EP1680095A2 - Preparation contenant du valsartan - Google Patents

Preparation contenant du valsartan

Info

Publication number
EP1680095A2
EP1680095A2 EP04797393A EP04797393A EP1680095A2 EP 1680095 A2 EP1680095 A2 EP 1680095A2 EP 04797393 A EP04797393 A EP 04797393A EP 04797393 A EP04797393 A EP 04797393A EP 1680095 A2 EP1680095 A2 EP 1680095A2
Authority
EP
European Patent Office
Prior art keywords
weight
valsartan
pharmaceutical formulation
amounts
formulation according
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.)
Withdrawn
Application number
EP04797393A
Other languages
German (de)
English (en)
Inventor
Beáta VLADOVICOVA
Mikulás LEHOCK
Viera Kormanova
Viera Hubinova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
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
Priority claimed from CZ20032984A external-priority patent/CZ20032984A3/cs
Priority claimed from CZ20041020A external-priority patent/CZ297417B6/cs
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP1680095A2 publication Critical patent/EP1680095A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the invention relates to a tablet containing the active substance valsartan, optionally valsartan in combination with hydrochlorothiazide, prepared via direct tabletting.
  • Valsartan a compound having the chemical name N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5- yl)[l,l'-biphenyl]-4-yl]methyl]-L-valine, of formula I
  • a mixture of the active substance, lactose and parts of corn starch was granulated via wet ' granulation and after drying mixed with the rest of the starch and calcium stearate and talc and subsequently compressed into tablets.
  • the first two components are granulated via wet granulation with a solution of the third and i . • ⁇ i l . • fourth components in water.
  • Components 5 and 6 are added to the dry granulate and the mixture, is filled into capsules.
  • the first to fifth components are mixed and compacted at pressures 25 to 65 kN.
  • the compacted material is further forced through a sieve.
  • Granulate produced in this way is mixed with magnesium stearate and the mixture is compressed into tablets.
  • the p e'sent invention consists in a pharmaceutical formulation in the f ⁇ rai of tablets, ' ' ' ! : "- - ' > containing valsartan, the'active substance used for treating hypertension, ⁇ pti ⁇ nal Vaisartan in combination with hydrochlorothiazide, which is obtainable by direct tabletting.
  • Hydrochlorothiazide is a thiazide diuretic, having diuretic and anti-hypertensive actions, and when combined with valsartan, the anti-hypertensive effect is enhanced.
  • Compressing of the tablet material prepared via dry mixing allows a preparation of cores and/or tablets of satisfactory parameters and the mentioned method of preparation and selection of additives according to the invention also secure good stability of the formulation and desired physical properties of the dosage form.
  • a tablet of a pharmaceutical formulation has to be sufficiently hard to withstand various types of stress during transportation. However, it has to disintegrate fast enough in contact with water, in order to be " able to release " the ' active substance into the solution before it passes through the upper 1 part of patient's digestive tract.
  • the values of hardness of the tablet and of release (dissolution) of the active substance are, therefore, two factors that are more or less antagonistic and conditions have always to be optimized.
  • additives are selected that have especially good tabletting properties. These include, above all, lactose granulate or microcrystalline cellulose.
  • Such a. substance is subsequently mixed with the active substance in a multiple excess so that its positive tabletting properties may prevail in the mixture.
  • Such an excess can, however, not be ensured in every case.
  • valsartan where the highest dose is 160 mg, such procedure would result in large, hard-to-swallow tablets weighing more than 1 g.
  • Patent application WO 9749394 points out the fact that it is possible to produce 300-mg tablets containing 160 mg valsartan by compacting as a surprising possibility. However, it would be a remarkably greater success if such a tablet could be produced without using any granulation.
  • a mixture capable to be directly tabletted, or a tablet produced via such technique preferably contains 30 to 60% of valsartan.
  • the tablet material described in this invention includes, apart from the valsartan active substance, optionally valsartan in combination with hydrochlorothiazide, other additives, of which the most important one is suitably selected filler, which has a decisive importance for quality of the produced tablets. For ensuring the function of direct tabletting it is necessary to select a filler having a defined particle size and in defined amount.
