EP1648451A2 - Fluconazole capsules with improved release - Google Patents

Fluconazole capsules with improved release

Info

Publication number
EP1648451A2
EP1648451A2 EP04743730A EP04743730A EP1648451A2 EP 1648451 A2 EP1648451 A2 EP 1648451A2 EP 04743730 A EP04743730 A EP 04743730A EP 04743730 A EP04743730 A EP 04743730A EP 1648451 A2 EP1648451 A2 EP 1648451A2
Authority
EP
European Patent Office
Prior art keywords
fluconazole
capsules
weight
optionally
particles
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Withdrawn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
EP04743730A
Other languages
German (de)
English (en)
French (fr)
Inventor
Pál FEKETE
Judit Virgula
Eva Furdyga
Magdolna Leventiszne Huszar
Imre Klebovich
Katalin Baloghne Nemes
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.)
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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 Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of EP1648451A2 publication Critical patent/EP1648451A2/en
Withdrawn legal-status Critical Current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
    • A61K31/395—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • Fluconazole is an important representative of the wide spectrum triazole antifungal medicinal active ingredients, which is mainly administered orally.
  • Chemically fluconazole is 2,4-difluoro-( ⁇ ),( ⁇ )-bis-(lH-l,2,4- triazole-1- yl- methyl)-benzylalcohol. Its chemical structure corresponds to the empirical formula and molecular weight of Ci3H 12 F 2 N 6 O and 306.3 g/mol, respectively. Fluconazole is white, crystalline solid, which is poorly soluble in water.
  • Fluconazole is administered in the therapy in form of tablets or capsules in strengths of 50 mg, 100 mg, 150 mg or 200 mg. Tablets containing fluconazole as active ingredient are marketed in the United States. In Europe, fluconazole containing capsules are introduced.
  • the fluconazole containing medicinal preparations marketed by the originator contain the following auxiliary agents:
  • Diflucan® capsules lactose, maize starch, magnesium stearate, silicone dioxide, sodium lauryl sulfate.
  • the active ingredient should be rapidly released from the medicinal preparation in order to prevent delayed absorption of said active ingredient as an effect pharmaceutical formulation.
  • Such medicinal preparations are characterized by short time interval to reach peak plasma concentration (t max : time to reach peak plasma concentration after administration), high peak plasma concentration (c max ) and low interindividual deviation of the aforementioned two pharmacokinetic variables.
  • said pharmacokinetic variables can be estimated on the basis of the active ingredient dissolution rate.
  • medicinal preparations having rapid and consistent in vitro dissolution rate are developed. Advantages of such preparations to the one having moderately slow dissolution are the following: - time required for absorption is short, since it is governed dominantly by the properties of the active ingredient, - the interindividual difference in the time required for absorption is low, because modulating effect of the formulation is negligible, - the possibility of interference during the absorption of the active ingredient is lower, because the time required for complete absorption is short.
  • interferences include, but are not limited to changes in peristaltic motion due to nausea or diarrhea, intake of medicines influencing drug absorption and, food ingestion.
  • fluconazole is administered in monodose, i.e. only one dose of the drug is ingested.
  • Another critical application is the fungal infection of the nail (onychomycosis), wherein the drug is taken once a week.
  • the object of the present invention is to provide rapidly and consistently dissolving capsules containing fluconazole, comprising fluconazole [2,4-diflouro-( ⁇ ),( ⁇ )-bis-(lH- 1,2,4- triazol-l-ylmethyl)benzylalcohol], granulated with an agent capable of providing hydrophilic superficial character for the granules and optionally with a surfactant, said granules admixed with other optional filling or auxiliary agents.
  • the basis of our invention is the recognition that a hydrophilic coating layer fashioned on the surface of fluconazole particles of hydrophobic nature significantly increase the dissolution rate of said hydrophobic fluconazole particles.
