WO2009096908A2 - Extended-release fluvastatin tablet - Google Patents

Extended-release fluvastatin tablet Download PDF

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Publication number
WO2009096908A2
WO2009096908A2 PCT/TR2008/000081 TR2008000081W WO2009096908A2 WO 2009096908 A2 WO2009096908 A2 WO 2009096908A2 TR 2008000081 W TR2008000081 W TR 2008000081W WO 2009096908 A2 WO2009096908 A2 WO 2009096908A2
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WO
WIPO (PCT)
Prior art keywords
molecular weight
tablet formulation
formulation according
release
poloxamer
Prior art date
Application number
PCT/TR2008/000081
Other languages
French (fr)
Other versions
WO2009096908A3 (en
Inventor
Sevgi Takka
Nevin Celebi
Llbeyi Agabeyoglu
Fusun Acarturk
Tuncer Degim
Zelihagul Degim
Fusun Tirnaksiz
Original Assignee
Sevgi Takka
Nevin Celebi
Llbeyi Agabeyoglu
Fusun Acarturk
Tuncer Degim
Zelihagul Degim
Fusun Tirnaksiz
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 Sevgi Takka, Nevin Celebi, Llbeyi Agabeyoglu, Fusun Acarturk, Tuncer Degim, Zelihagul Degim, Fusun Tirnaksiz filed Critical Sevgi Takka
Publication of WO2009096908A2 publication Critical patent/WO2009096908A2/en
Publication of WO2009096908A3 publication Critical patent/WO2009096908A3/en

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K9/2022—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 a matrix tablet formulation which provides extended- release fluvastatin and the process for preparing this formulation.
  • Prior Art Fluvastatin is a synthetic HMG CoA reductase inhibitor and is disclosed in US 4739073. It is used in the treatment of hypercholesterolemia and atherosclerosis, since it can reduce blood cholesterol.
  • fluvastatin is [R*, S*-(E)]-( ⁇ )-7-[3-(4-fIuorophenyl)-l-(l- methylethyl)-lH-indol-2-yl]-3,5-dehydroxy-6-heptenoic acid, with the chemical structure thereof illustrated below.
  • Extended-release tablet formulations containing fluvastatin sodium are disclosed in WOOO 1525. According to this patent, extended-release formulations are prepared using a non-ionic hydrophilic polymer together with hydroxypropyl methylcellulose
  • Non-ionic hydrophilic polymers are chosen from among hydroxyethylcellulose having an average molecular weight of between 90,000 and
  • hydroxypropyl cellulose having an average molecular weight of between 370,000 and 1,500,000 and poly(ethylene oxide) having an average molecular weight of between 100,000 and 500,000.
  • the most important advantage of the present invention is that it is obtainable via the direct compression method. As water is not used in the formulation, tablets will remain stable during long storage periods. Formulations providing extended-release which are prepared using the economical direct compression method are advantageous in this respect.
  • the object of the present invention is to develop a fluvastatin tablet providing extended-release that can be taken orally once daily.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising fluvastatin, at least one hydrophilic polymer that is made up of the block copolymer (poloxamer) poly(oxyethylene) - poly(oxypropylene), which is a surface active agent.
  • the pharmaceutical product of the invention contains a HPMC with high and low molecular weight and a surfactant poloxamer 407 and/or poloxamer 188.
  • hydroxypropyl methylcellulose HPMC having low and high viscosity and an average molecular weight of between 26,000 and 220,000 and a poloxamer having an average molecular weight of between 6,000 and 12,000 is used.
  • the pharmaceutical product according to the present invention contains a diluent that is selected from the group comprising, for example, microcrystalline cellulose, calcium phosphates, lactose and mannitol.
  • the diluent is used at an amount between 5 and 22 % by weight of the total composition. Since it also serves as a dry fixative in direct compression formulations, microcrystalline cellulose is especially preferred. This substance is commercially available under the trade name AVICEL ® .
  • the pharmaceutical product of the present invention contains at least one glidant selected from the group comprising, for example, talc, corn starch, hydrophilic silica and aerosil. Aerosil is especially preferred according to the invention.
  • the pharmaceutical product according to the invention also contains at least one lubricant selected from the group comprising fatty acids and the salts thereof.
  • lubricant selected from the group comprising fatty acids and the salts thereof.
  • Magnesium stearate is especially preferred according to the invention.
  • the HMPC used in the pharmaceutical compositions disclosed herein is commercially available from Dow Chemical under the trade name METHOCEL ® .
  • the HPMC preferably contains a substitute hydroxypropyl (HP) functionality in an amount ranging between 7 and 12 %. It preferably has a normal viscosity (2.0 % HPMC in water) of 100 to 100,000 cps.
  • the HPMC used in the formulation is a combination of high and low molecular weight HPMC.
  • the HPMC of high molecular weight is Methocel Kl 5M and Methocel KlOOM and the HPMC of low molecular weight is Methocel KlOOLV, which are commercially available.
  • the [poly(oxyethylene)-poly(oxypropylene)] block copolymer which has a molecular weight of 6,000 to 12,000 is known as Poloxamer.
  • the poly(oxypropylene) present in Poloxamer 407 has a molecular weight of 4,000, and poly(oxyethylene) is present at an amount of 70 %.
  • the poly(oxypropylene) present in Poloxamer 188 has a molecular weight of 1 ,800, and poly(oxyethylene) is present at an amount of 80 %.
  • the surface active agent and HPMC form a gel matrix.
  • the pharmaceutically active agent is constantly released from the gel matrix.
  • Low molecular weight hydrophilic polymer gel attempts to reduce the viscosity of the formulation to a suitable level.
  • compositions of the present invention are used for the treatment or prevention of high cholesterol.
  • Fluvastatin sodium and other substances are weighed individually and mixed together in a mixer except for magnesium stearate. Magnesium stearate is then added and mixed for an additional period. The tablet is pressed.
  • the amounts are provided as mg.

