WO2013013657A1 - Composition pharmaceutique solide comprimée contenant du valsartan particulaire amorphe en tant que principe actif - Google Patents

Composition pharmaceutique solide comprimée contenant du valsartan particulaire amorphe en tant que principe actif Download PDF

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Publication number
WO2013013657A1
WO2013013657A1 PCT/DE2012/000740 DE2012000740W WO2013013657A1 WO 2013013657 A1 WO2013013657 A1 WO 2013013657A1 DE 2012000740 W DE2012000740 W DE 2012000740W WO 2013013657 A1 WO2013013657 A1 WO 2013013657A1
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WO
WIPO (PCT)
Prior art keywords
valsartan
film
value
composition according
μπι
Prior art date
Application number
PCT/DE2012/000740
Other languages
German (de)
English (en)
Other versions
WO2013013657A8 (fr
Inventor
Jessica Schönborn
Original Assignee
Stada Arzeimittel Ag
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 Stada Arzeimittel Ag filed Critical Stada Arzeimittel Ag
Priority to EP12769586.4A priority Critical patent/EP2736494A1/fr
Publication of WO2013013657A1 publication Critical patent/WO2013013657A1/fr
Publication of WO2013013657A8 publication Critical patent/WO2013013657A8/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
    • A61K9/16—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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61K9/2004—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • a compressed solid pharmaceutical composition comprising amorphous particulate valsartan as an active ingredient
  • the present invention relates to a compressed solid pharmaceutical composition
  • a compressed solid pharmaceutical composition comprising amorphous
  • Valsartan is the International Nonproprietary Name (INN) for (S) -3-methyl-2- ⁇ N- [2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] pentanamido ⁇ butanoic acid.
  • INN International Nonproprietary Name
  • Valsartan has the following structural formula:
  • Valsartan is a aus antagonist drug used in the treatment of hypertension and mild to moderate congestive heart failure if ACE inhibitor therapy is inappropriate (cf.
  • Composition - such as a tablet - desirable in which the valsartan is contained in amorphous form.
  • Amorphous valsartan however, has relatively poor compression properties, which is why pressed
  • Valsartan tablets have relatively poor mechanical properties.
  • corresponding tablets have a low breaking strength and high
  • Friability levels which is why the tablets can not be handled safely or are difficult to be filmed film and accordingly, the applied films do not adhere sufficiently to the surface of the tablet and peel off accordingly easy.
  • Object of the present invention is therefore, a
  • compressed solid pharmaceutical composition comprising amorphous particulate valsartan which has relatively good mechanical properties.
  • compressed solid pharmaceutical composition comprising amorphous particulate valsartan as an active ingredient and a granular dry binder.
  • composition according to the invention can, for example in the form of tablets breaking strength
  • Composition as well as the applied compression pressure.
  • breaking strength of tablets It is particularly preferred that the breaking strength be measured by means of a tablet hardness tester by uniaxial vertical
  • the breaking strength is measured by means of a tablet hardness tester from ERWEKA International AG, Switzerland, type of device: TBH 250
  • Round tablets i. Tablets having a circular cross-section such as e.g. round flat biplane
  • Tablets are crushed across the ridge (i.e., radially) during fracture toughness measurement.
  • the friability is according to the invention according to the Ph.Eur., 6.
  • composition of the invention contains a granular SO dry binder.
  • Granular dry binders
  • Powder particles are.
  • the granular dry binder is contained in compacted form along with the other components.
  • Valsartan is amorphous.
  • An XRD spectrum of amorphous substances is substantially or preferably completely free of
  • composition according to the invention is a "compressed"
  • composition Composition. Pressed compositions are known in the art. They are made by crimping one
  • the valsartan has a DlO value of less than 5 ⁇ , a
  • An amorphous valsartan of such quality has a favorable bioavailability profile and results in
  • compositions of the invention with very good
  • Valsartan has a DlO value in a range of 2 ⁇ to 3 ⁇ 25, a D50 value in a range of 29 ⁇ to 50 ⁇ and a D90 value in a range of 130 ⁇ to 260 ⁇ .