  • the aforementioned hydrophilic layer residing on the surface of hydrophobic particles inhibits said particles to stick together in the dissolving medium, which process can result in diminished wetted surface during the dissolution process, and in conclusion, in diminished dissolution rate.
  • said hydrophilic layer facilitates the hydration of the individual particles producing rapid and consistent superficial wetting of said hydrophilically coated particles and also rapid dissolution thereof.
  • a process for the manufacture of fluconazole capsules, wherein said fluconazole particles are coated with an agent providing hydrophilic character to the particles and optionally with a surfactant and granules resulting from the above mentioned process are optionally admixed with one or more filling agents or another pharmaceutically acceptable auxiliary agents.
  • a carbohydrate of low molecular weight as hydrophilic agent is suitable for ensuring the favourable dissolution of fluconazole capsules when sprayed on the surface of the active ingredient at least in an amount of 5 weight%, more favourable in an amount of 10-20 weight%, calculated on the basis of the weight of the active ingredient.
  • Capsules prepared in this manner exhibit faster and more consistent in vitro dissolution and provide fast absorption and more consistent blood plasma concentration when compared to preparations known in the art.
  • Fluconazole capsules according to the present invention are comprising fluconazole containing granules produced by granulating fluconazole with 5-20 weight% of an agent capable to provide hydrophilic superficial character for the granules and optionally with 0.1-1 weight% surfactant calculated on the basis of said active ingredient, optionally admixed with 10-60 weight% filling agent, 5-30 weight% disintegrant, 0.1-2 weight% lubricant and 0.1-2 weight% glidant calculated on the basis of the filling weight of said capsule, wherein the fluconazole content of the capsule fill is 30-85 weight%, calculated on the basis of the filling weight.
  • Said fluconazole containing granules having a hydrophilic superficial layer are prepared by spraying the aqueous solution of an agent capable to provide hydrophilic character onto the fluconazole particles and by evaporating the water.
  • Agents capable to provide hydrophilic character are substances which form a hydrophylic layer on particles when sprayed onto said particles directly or in solution, thus facilitating the wetting of said particles and increasing dissolution rate.
  • These agents include carbohydrates of low molecular weight, such as sugar alcohols and sugars.
  • sugar alcohols are mannitol, sorbitol or maltitol, while preferable sugars include lactose, glucose, fructose or saccharose; the most preferably, lactose is used. Lactose is preferable since in its presence no stability problems are anticipated.
  • surfactants generally used in oral pharmaceutical preparations can be applied, such as non-ionic surfactants, which include among others polyethylene-fatty acid esters or ethers, sugar-esters; anionic surfactants including sodium lauryl sulfate or sodium dioctyl-sulfosuccinate.
  • the amount of the surfactant is usually 0.1-1 weight%.
  • sodium lauryl sulfate can be used.
  • filling agents can be used to facilitate formulation. Filling agents used in the capsules according to the present invention are selected from those usually applied in capsule production.
  • These agents include inorganic substances, such as calcium hydrogenphosphate dihydrate and organic substances.
  • carbohydrates e.g. carbohydrates of low molecular weight, sugars, e.g. fructose, glucose, or the most preferably, lactose; sugar alcohols, e.g. mannitol, sorbitol or maltitol; cellulose derivatives, e.g. microcrystalline cellulose could be used in an amount of 10-60 % calculated on the weight of the preparation.
  • composition according to the present invention can contain further auxiliary agents.
  • Said auxiliary agents include lubricants useful in automated capsule filling process. Said lubricant's role is to decrease the friction between the particles of the formulation and the filling tubes.
  • Lubricants known in the state of the art could be used in the production of the capsules according to the present invention.
  • Such lubricants include stearic acid, hydrogenated vegetable oils, paraffins, alkali earth metal salts of stearic acid, such as magnesium stearate or calcium stearate.
  • Amount of the lubricant is between 0.1-2.0 weight% calculated on the basis of the weight of preparation.