  • valsartan optionally its mixture with hydrochlorothiazide
  • particle sizes of the filler in the range of 10 to 1000 ⁇ m, preferably 50 to 400 ⁇ m, and its contents of 20 to 60% by weight, preferably 40 to 60% by weight.
  • the filler can be selected from the group including microcrystalline cellulose, lactose, the polyalcohols mannitol or sorbitol, calcium hydrogen phosphate and combinations of microcrystalline cellulose with a mono- or oligo-saccharide or polyalcohol.
  • a preferable composition of the filler according to this invention is microcrystalline cellulose having a particle size of 10 to 1000 ⁇ m, preferably 50 to 190 ⁇ m, especially preferably 90 ⁇ m, in amounts above 40 to 60% by weight, spray-dried anhydrous lactose having a particle size of 10 to 250 ⁇ m, preferably 150 to 250 ⁇ m, in amounts of 30 to 60%, compact lactose hydrate having a particle size of 10 to 250 ⁇ m, in amounts 40 to 60% by weight, a polyalcohol selected from mannitol or sorbitol, which is compacted and has a particle size of 100 to 850 ⁇ m, preferably 200 to 400 ⁇ m, in amounts of 40 to 60% by weight, calcium hydrogen phosphate having a particle size of 10 to 200 ⁇ m in amounts of 40 to 60 % by weight, a combination ' of microcrystalline cellulose with lactose, preferably spray-dried anhydrous lactose, ' " in a weight ratio' of 1:2 to 2:1
  • Microcrystalline cellulose optionally its mixture with another filler, is an especially referred filler.
  • a suitable combination of fillers by combining advantageous properties of both the components, it is possible to achieve a composition with minimal size of the tablet.
  • Microcrystalline cellulose with lactose or ⁇ polyalcohols like mannitol is a preferable combination.
  • the tablet contains 3 to 10% of a disintegrating agent, of which 1 the 1 sodium salt of carboxymethyl starch appears to b the 'preferable ' '' one: -This substance will further improve disintegration rate of the tablet and allow f ⁇ r : achieving an 20 excellent release rate of the active substance.
  • the tabletting mixture includes substances that improve its flow properties.
  • Colloidal silica sica colloidalis anhydrica
  • Theses ' substances are important for avoiding fluctuations- o ⁇ 'the tablet weight, caused by inappropriate flow of the solid mixture through ' the " hopper into the high- performance tabletting machine.
  • the mixture can also contain an antiadhesive, preferably magnesium stearate, in amounts of 30 0.1 to 10% by weight, preferably 0.5 to 4% by weight.
  • an antiadhesive preferably magnesium stearate
  • Tablets prepared according to the invention ensure reproducibility of the production process.
  • the preparation of the tablet material has the advantages of not being demanding in terms of energy and time.
  • Mixing I active substance, microcrystalline cellulose and carboxymethylamylum natricum are mixed in a homogenizing device for 15 minutes.
  • Mixing II final treatment - silicii dioxidum colloidale and magnesii stearas - are added and mixed in a homogenizing device for 15 minutes.
  • Fracture resistance which is necessary for maintaining the integrity of tablets during transport
  • rate of release of the active substance into the dissolution medium the value of which indicates the availability of the drug for the patient's organism. Both values were measured using standard procedures. 0
  • the tablets prepared via the procedure had fracture resistance of at least 70N, which indicates that they will not be damaged during usual transport.
  • the tablet core was coated as in Example 1.
  • the tablet core was coated as in Example 1.
  • the tablet core was coated as in Example 1.
  • the tablet core was coated as in Example 1.
  • Fracture resistance which is necessary for maintaining the integrity of tablets during transport
  • rate of release of the active substance into the dissolution medium the value of which indicates the availability of 5 the 'drug' for trie patient' s organism. Both values were measUred using standard ! p'roc ! edures.
  • The' tablets prepared via the procedure had fracture resistance of at least 70 ⁇ SF, ri wh indicates that r t e ⁇ will' rib tb ' e '- " damaged during Usual'transport.' 0 iDuririjg te'stihg the rate of release of the active substance, at least 75% of the total content of the ' active-' ⁇ ubs'tance was released within 45 minutes. Such a result is in very good agreement with the already registered arid sold preparation Diovan of Novartis.
  • the tablet was produced by the procedure of Example 2.
  • the tablet core was coated as in Example 1.
  • Example 2 Treatment conducted as in Example 2.
  • the tablet core was coated as in Example 1.
  • the tablet core was coated as in Example 1.
  • Example 6 iC.oiiip sitipri having less than 35% valsartan