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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a fluvastatin matrix tablet providing extended-release, which is characterized in that it is prepared via the direct compression method and contains at least one cellulose polymer compound as a gel forming agent and poloxamer as a surfactant.

Description

EXTENDED-RELEASE FLUVASTATIN TABLET
DESCRIPTION
Technical Field
The present invention relates to a matrix tablet formulation which provides extended- release fluvastatin and the process for preparing this formulation.
Prior Art Fluvastatin is a synthetic HMG CoA reductase inhibitor and is disclosed in US 4739073. It is used in the treatment of hypercholesterolemia and atherosclerosis, since it can reduce blood cholesterol.
The chemical name of fluvastatin is [R*, S*-(E)]-( ±)-7-[3-(4-fIuorophenyl)-l-(l- methylethyl)-lH-indol-2-yl]-3,5-dehydroxy-6-heptenoic acid, with the chemical structure thereof illustrated below.
Figure imgf000002_0001
(D
Conventional drugs of the statin group which provide immediate release (e.g. those that provide release within 2 hours) can lead to side effects as they accumulate in the liver. Indeed, medicaments that provide immediate release may result in exceeding peak concentrations in blood within a short period in some patients. Formulations that provide extended-release is used to reduce the side effects which resulted from drugs of the statin group passing into systemic circulation in a short time. The extended-release product which contains fluvastatin sodium is available commercially under the trade name of LESCOL XL.
Extended-release tablet formulations containing fluvastatin sodium are disclosed in WOOO 1525. According to this patent, extended-release formulations are prepared using a non-ionic hydrophilic polymer together with hydroxypropyl methylcellulose
(HPMC). Non-ionic hydrophilic polymers are chosen from among hydroxyethylcellulose having an average molecular weight of between 90,000 and
1,300,000, hydroxypropyl cellulose having an average molecular weight of between 370,000 and 1,500,000 and poly(ethylene oxide) having an average molecular weight of between 100,000 and 500,000.
Extended-release formulations prepared with HPMC which allow the tablet colour to remain stable are mentioned in WOO 178680.
The most important advantage of the present invention is that it is obtainable via the direct compression method. As water is not used in the formulation, tablets will remain stable during long storage periods. Formulations providing extended-release which are prepared using the economical direct compression method are advantageous in this respect.
Summary of the Invention
The object of the present invention is to develop a fluvastatin tablet providing extended-release that can be taken orally once daily.
The present invention relates to a pharmaceutical composition comprising fluvastatin, at least one hydrophilic polymer that is made up of the block copolymer (poloxamer) poly(oxyethylene) - poly(oxypropylene), which is a surface active agent.
The pharmaceutical product of the invention contains a HPMC with high and low molecular weight and a surfactant poloxamer 407 and/or poloxamer 188.
In order to obtain the fluvastatin tablet of the present invention which provides extended-release, hydroxypropyl methylcellulose (HPMC) having low and high viscosity and an average molecular weight of between 26,000 and 220,000 and a poloxamer having an average molecular weight of between 6,000 and 12,000 is used.
The pharmaceutical product according to the present invention contains a diluent that is selected from the group comprising, for example, microcrystalline cellulose, calcium phosphates, lactose and mannitol. The diluent is used at an amount between 5 and 22 % by weight of the total composition. Since it also serves as a dry fixative in direct compression formulations, microcrystalline cellulose is especially preferred. This substance is commercially available under the trade name AVICEL®.
The pharmaceutical product of the present invention contains at least one glidant selected from the group comprising, for example, talc, corn starch, hydrophilic silica and aerosil. Aerosil is especially preferred according to the invention.
The pharmaceutical product according to the invention also contains at least one lubricant selected from the group comprising fatty acids and the salts thereof. Magnesium stearate is especially preferred according to the invention.
The HMPC used in the pharmaceutical compositions disclosed herein is commercially available from Dow Chemical under the trade name METHOCEL®. The HPMC preferably contains a substitute hydroxypropyl (HP) functionality in an amount ranging between 7 and 12 %. It preferably has a normal viscosity (2.0 % HPMC in water) of 100 to 100,000 cps. The HPMC used in the formulation is a combination of high and low molecular weight HPMC. The HPMC of high molecular weight is Methocel Kl 5M and Methocel KlOOM and the HPMC of low molecular weight is Methocel KlOOLV, which are commercially available.
The [poly(oxyethylene)-poly(oxypropylene)] block copolymer, which has a molecular weight of 6,000 to 12,000 is known as Poloxamer. The poly(oxypropylene) present in Poloxamer 407 has a molecular weight of 4,000, and poly(oxyethylene) is present at an amount of 70 %. The poly(oxypropylene) present in Poloxamer 188 has a molecular weight of 1 ,800, and poly(oxyethylene) is present at an amount of 80 %. When administered orally, the surface active agent and HPMC form a gel matrix. The pharmaceutically active agent is constantly released from the gel matrix. Low molecular weight hydrophilic polymer gel attempts to reduce the viscosity of the formulation to a suitable level.
The pharmaceutical compositions of the present invention are used for the treatment or prevention of high cholesterol.
Examples
Preparation method
Fluvastatin sodium and other substances are weighed individually and mixed together in a mixer except for magnesium stearate. Magnesium stearate is then added and mixed for an additional period. The tablet is pressed.
Dissolution Test:
Conducted in apparatus I at 50 rpm according to the USP 27 method. 1000 ml of phosphate buffer with a pH of 6.8 or water is used. The formulations developed are compared with the commercial preparation LESCOL XR.
Table 1. Compounds of the examples*
Figure imgf000006_0001
the amounts are provided as mg.
Table 2. Results of the dissolution test (pH 6.8 phosphate buffer)
Figure imgf000006_0002