  • calcium or magnesium stearate the most preferably, magnesium stearate can be used.
  • capsules according to the present invention can contain a disintegrant to enhance dispersion of the capsule fill in an aqueous medium after administration.
  • Disintegrants generally used in the pharmaceutical technology can be used in the composition of the present invention, e.g. starch, starch derivatives, partially hydrolyzed starch or starch derivatives, e.g. sodium carboxymethyl starch, cellulose derivatives, e.g. sodium carboxymethyl cellulose, polivinyl-pyrrollidone.
  • starch more preferably, partially hydrolyzed, cross-linked starch can be applied. Usual amount of the disintegrant is 0.5-30 weight% calculated on the basis of the weight of the composition.
  • colloidal silicone dioxide has multiple effect. It is useful to improve the gliding property of the powder mixture and the precision of metering. Said compound may shorten the disintegration time of the capsules due to its hydrophilic character and may accelerate the dissolution of the active ingredient. Colloidal silicone dioxide is added in a powder-mixing procedure in an amount of 0.1-2 weight% calculated on the basis of the weight of the composition.
  • Further object of the present invention is to provide a process for the manufacture of capsules containing fluconazole with rapid and consistent dissolution property, characterized in that a solution containing an agent capable to provide hydrophilic surface property and optionally a surfactant is sprayed onto the surface of fluconazole [2,4-diflouro-( ⁇ ),( ⁇ )-bis-(l H- 1 ,2,4-triazole- 1 - ylmethyl)benzylalcohol] particles, the resulting treated particles are mixed and homogenized with filling and auxiliary agents and filled into capsules.
  • solution of 5-20 weight% agent capable to provide hydrophilic surface property and optionally 0.1-1 weight 0 /- surfactant calculated on the basis of the weight of fluconazole is sprayed onto the surface of fluconazole particles comprising 30-85 % of the weight of the medicinal composition, the resulting coated particles are admixed and homogenized with 10-60 % filling agent, 5-30 % disintegrant, 0.1- 2.0 % lubricant and 0.1-2 % glidant, wherein amounts of said filling agent, disintegrant, lubricant and glidant are calculated on the basis of the desired weight of the composition, and filling the resulting mixture into capsules.
  • Surfactant may optionally be sprayed onto the surface of fluconazole particles together with the agent capable to produce a hydrophilic surface property. Spraying is preferably performed in the fluidized state, since this method provides fast evaporation of water.
  • the solution to be sprayed contains 10-40 weight% agent capable to produce a hydrophilic surface on the surface of the said hydrophobic active ingredient particles and optionally 0.1-1 weight% surfactant.
  • amounts of the agent capable to provide hydrophilic surface is 15-25 weight%, while the amount of the surfactant is 0.1-0.5 weight%.
  • the agent capable to provide hydrophilic surface property on the fluconazole particles and optionally the surfactant are dissolved in water.
  • the temperature of water is between 25 and 90°C, preferably between 40 and 70°C, the most preferably, between 55 and 65°C.
  • the solution is thermostated during spraying at temperature between 25 and 90°C, preferably 40-70°C, the most preferably, between 55 and 65°C.
  • the temperature of fluidizing air is between 25 and 80°C, preferably 40 and 70°C, the most preferably, 55 and 65°C.
  • the pressure required for adequate spraying and the air volumetric flow rate could be determined by a person skilled in the art and according the apparatus used.
  • the fluidized drying is continued until the humidity of the resulting granules decrease to 0.2-4%, preferably 0.5-3%, the most preferably, 1-2 %.
  • the dried granules are screened using a sieve of 0.5 to 1.5 mm, preferably 0.6-1.2 mm, the most preferably, 0.8- 1.0 mm mesh.
  • Granules are optionally admixed with filling agent and other auxiliary agents, homogenized and filled into capsules.
  • the test was performed in a paddle apparatus according to Ph. Eur. at 50 rpm.
  • the dissolving medium was 500 ml 0.1 M HCl. Samples were analyzed by high-performance liquid chromatography.
  • Table 3 demonstrates the maximum plasma concentration (c max ) and time required to reach maximum plasma concentration (t max ) together with their deviation, maximum and minimum values obtained in the above mentioned pharmacokinetic study.