  • the DlO value is understood to be the particle size at which 10% of the particles, based on the volume, are smaller than the D10 value and 90% of the volume
  • D50 value is the particle size
  • the D90 value means the particle size at which 90% of the particles are smaller than the D90 value by volume and 10% of the particles by volume are greater than the D90 value.
  • the determination of the D10, D50 and D90 value is carried out by means of laser diffraction using a device with the name "Mastersizer 2000” from the company “Malvern Instruments” according to the European Pharmacopoeia (Ph. Eur.) 6th edition, 6th supplement,
  • Laser diffractometry pages 6825-6830
  • the settings are as follows: dispersing system Scirocco 2000, measuring range (result ranges) 0.02 to 2000 ⁇ ; evaluation (reporting) Mie; calculation model (calculation
  • the granular dry binder contained in the composition of the present invention may contain an active ingredient, for example, amorphous valsartan or HCT
  • Pharmaceutical agent is, in particular, free from
  • composition comprises, in addition to valsartan, a second active pharmaceutical ingredient, HCT.
  • Dry binder granulate may be a wet granulate or a dry granulate, wherein a moist granulate is preferred according to the invention. If a moist granulate is present, then one can
  • the dry binder comprises a binder granules
  • Cellactose and hypromellose is where the hypromellose is the binder (cellactose consists of cellulose powder and lactose monohydrate). It was found that in particular this binder granules to particularly favorable mechanical properties of the inventive
  • Composition leads.
  • the dry binder granules have a D10 value of greater than or equal to 35 ⁇ , a D50 value of greater than / equal to 100 ⁇ and a D90 value of less than 1000 ⁇ .
  • the D10, D50 and D90 values are as defined above and to be determined as stated above.
  • the dry binder granules have a D10 value in a range from 35 / xm to 90 / xm, a D50 value in a range of 100 ⁇ to 180 / xm and a D90 value in a range of 500 / xm to 1000 / xm.
  • the weight ratio of the valsartan to the dry binder is from 5: 1 to 1: 1. Such a weight ratio leads to favorable mechanical properties of
  • the composition further comprises a disintegrant wherein the weight ratio of the valsartan to the disintegrant is from 8: 1 to 3: 1.
  • composition causes.
  • inventively preferred composition causes.
  • Blasting agent is Crosscarmellose sodium.
  • the composition comprises 30% by weight to 70% by weight of the valsartan and 10% by weight to 40% by weight of the dry binder. This will make favorable mechanical properties of
  • composition according to the invention it is provided that the composition further comprises one or more pharmaceutical excipients.
  • Auxiliaries preferred according to the invention are selected from the group consisting of a filler, filler mixture, flow regulator,
  • Lubricant mixture a Mold release agent mixture.
  • other binders may be included in the composition.
  • Pharmaceutical / n adjuvant / s according to the invention is preferably 0.5 wt .-% to 30 wt .-% and more preferably 5 wt .-% to 10 wt .-%.
  • the composition is a tablet.
  • the tablet may, if desired, be film-coated to give a film-coated tablet.
  • the present invention further relates to a powdery mixture for the preparation of an inventive
  • composition comprising
  • the mixture according to the invention is for the production of
  • Valsartan has a D10 value of less than 5 ⁇ , a D50 value of less than 60 ⁇ and a D90 value of less than 300 ⁇ .
  • Valsartan has a D10 value in a range of 2 ⁇ to 3 ⁇ , a D50 value in a range of 29 ⁇ to 50 ⁇ and a D90 value in a range of 130 ⁇ to 260 ⁇ . According to a further preferred embodiment of the mixture according to the invention, it is provided that the
  • Dry binder is free of valsartan.
  • Dry binder comprising a binder granules
  • Dry binder granules have a D10 value of greater than or equal to 10 35 ⁇ m, a D50 value of greater than or equal to 100 ⁇ m and a D90 value of less than 1000 ⁇ m.
  • 25 dry binder granules have a D10 value in a range of 35 ⁇ m to 90 ⁇ m, a D50 value in a range of 100 ⁇ m to 180 ⁇ m, and a D90 value in a range of 500 ⁇ m to 1000 ⁇ m.
  • Mixture further comprises a disintegrant, wherein the
  • Mixture 30 wt .-% to 70 wt -.% Of the valsartan and 10 wt .-% to 40 wt .-% of the dry binder comprises.
  • the present invention further relates to a process for the preparation of a composition according to the invention, comprising the steps of a) providing a mixture according to the invention;