Landscapes

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

Abstract

Cette invention concerne une composition pharmaceutique comprenant du valsartan, éventuellement une combinaison de valsartan et d'hydrorochlorothiazide. Cette composition, qui se présente sous forme de cachets, comprend un excipient dont la taille des particules se situe entre 10 et 1000 µm, de préférence entre 50 et 400 mm, à raison de 20 à 60, de préférence de 40 à 60% en poids du poids total de la préparation.
EP04797393A 2003-11-03 2004-11-02 Preparation contenant du valsartan Withdrawn EP1680095A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CZ20032984A CZ20032984A3 (cs) 2003-11-03 2003-11-03 Tableta s obsahem valsartanu vyrobená přímým tabletováním
CZ20041020A CZ297417B6 (cs) 2004-10-07 2004-10-07 Lécivý prípravek obsahující valsartan
PCT/CZ2004/000073 WO2005041941A2 (fr) 2003-11-03 2004-11-02 Preparation contenant du valsartan

Publications (1)

Publication Number Publication Date
EP1680095A2 true EP1680095A2 (fr) 2006-07-19

Family

ID=34553093

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04797393A Withdrawn EP1680095A2 (fr) 2003-11-03 2004-11-02 Preparation contenant du valsartan

Country Status (5)

Country Link
EP (1) EP1680095A2 (fr)
EA (1) EA008063B1 (fr)
PL (1) PL382044A1 (fr)
SK (1) SK50472005A3 (fr)
WO (1) WO2005041941A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR200703568A1 (tr) 2007-05-24 2008-07-21 Sanovel �La� Sanay� Ve T�Caret Anon�M ��Rket� Valsartan formülasyonları
DE102008047910A1 (de) 2008-09-19 2010-03-25 Molkerei Meggle Wasserburg Gmbh & Co. Kg Tablettierhilfsstoff auf Laktose- und Cellulosebasis
EP2405899A2 (fr) 2009-03-11 2012-01-18 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Préparations de valsartan
DE102011108762A1 (de) * 2011-07-28 2013-01-31 Stada Arzneimittel Ag Verpresste feste pharmazeutische Zusammensetzung, umfassend amorphes partikuläres Valsartan als Wirkstoff
EP4295839A1 (fr) 2022-06-20 2023-12-27 KRKA, d.d., Novo mesto Combinaison de valsartan et d'indapamide

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9613470D0 (en) * 1996-06-27 1996-08-28 Ciba Geigy Ag Small solid oral dosage form
TR200805275T2 (tr) * 1998-12-23 2008-09-22 Novartis Ag AT-1 veya AT-2 reseptörlerindeki artışın neden olduğu hastalıkların tedavisi için AT-1 reseptör antagonisti veya AT-2 reseptör modülatörünün kullanımı@

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005041941A2 *

Also Published As

Publication number Publication date
WO2005041941A2 (fr) 2005-05-12
PL382044A1 (pl) 2007-08-06
SK50472005A3 (sk) 2005-09-08
EA200500973A1 (ru) 2006-02-24
EA008063B1 (ru) 2007-02-27
WO2005041941A3 (fr) 2006-04-20

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