EP1850842A1 - Preparations pharmaceutiques comprenant du nebivolol et un polymere hydrophile - Google Patents

Preparations pharmaceutiques comprenant du nebivolol et un polymere hydrophile

Info

Publication number
EP1850842A1
EP1850842A1 EP06706764A EP06706764A EP1850842A1 EP 1850842 A1 EP1850842 A1 EP 1850842A1 EP 06706764 A EP06706764 A EP 06706764A EP 06706764 A EP06706764 A EP 06706764A EP 1850842 A1 EP1850842 A1 EP 1850842A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
nebivolol
composition according
composition
hydrophilic polymer
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Withdrawn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
EP06706764A
Other languages
German (de)
English (en)
Inventor
Schumann Christof
Renz Jessica
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.)
Stada Arzneimittel AG
Original Assignee
Stada Arzneimittel 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 Arzneimittel AG filed Critical Stada Arzneimittel AG
Publication of EP1850842A1 publication Critical patent/EP1850842A1/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Withdrawn legal-status Critical Current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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to solid pharmaceutical compositions comprising the active ingredient nebivolol or one of its pharmaceutically acceptable salts.
  • Nebivolol the chemical name of which is ( ⁇ ) - [R * [S * [S * - (S * )]]]] - ⁇ , ⁇ ⁇ - [imino-bis (methylene) bis- [6-fluoro-3,4- dihydro-2H-1-benzopyran-2-methanol] is a highly selective ßr receptor antagonist which also has vasodilatory properties. Compared to other cardioselective beta-blockers nebivolol does not lead to a significant narrowing of the bronchi, so it is particularly suitable for the production of antihypertensives.
  • Nebivolol and process for its preparation are described in the European patent applications EP 0 145 067 A and especially EP 0 334429 A.
  • Nebivolol pharmaceutical compositions containing them are currently marketed in Germany under the designation "Bystolic ®" in the form of tablets.
  • European Patent Application EP 0 145 067 A describes a tablet formulation which, in addition to the active ingredient and other customary auxiliaries, must include sodium dodecylsulfate (also referred to as "SDS") SDS is a surface-active substance, ie a wetting agent is to be increased by the addition of which the solubility of the drug. also of marketed "Bystolic ®” tablets contain polysorbate 80 with such a wetting agent.
  • wetting agents has various disadvantages. So they show because of their high irritation potential, especially against mucous membranes, a poor compatibility. Furthermore, they can adversely affect the stability of dosage forms because they can interact with drugs and / or adjuvants. Finally, the production of wetting forms containing wetting agents, in particular by wet granulation, can be problematic because foaming may occur.
  • the object of the present invention is to provide pharmaceutical compositions comprising nebivolol or a pharmaceutically acceptable salt thereof, which ensure an improved release of the active ingredient.
  • nebivolol or its salts containing formulation should be specified, in which the addition of wetting agents can be completely dispensed with in order to avoid the associated disadvantages.
  • the formulations according to the invention are solid dosage forms such as, for example, suppositories, granules, pellets or, more preferably, tablets.
  • the tablet formulations according to the invention can be produced, for example, by means of direct compression, dry granulation or wet granulation. Particularly preferred is the preparation of the tablets according to the invention by means of wet granulation.
  • Hydrophilic polymers to be used according to the invention are in particular those polymers which have solubilizing or hydrotropic properties, for example polyvinylpyrrolidones, polyvinyl alcohols or polyethylene glycols.
  • Preferred polyvinyl pyrrolidones are the products available under the trade names Kollidon 12, 17, 25, 30 and 90, respectively.
  • Polyvinyl alcohols to be used in the present invention are available under the trade names Elvanol, Gelvatol, Lemol, Mowiol, Pe-ve-gel, Polyviol, Vinaviol, Vinol 125 and Vinylone.
  • Preferred polyethylene glycols are those of the Macrogol series, in particular Macrogol 200, 300, 400, 600, 1000, 1500, 3000, 3350, 4000, 6000, 8000, 20,000 and 35,000, respectively.
  • hydrophilic polymers are the polyvinylpyrrolidones obtainable under the trade names Kollidon 25 and Kollidon 30, the polyvinyl alcohol available under the trade name Mowiol 04 / Ml and also polyethylene glycol 4000.
  • the hydrophilic polymer is added as a binder to the granulation liquid used for the granulation.
  • the content of hydrophilic polymer is preferably between 0.5 and 25 wt .-%, based on the weight of the formulation.
  • the novel formulations lierungen further adjuvants, which are known in the art for the preparation of the desired drug form per se.
  • suppositories these are, for example, waxes and triglycerides
  • additional binders such as, for example, hydroxypropylmethylcellulose, lubricants and lubricants such as magnesium stearate or silica
  • fillers such as lactose or microcrystalline cellulose, dyes and, if used Tablets, conventional coating materials.
  • the tablets according to the invention contain at least one conventional disintegrant, by the addition of which the release of the active ingredient from the preparation is additionally promoted.
  • the disintegrant content of the composition is between 0.5 to 35% by weight, again based on the weight of the formulation.
  • the disintegrant can be incorporated intra- and / or extragranular.
  • Particularly preferred disintegrants are sodium starch glycolate, sodium carboxymethylcellulose (croscarmellose sodium) and crospovidone, but it is also possible to use other disintegrants known to those skilled in the art, such as microcrystalline cellulose or starch.