  • Film-coated tablets were prepared as a composition according to the invention having the formulation given in Table 1.
  • the preparation of the film-coated tablets was carried out by first the cellactose with an aqueous solution of hypromellose
  • the resulting film-coated tablets had a breaking strength according to Ph.Eur. 2.9.8 from 50 N (mean) to (extreme values: (min) 40 N and (max) 60 N).
  • Film-coated tablets were measured by means of a tablet hardness tester from ERWEKA International AG, Switzerland, device type: TBH 250 IC. The orientation of the film-coated tablets was at the
  • Film-coated tablets were prepared as a composition according to the invention with the formulation given in Table 2.
  • Opadry ® colored, composed of 5, 00 mg hypromellose, macrogol, titanium dioxide, iron oxide,
  • Film-coated tablets were prepared as a composition according to the invention with the formulation given in Table 3.
  • Opadry ® colored, composed of 10, 00 mg hypromellose, macrogol, titanium dioxide, iron oxide,
  • the resulting round flat biplane film-coated tablets had a breaking strength according to Ph.Eur. 2.9.8 from 130 N (mean) to (extreme values: (min) 100 N and (max) 160 N).
  • the breaking strength of the film-coated tablets was determined using a tablet hardness tester from ERWEKA International AG,
  • Film-coated tablets were prepared as a composition according to the invention with the formulation given in Table 5.
  • the preparation of the film-coated tablets was carried out by first the cellactose with an aqueous solution of hypromellose
  • the resulting film-coated tablets had a breaking strength L0 according to Ph.Eur. 2.9.8 from 65 N (mean) to (extreme values:
  • Film-coated tablets were measured by means of a tablet hardness tester from ERWEKA International AG, Switzerland, device type: TBH 250 IC. The orientation of the film-coated tablets was at the
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Film coated tablets were prepared as a composition according to the invention with the formulation given in Table 6.
  • Opadry ® colored, composed of 10, 00 mg hypromellose, macrogol, titanium dioxide, iron oxide,
  • the resulting round flat biplane film-coated tablets had a breaking strength according to Ph.Eur. 2.9.8 from 180 N (mean) to (extreme values: (min) 100 N and (max) 260 N).
  • the breaking strength of the film-coated tablets was measured by means of a tablet hardness tester from ERWEKA International AG, Switzerland, device type: TBH 250 IC.
  • the orientation of the film-coated tablets during the measurement was such that they were broken across the web (i.e., radially).
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Film-coated tablets were prepared as a composition according to the invention with the formulation given in Table 7.
  • Opadry ® colored, composed of 10, 00 mg hypromellose, macrogol, titanium dioxide, iron oxide,
  • Embodiment 5 The resulting round flat biplane film-coated tablets had a breaking strength according to Ph.Eur. 2.9.8 from 180 N (mean) to (extreme values: (min) 100 N and (max) 260 N).
  • the breaking strength of the film-coated tablets was measured by means of a tablet hardness tester from ERWEKA International AG, Switzerland, device type: TBH 250 IC.
  • the orientation of the film-coated tablets during the measurement was such that they were broken across the web (i.e., radially).
  • the resulting round flat biplane film-coated tablets had a breaking strength according to Ph.Eur. 2.9.8 from 140 N (mean) to (extreme values: (min) 120 N and (max) 160 N).
  • the breaking strength of the film-coated tablets was measured by means of a tablet hardness tester from ERWEKA International AG, Switzerland, device type: TBH 250 IC.
  • the orientation of the Film-coated tablets were so measured during the measurement that they were broken over the web (ie radially).
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Film-coated tablets were prepared as a composition according to the invention with the formulation given in Table 9.
  • Embodiment 5 The resulting round flat biplane film-coated tablets had a breaking strength according to Ph.Eur. 2.9.8 from 140 N (mean) to (extreme values: (min) 120 N and (max) 160 N).
  • the breaking strength of the film-coated tablets was measured by means of a tablet hardness tester from ERWEKA International AG, Switzerland, device type: TBH 250 IC.
  • the orientation of the film-coated tablets during the measurement was such that they were broken over the web (ie radially).

