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WO2003105905A1 - Composition a liberation controlee contenant de la felodipine et procede de preparation de celle-ci - Google Patents

Composition a liberation controlee contenant de la felodipine et procede de preparation de celle-ci Download PDF

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Publication number
WO2003105905A1
WO2003105905A1 PCT/KR2003/000552 KR0300552W WO03105905A1 WO 2003105905 A1 WO2003105905 A1 WO 2003105905A1 KR 0300552 W KR0300552 W KR 0300552W WO 03105905 A1 WO03105905 A1 WO 03105905A1
Authority
WO
WIPO (PCT)
Prior art keywords
sucrose
felodipine
fatty acid
copolymer
composition
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.)
Ceased
Application number
PCT/KR2003/000552
Other languages
English (en)
Inventor
Kye Kwan Lee
Dong Soo Lee
Yun Seok Rhee
Jun Hee Jang
Sun Oh Jeoung
Sang Jin Kim
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.)
Whan In Pharm Co Ltd
Original Assignee
Whan In Pharm Co Ltd
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 Whan In Pharm Co Ltd filed Critical Whan In Pharm Co Ltd
Priority to AU2003215947A priority Critical patent/AU2003215947A1/en
Publication of WO2003105905A1 publication Critical patent/WO2003105905A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or 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
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to a controlled release composition
  • a controlled release composition comprising felodipine, a fatty acid ester of sucrose and a copolymer of methacrylic acid and a method for producing the same.
  • Felodipine whose chemical name is 4-(2,3-dichlorophenyl)-l,4-dihydro-2,6- dimethyl-3,5-pyridindicarboxylic acid ethylmethyl ester, is a drug with calcium antagonistic activity which is useful for treating circulatory system diseases and has a very low solubility in water of 0.5 mg/L.
  • 9,623,499 disclosed methods for producing controlled release preparations comprising felodipine, in which the dissolution rate of felodipine has been improved by solubilization, by melting felodipine under a high temperature with polyethylene glycols, Poloxamer and the like, which have a high molecular weight, in order to increase the water solubility of felodipine, and the mixture is formulated into controlled release preparations using a water-soluble polymer or fat-soluble polymer as a base for sustained release agents.
  • these methods have disadvantages that their preparation procedures require particular care of safety in practical use.
  • Korean Patent Publication No. 95-2147, US PAT NO. 4,803,081 and US PAT NO. 4,942,040 remarkably improved the water solubility of felodipine by using non- ionic surfactants such as Cremophor®.
  • the methods described in the above the patents have a disadvantage that felodipine precipitates as time passes.
  • Korean Patent Publication No. 10-315872 disclosed a method for producing a sustained release preparation, comprising the steps of dissolving felodipine in an organic solvent, adding polyvinylpyrrolidone to the solution to form a binder solution and then adding the binder solution to an excipient mixture including a cellulose polymer, followed by combining the mixture.
  • Korean Laid-Open Publication No. 2001-0073461 disclosed a method for producing a solid dispersion, in which felodipine and an enteric coating polymer are dissolved in a mixture of a polar solvent and a non-polar solvent and the solid dispersion is formed using a spray-dryer or mixer.
  • felodipine there is no need for use of the enteric coating polymer to reduce its release in the stomach.
  • the method needs complex equipments and processes and is not environmentally friendly way since toxic organic solvents such as dichloromethane or chloroform has to be used in the process.
  • the methods for producing a solid dispersion to increase the dissolution rate for a poorly soluble material are largely divided into two types: the melting methods and the solvent methods.
  • the melting methods are carried out by melting a poorly soluble drug with a carrier by heating, uniformly mixing and cooling the melt.
  • heating may deteriorate the stability of a drug and the properties of the drug such as solubility may be changed by the cooling rate.
  • the solid dispersion is formed with cooling, the increased viscosity of the reaction mixture makes stirring more difficult. Therefore, it is not easy to produce a uniformly mixed solid dispersion of the drag and carriers so that the mass production of the solid dispersion in industrial application may have difficulties.
  • the solvent methods are carried out by dissolving a poorly soluble drug and carriers in a solvent that can solubilize the drug and carriers at the same time and then removing the solvent by drying to produce a solid dispersion.
  • this method has a defect that residual solvent may affect physical and chemical stability of the formed solid dispersion.
  • the drug and carrier may precipitate due to the differences of solubility of the drug and carrier in the solvent.
  • the increased viscosity of the reaction mixture makes stirring more difficult. Therefore, it is not easy to produce a uniformly mixed solid dispersion of the drug and earners and the mass production of the solid dispersion in industrial application may have difficulties.
  • the solid dispersions produced from the two types of methods should be further subjected to an additional process for dosage formulation, such as preparation of pellets or preparation of matrix tablets to form controlled release formulations, making the production process complicated.
  • fatty acid ester of sucrose can be a superior carrier for a solid dispersion of felodipine and the solid dispersion of felodipine using the fatty acid ester of sucrose shows an increased solubility of felodipine.
  • the present invention has been completed based on such findings.
  • the present inventors have found that the method according to the present invention can effectively solve the problems of the prior art, such as residual organic solvent, difficulty in stirring due to the high viscosity of the solid dispersion at the end phase of drying, and unumformity of content, and the controlled release of a drug in a desired form can be achieved without an additional process of dosage formulation, and have thereby completed the present invention.