  • the active substance nebivolol is present in its free form or in the form of a pharmaceutically acceptable acid addition salt in the formulations according to the invention.
  • Suitable acid addition salts include the hydrochloride, the hydrobromide, the sulfate, the nitrate, the phosphate and salts of organic acids, such as the acetate, mesylate, besylate and others.
  • the compositions according to the invention particularly preferably contain nebulolol hydrochloride.
  • the active ingredient is preferably contained in micronized form, wherein the micronization can be carried out by conventional methods, for example by means of grinding in suitable mills or sieving by means of suitable sieves.
  • the micronization can be carried out by conventional methods, for example by means of grinding in suitable mills or sieving by means of suitable sieves.
  • at most 50% of the active substance particles have a diameter of more than 10 ⁇ m, preferably more than 8 ⁇ m, with at most 10% of the particles having a diameter of more than 20 ⁇ m.
  • the specific one Surface of the micronized active ingredient is preferably at least 2x 10 m J- / Ikg, more preferably at least 3 x 10 3 m 2 / kg.
  • the active ingredient content of the compositions according to the invention is preferably between 0.5 and 25% by weight, based on the weight of the total formulation;
  • the formulations preferably contain between 0.1 and 50 mg of active ingredient.
  • a dosage unit according to the invention contains 1, 5 or 10 mg of the active ingredient, calculated on the basis of the free nebivolol base.
  • composition according to the invention is that they have no
  • compositions according to the invention have content of a wetting agent such as polysorbates from the TWEEN ® series or other surfactants from the SPAN ® series or SDS.
  • a wetting agent such as polysorbates from the TWEEN ® series or other surfactants from the SPAN ® series or SDS.
  • Another essential feature of the compositions according to the invention is that the active ingredient is released much faster than from previously known compositions.
  • the active ingredient is released from the erf ⁇ ndungs- compositions according to 30 minutes to more than 80%.
  • the active ingredient is released after 15 minutes to at least 75%, more preferably after 10 minutes to at least 75% and particularly preferably after 5 minutes to at least 75% from the tablets of the invention (measured according to Ph.Eur., Method 2.9.3, Blattrühepparatur, 0.1 N HCl, 50 rpm).
  • Example 1 Tablets of the following composition are prepared:
  • the preparation is carried out by sieving and mixing micronised nebivolol HCl (at least 90% ⁇ 20 ⁇ m, specific surface area> 2000 m 2 / kg), lactose monohydrate, partially pregelatinized maize starch and a portion of croscarmellose sodium.
  • polyvinylpyrrolidone (Kollidon 25) is dissolved in water.
  • the mixture is granulated with the polyvinylpyrrolidone solution and the wet granules are sieved.
  • the granules are dried and then sieved.
  • Croscarmellose sodium, crospovidone and silica fumed are sieved and mixed with the resulting granules; Magnesium stearate is added to the resulting mixture.
  • the resulting mixture is compressed into tablets.
  • the preparation is made by sieving and mixing micronised nebivolol HCl, lactose monohydrate, partially pregelatinized cornstarch and a portion of croscarmellose sodium.
  • polyvinylpyrrolidone (Kollidon 30) is dissolved in water. Then, the mixture is granulated with the polyvinylpyrrolidone solution and the wet granules are sieved. The granules are dried and then sieved. Croscarmellose sodium and silica fumed are sieved and mixed with the resulting granules; Magnesium stearate is added to the resulting mixture. Finally, the resulting mixture is compressed into tablets.
  • the preparation is made by sieving and mixing nebivolol HCl, lactose monohydrate and partially pregelatinized cornstarch.
  • polyvinylpyrrolidone Kerdon 90
  • the mixture is granulated with the polyvinylpyrrolidone solution and the wet granules are sieved.
  • the granules are dried and then sieved.
  • Sodium starch glycolate and silica fumed are sieved and mixed with the resulting granules; Magnesium stearate is added to the resulting mixture.
  • the resulting mixture is compressed into tablets.
  • the preparation is made by sieving and mixing nebivolol HCl, lactose monohydrate, partially pregelatinized maize starch and part of croscarmellose sodium.
  • polyvinyl alcohol Movable Polyvinyl alcohol (Mowiol 04 / Ml) is dissolved in water.
  • the mixture is granulated with the polyvinylpyrrolidone solution and the wet granules are sieved.
  • the granules are dried and then sieved.
  • Croscarmellose sodium and silica fumed are sieved and mixed with the resulting granules; Magnesium stearate is added to the resulting mixture.
  • the resulting mixture is compressed into tablets.
  • the preparation is made by sieving and mixing nebivolol HCl, lactose monohydrate and partially pregelatinized cornstarch.
  • Polyethylene glycol 4000 (Macrogol 4000) is dissolved in water in parallel. Then the mixture is granulated with the polyethylene glycol 4000 solution and the wet granules are sieved. The granules are dried and then sieved. Croscarmellose sodium and silica fumed are sieved and mixed with the resulting granules; Magnesium stearate is added to the resulting mixture. Finally, the resulting mixture is compressed into tablets.
  • Example 1 To determine the release of active ingredient from the tablets according to the invention, the formulation according to Example 1 according to the European Pharmacopoeia in the current version, Method 2.9.3, Blattrühpparatur or in the U.S. Pat. Pharmacopeia (USP) as amended, Chapter (711) Dissolution, Apparatus 2, subjected to a defined test.
  • the medium used was 0.1 N hydrochloric acid; the revolution speed was 50 rpm.