Claims

1. A extended-release tablet formulation comprising fluvastatin or a pharmaceutically acceptable salt thereof characterized in that the tablet is prepared via direct compression and contains hydroxypropyl methylcellulose as a gel forming agent and poloxamer as a surfactant.
2. The tablet formulation according to claim 1 wherein the formulation comprises a mixture of high and low molecular weight hydroxypropyl methylcellulose.
3. The tablet formulation according to claim 1 wherein the ratio of high molecular weight hydroxypropyl methylcellulose to low molecular weight hydroxypropyl methylcellulose is between 3: 1 and 2:1.
4. The tablet formulation according to claim 1 wherein the formulation comprises poloxamer having a molecular weight between 6,000 and 12,000.
5. The tablet formulation according to claim 1 , wherein the amount of the poloxamer present in the composition is 10 to 25 % of the total weight.
6. The tablet formulation according to claim 1 , wherein the amount of the fluvastatin or a pharmaceutically acceptable salt thereof present in the composition is 10 to 40 % of the total weight.
7. The tablet formulation according to claim 1, wherein microcrystalline cellulose is used as a diluent and aerosil and/or magnesium stearate is used as lubricant agents.
8. The tablet formulation according to claim 1 comprising a mixture of high and low molecular weight hydroxymethyl cellulose, poloxamer, microcrystalline cellulose and aerosil and magnesium stearate.
9. The pharmaceutical composition according to claim 1 characterized in that in a phosphate buffer of pH of 6.8, the release of active ingredient shows zero degree kinetics.
PCT/TR2008/000081 2008-01-30 2008-07-15 Extended-release fluvastatin tablet WO2009096908A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2008/00634A TR200800634A2 (en) 2008-01-30 2008-01-30 Fluvastatin tablet for extended release.
TR2008/00634 2008-01-30

Publications (2)

Publication Number Publication Date
WO2009096908A2 true WO2009096908A2 (en) 2009-08-06
WO2009096908A3 WO2009096908A3 (en) 2009-10-15

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TR (1) TR200800634A2 (en)
WO (1) WO2009096908A2 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097194A1 (en) * 2004-04-10 2005-10-20 Hanmi Pharm. Co., Ltd. Sustained release formulation for oral administration of hmg-coa reductase inhibitor and method for the preparation thereof
WO2007031801A1 (en) * 2005-09-14 2007-03-22 Pharmathen S.A. IMPROVED PHARMACEUTICAL COMPOSITION CONTAINING HMG-CoA REDUCTASE INHIBITOR AND METHOD FOR THE PREPARATION THEREOF
WO2008006715A2 (en) * 2006-07-13 2008-01-17 Unilever Plc Improvements relating to pharmaceutical compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097194A1 (en) * 2004-04-10 2005-10-20 Hanmi Pharm. Co., Ltd. Sustained release formulation for oral administration of hmg-coa reductase inhibitor and method for the preparation thereof
WO2007031801A1 (en) * 2005-09-14 2007-03-22 Pharmathen S.A. IMPROVED PHARMACEUTICAL COMPOSITION CONTAINING HMG-CoA REDUCTASE INHIBITOR AND METHOD FOR THE PREPARATION THEREOF
WO2008006715A2 (en) * 2006-07-13 2008-01-17 Unilever Plc Improvements relating to pharmaceutical compositions

Also Published As

Publication number Publication date
TR200800634A2 (en) 2009-02-23
WO2009096908A3 (en) 2009-10-15

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