 2010-07-08 | 2012-01-12 | Ratiopharm Gmbh | Oral dosage form of deferasirox |
| WO2014136079A1 (en) * | 2013-03-08 | 2014-09-12 | Novartis Ag | Oral formulations of deferasirox |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019151967A3 (en) * | 2017-12-29 | 2019-10-17 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Water-dispersible tablet formulations comprising deferasirox |
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