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)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des préparations pharmaceutiques solides comprenant du nébivolol à libération améliorée du principe actif. Lesdites compositions contiennent un polymère hydrophile, comme par ex. du polyvinylpyrrolydone, de l'alcool polyvinylique ou du polyéthylène-glycol et sont exemptes d'agents mouillants.
EP06706764A 2005-02-11 2006-02-09 Preparations pharmaceutiques comprenant du nebivolol et un polymere hydrophile Withdrawn EP1850842A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005006553 2005-02-11
PCT/EP2006/001124 WO2006084684A1 (fr) 2005-02-11 2006-02-09 Preparations pharmaceutiques comprenant du nebivolol et un polymere hydrophile

Publications (1)

Publication Number Publication Date
EP1850842A1 true EP1850842A1 (fr) 2007-11-07

Family

ID=36118263

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06706764A Withdrawn EP1850842A1 (fr) 2005-02-11 2006-02-09 Preparations pharmaceutiques comprenant du nebivolol et un polymere hydrophile

Country Status (2)

Country Link
EP (1) EP1850842A1 (fr)
WO (1) WO2006084684A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7838552B2 (en) 2004-06-04 2010-11-23 Forest Laboratories Holdings Limited Compositions comprising nebivolol
CN101006081B (zh) 2004-07-30 2011-02-09 托伦特药物有限公司 奈必洛尔及其药学可接受盐、制备方法以及奈必洛尔的药物组合物
DE102006036579A1 (de) * 2006-08-04 2008-02-07 Alfred E. Tiefenbacher Gmbh & Co.Kg Pharmazeutische Zusammensetzung
EP1886674B1 (fr) * 2006-08-04 2010-03-31 Alfred, E. Tiefenbacher Gmbh & Co. Kg Composition pharmaceutique comprenant du nebivolol
JP5448844B2 (ja) 2007-01-22 2014-03-19 ミラン ファーマシューティカルズ ユーエルシー ネビボロールを含む固体の医薬組成物
WO2019183470A2 (fr) 2018-03-22 2019-09-26 Incarda Therapeutics, Inc. Nouvelle méthode pour ralentir le rythme ventriculaire

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0298666A2 (fr) * 1987-07-08 1989-01-11 American Home Products Corporation Compositions contenant de l'ibuprofen séchées par atomisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1337429C (fr) * 1983-12-05 1995-10-24 Guy Rosalia Eugene Van Lommen Derives du 2,2'-imino-bis-ethanol
TW355683B (en) * 1994-02-17 1999-04-11 Janssen Pharmaceutica Nv Composition containing micronized nebivolol
WO2005099699A1 (fr) * 2004-04-07 2005-10-27 Sepracor Inc. Combinaison de (s)-amlodipine et d'un betabloquant, et procedes pour la reduction de l'hypertension

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0298666A2 (fr) * 1987-07-08 1989-01-11 American Home Products Corporation Compositions contenant de l'ibuprofen séchées par atomisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Römpp-Lexicon Chemie", 1999, GEORG THIEME VERLAG, pages: 3515 - 3517 *
See also references of WO2006084684A1 *

Also Published As

Publication number Publication date
WO2006084684A1 (fr) 2006-08-17

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