  • Plasma concentration values are higher in all cases after administration of the composition of the present invention than for Diflucan ® capsules, while deviations of plasma concentrations are lower for the composition according to the present invention (Table 4). Lower relative standard deviations obtained for the composition according to the present invention than those for Diflucan® capsules for each plasma sampling time after administration proved the more consistent absorption of the composition according to the present invention.
  • Plasma concentration of fluconazole after single oral administration of capsules according to the present invention 150 mg
  • the test was performed in a paddle apparatus according to Ph. Eur. at 50 rpm.
  • the dissolving medium was 500 ml 0.1 M HCl. Samples were analyzed by high-performance liquid chromatography.
  • immediate release oral fluconazole compositions can be prepared by using the apparatus and equipments of pharmaceutical technology known from the prior art.
  • aqueous solution of a portion of the lactose used as filling agent in the original preparation together with sodium lauryl sulfate is sprayed onto the particles of the active ingredient, admixed and homogenized with starch, magnesium stearate and hydrophilic colloidal silicone dioxide and filled into hard gelatine capsules.
  • fluconazole capsules characterized by fast and consistent absorption are obtained.
  • Amount of fluconazole present in the composition can vary between 30-85 weight% on the basis of the mass of the composition, taking into account the amount of other ingredients. Considering that fluconazole may be applied in monodose, which may be as high as 200 mg, it is advantageous to produce fluconazole capsules containing at least 40 weight% fluconazole.
  • Example 1 Capsules of the following composition were produced in a laboratory scale.
  • a portion of approx. 200 g is removed from the homogenate obtained in the above described process and used for preparing a pre-blend with the magnesium stearate.
  • the pre-blended mixture has been reloaded to the homogenizing container and the whole mass of the blend was homogenated for further 2 minutes.
  • the final blend was filled into capsules. Dissolution data of the capsule
  • Example 2 Capsules of the following composition were produced on a pilot plant scale.
  • Sodium lauryl sulfate is dissolved in purified water, the solution is heated to 60°C and lactose monohydrate is added. The mixture is stirred until complete dissolution.
  • the active ingredient is transferred into the fluidizing container of a Glatt GPCG 15 apparatus and is fluidized at 60°C air temperature.
  • the granulating solution is sprayed onto the particles of the active ingredient at a pressure of 250 kPa. Subsequently the mixture is dried until its humidity is less than 2 %. Dried granules are regranulated using a Diaf granulating apparatus. Weight of the granules was determined and amounts of the components of the outer phase were calculated on the basis of the actual weight of the granules.
  • Example 3 In order to provide test preparation for the pharmacokinetic study of the composition according to the present invention, 150mg capsules were produced on a 100.000 ea batch scale.
  • Capsules of 150 mg were produced using the process described in Example 2.
  • Example 4 Capsules of the following composition were produced on a laboratory scale.
  • Lactose monohydrate is dissolved in approx.400 g water heated approximately 60°C under stirring.
  • the active ingredient is transferred into a Glatt GPCG 1 fluid bed granulating apparatus and the solution is sprayed onto the particles, while the temperature of the solution was kept between 40 and 60°C.
  • Coated particles are dried in the same apparatus and regranulated using a manual sieve of. 0.8 mm mesh.
  • Granules and pregelatinized starch (Starch 1500) are homogenized for 5 minutes in an Engelsmann drum mixer. Approximately 200 g of the blend obtained in this manner is removed and mixed with the pre-weighed magnesium stearate. This pre-mix was reloaded to the homogenizing drum and homogenized for further 2 minutes.
  • the final blend was filled into hard gelatin capsules of arriving0" size with an average filling weight of 233.0 mg. Active ingredient content of the capsules is 150 mg. Dissolution testing