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

Abstract

La présente invention concerne une composition pharmaceutique solide comprimée contenant du valsartan particulaire amorphe en tant que principe actif. L'invention vise à pouvoir préparer une composition pharmaceutique solide comprimée contenant du valsartan particulaire amorphe qui présente des propriétés mécaniques relativement bonnes. A cet effet, la composition selon l'invention comprend un agent siccatif sous forme de granulés.
PCT/DE2012/000740 2011-07-28 2012-07-24 Composition pharmaceutique solide comprimée contenant du valsartan particulaire amorphe en tant que principe actif WO2013013657A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12769586.4A EP2736494A1 (fr) 2011-07-28 2012-07-24 Composition pharmaceutique solide comprimée contenant du valsartan particulaire amorphe en tant que principe actif

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE201110108762 DE102011108762A1 (de) 2011-07-28 2011-07-28 Verpresste feste pharmazeutische Zusammensetzung, umfassend amorphes partikuläres Valsartan als Wirkstoff
DE102011108762.5 2011-07-28

Publications (2)

Publication Number Publication Date
WO2013013657A1 true WO2013013657A1 (fr) 2013-01-31
WO2013013657A8 WO2013013657A8 (fr) 2013-03-28

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Country Status (3)

Country Link
EP (1) EP2736494A1 (fr)
DE (1) DE102011108762A1 (fr)
WO (1) WO2013013657A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025566A1 (fr) * 2003-09-18 2005-03-24 Nobel Ilac Sanayi Ve Ticaret As Formulations pharmaceutiques a administration par voie orale contenant le principe actif irbesartan
WO2005041941A2 (fr) * 2003-11-03 2005-05-12 Zentiva, A.S. Preparation contenant du valsartan
EP1674080A1 (fr) * 2004-12-24 2006-06-28 KRKA, D.D., Novo Mesto Composition pharmaceutique comprenant du valsartan
EP1897537A1 (fr) * 2006-09-04 2008-03-12 Novartis AG Composition contenant un antagoniste des récepteurs de l'angiotensine II
WO2009113091A2 (fr) * 2008-01-24 2009-09-17 Usv Limited Compositions pharmaceutiques contenant du valsartan

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025566A1 (fr) * 2003-09-18 2005-03-24 Nobel Ilac Sanayi Ve Ticaret As Formulations pharmaceutiques a administration par voie orale contenant le principe actif irbesartan
WO2005041941A2 (fr) * 2003-11-03 2005-05-12 Zentiva, A.S. Preparation contenant du valsartan
EP1674080A1 (fr) * 2004-12-24 2006-06-28 KRKA, D.D., Novo Mesto Composition pharmaceutique comprenant du valsartan
EP1897537A1 (fr) * 2006-09-04 2008-03-12 Novartis AG Composition contenant un antagoniste des récepteurs de l'angiotensine II
WO2009113091A2 (fr) * 2008-01-24 2009-09-17 Usv Limited Compositions pharmaceutiques contenant du valsartan

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Europäischen Arzneibuch (Ph. Eur.", article "Bestimmung der Partikelgröße durch Laserdiffraktometrie", pages: 6825 - 6830
"Europäischen Arzneibuch (Ph.Eur.", article "Bruchfestigkeit von Tabletten", pages: 355
"Mastersizer 2000", MALVERN INSTRUMENTS
"Mutschler Arzneimittelwirkungen, Lehrbuch der Pharmakologie und Toxikologie", 2008, WISSENSCHAFTLICHE VERLAGSGESELLSCHAFT MBH STUTTGART, pages: 551
"Ph.Eur.", article "Friabilität von nicht überzogenen Tabletten", pages: 6820 - 6821
CASALDERREY M ET AL: "A comparison of cellactose with two ad hoc processed lactose-cellulose blends as direct compression excipients.", CHEMICAL & PHARMACEUTICAL BULLETIN APR 2000, vol. 48, no. 4, April 2000 (2000-04-01), pages 458 - 463, XP002687793, ISSN: 0009-2363 *
MUNOZ-RUIZ A ET AL: "Rheology and compression characteristics of lactose based direct compression excipients", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 95, no. 1-3, 30 June 1993 (1993-06-30), pages 201 - 207, XP025568702, ISSN: 0378-5173, [retrieved on 19930630], DOI: 10.1016/0378-5173(93)90407-7 *

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WO2013013657A8 (fr) 2013-03-28
EP2736494A1 (fr) 2014-06-04
DE102011108762A1 (de) 2013-01-31

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