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP04743730A 2003-07-02 2004-06-30 Fluconazole capsules with improved release Withdrawn EP1648451A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0302030A HU227142B1 (en) 2003-07-02 2003-07-02 Capsule of improved release containing fluconazole
PCT/HU2004/000071 WO2005002553A2 (en) 2003-07-02 2004-06-30 Fluconazole capsules with improved release

Publications (1)

Publication Number Publication Date
EP1648451A2 true EP1648451A2 (en) 2006-04-26

Family

ID=89981480

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04743730A Withdrawn EP1648451A2 (en) 2003-07-02 2004-06-30 Fluconazole capsules with improved release

Country Status (10)

Country Link
EP (1) EP1648451A2 (sk)
CN (1) CN1812783A (sk)
BG (1) BG109430A (sk)
CZ (1) CZ200657A3 (sk)
EA (1) EA008585B1 (sk)
HU (1) HU227142B1 (sk)
PL (1) PL380995A1 (sk)
SK (1) SK50132006A3 (sk)
UA (1) UA82532C2 (sk)
WO (1) WO2005002553A2 (sk)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005005446A1 (de) 2005-02-04 2006-08-10 Grünenthal GmbH Bruchfeste Darreichungsformen mit retardierter Freisetzung
DE10361596A1 (de) 2003-12-24 2005-09-29 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform
DE102004032049A1 (de) 2004-07-01 2006-01-19 Grünenthal GmbH Gegen Missbrauch gesicherte, orale Darreichungsform
GB0900786D0 (en) * 2009-01-19 2009-03-04 Natracine Uk Ltd Therapeutic compositions
MD3971C2 (ro) * 2009-04-29 2010-06-30 Дмитрий СКУРТУ Scaun-trenajor
EP2736495B1 (en) 2011-07-29 2017-08-23 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
SI2736497T1 (sl) 2011-07-29 2017-12-29 Gruenenthal Gmbh Tableta, odporna proti zlorabi, ki zagotavlja takojšnje sproščanje zdravila
JP6449871B2 (ja) 2013-07-12 2019-01-09 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング エチレン−酢酸ビニルポリマーを含有する改変防止剤形
CN105616378A (zh) * 2014-10-31 2016-06-01 康普药业股份有限公司 一种氟康唑胶囊及其制备方法
JP2018526414A (ja) 2015-09-10 2018-09-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 乱用抑止性の即放性製剤を用いた経口過剰摂取に対する保護
CN113230236A (zh) * 2021-04-29 2021-08-10 山东优杰生物科技有限公司 祛除灰指甲草本贴及其制备方法

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HUT75616A (en) * 1992-03-17 1997-05-28 Pfizer Method for prooucing porous delivery devices
US6214386B1 (en) * 1995-11-22 2001-04-10 Recordati, S.A. Prompt-release oral pharmaceutical compositions for extemporaneous suspensions
EP1163234B1 (en) * 1999-03-24 2005-10-26 R.P. Scherer Technologies, Inc. Pharmaceutical formulations with improved aqueous solubility
KR100694667B1 (ko) * 1999-12-08 2007-03-14 동아제약주식회사 생체내이용률 향상과 개인간 및 개인내 흡수 편차를감소시킨 이트라코나졸 함유 항진균성 제제
RU2201230C1 (ru) * 2001-12-24 2003-03-27 Закрытое акционерное общество "Брынцалов-А" Лекарственное средство флузол, обладающее противогрибковым действием

Non-Patent Citations (1)

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See references of WO2005002553A2 *

Also Published As

Publication number Publication date
BG109430A (en) 2006-11-30
CN1812783A (zh) 2006-08-02
CZ200657A3 (cs) 2006-04-12
PL380995A1 (pl) 2007-04-16
UA82532C2 (uk) 2008-04-25
HUP0302030A2 (hu) 2005-03-29
WO2005002553A3 (en) 2005-03-24
EA008585B1 (ru) 2007-06-29
WO2005002553A2 (en) 2005-01-13
SK50132006A3 (sk) 2006-05-04
HU0302030D0 (en) 2003-09-29
HU227142B1 (en) 2010-08-30
EA200600085A1 (ru) 2006-08-25

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