  • the present invention is directed to a controlled release composition
  • a controlled release composition comprising felodipine, a fatty acid ester of sucrose and a copolymer of methacryhc acid.
  • the fatty acid ester of sucrose used in the composition of the present invention is used to increase water solubility of felodipine and its content can be preferably 0.1 to 5 parts by weight, more preferably 0.5 to 2 parts by weight, based on 1 part by weight of felodipine.
  • the fatty acid ester of sucrose used in the composition according to the present invention has advantages that the solubility of felodipine can be considerably increased and moreover, such effect can be achieved only in a small amount as compared to other carriers for solid dispersion.
  • Preferred fatty acid esters of sucrose that can be used in the present invention include ester compounds consisting of sucrose and fatty acids.
  • Monoester is such a sucrose ester that is combined one mole of fatty acid with one mole of sucrose. Diester is obtained using two moles of fatty acid and triester is obtained using three moles of fatty aicd.
  • Representative examples of such fatty acid esters of sucrose include sucrose monostearate, sucrose distearate (commercially available from Gattefosse under the trade name SUCRO ESTER 7), sucrose mono-distearate (commercially available from Gattefosse under the trade name SUCRO ESTER 11), sucrose monopalmitate (commercially available from Gattefosse under the trade name
  • sucrose dipalmitate sucrose monolaurate, sucrose dilaurate, sucrose monooleate, sucrose dioleate, sucrose monocaprate, sucrose dicaprate, sucrose monocaprylate, sucrose dicaprylate, sucrose monomyristate, sucrose dimyristate, sucrose monolinolenate, sucrose dilinolenate and the like.
  • sucrose dipalmitate sucrose monolaurate, sucrose dilaurate, sucrose monooleate, sucrose dioleate, sucrose monocaprate, sucrose monocaprate, sucrose monocaprylate, sucrose dicaprylate, sucrose monomyristate, sucrose dimyristate, sucrose monolinolenate, sucrose dilinolenate and the like.
  • the copolymer of methaciylic acid used in the composition of the present invention is used to make felodipine release in a controlled way and its content can be preferably 0.1 to 10 parts by weight, more preferably 1 to 5 parts by weight, based on 1 part by weight of felodipine.
  • the copolymer of methaciylic acid is advantageous in that altering the content of the copolymer can easily control the dissolution rate of felodipine.
  • Preferred copolymers of methaciylic acids which can be used in the present invention include copolymers of methacryhc acid with acrylic esters or methaciylic esters.
  • Representative examples of such copolymers include poly(butyl methacrylate,
  • the composition may further comprise an excipient including one selected from the group consisting of lactose, dextrin, starches, microcrystalline cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyethylene glycols, polyoxyethylene glycolated natural or hydrogenated castor oil derivatives, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene-fatty acid esters, polyoxyethylene-polyoxypropylene block copolymer, sodium dioctyl sulfosuccinate or sodium lauryl sulfate, phospholipids, propylene glycol mono-fatty acid esters or propylene glycol di-fatty acid esters, trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyo
  • the present invention is directed to a method for preparing a controlled release composition of felodipine comprising the steps of dissolving felodipine, a fatty acid ester of sucrose and a copolymer of methacryhc acid in an organic solvent, combining the solution with an excipient and drying the solvent.
  • the components of felodipine, the fatty acid ester of sucrose and the copolymer of methacryhc acid may be heated, preferably at the range of 40 ° C to 80 ° C to be readily dissolved in the organic solvent.
  • the organic solvent useful in the method according to the present invention is any one that can dissolve felodipine, the fatty acid ester of sucrose and the copolymer of methaciylic acid, including, for example, methanol, ethanol, isopropanol, acetone and methylene chloride, or a mixture of two or more thereof.
  • the content of the organic solvent is preferably 1 to 50 parts by weight, more preferably 4 to 20 parts by weight, based on 1 part by weight of felodipine.
  • the method according to the present invention in which felodipine, a fatty acid ester of sucrose and a copolymer of methacryhc acid are dissolved in an organic solvent and the solution is uniformly combined with an excipient, followed by drying solvent, can effectively solve the problems involved in using conventional solid dispersions, such as residual organic solvent, difficulty in stirring due to the high viscosity of the solid dispersions at the end phase of drying, and ununiformity of content. Also, it makes possible to achieve controlled release of the drug in a desired form without an additional process for dosage formulation, resulting in simplifying the production process.
  • compositions of felodipine having an advantage in terms of quality control of the products.
  • the composition of the present invention can be formulated into tablets, capsules, granules or pellets and the tablet dosage form is particularly preferred.
  • the composition may be directly filled in hard capsule as granules, may be mixed with a lubricant and other pharmaceutical additives and filled in hard capsule as powders or granules, or may be mixed with a pharmaceutical additive necessary for tabletting and compressed to form tablets.
  • Fig. 1 is a graph showing the results of the dissolution test according to Experiment Example 2 (0 : raw material of felodipine, I : Preparation Example 1, I : Preparation Example 2 and A : Preparation Example 3); and
  • Fig. 2 is a graph showing the results of the dissolution test according to Experiment Example 3 (0 : Example 1, 1 : Example 2, D : Example 3, I : Example 4 and A : Example 5).
  • Controlled release tablets containing the following composition were prepared as follows.
  • Sucrose monopalmitate (SUCRO ESTER 15, manufactured by Gattefosse) 5 g Poly(ethyl acrylate, methyl methacrylate, trimethylammomoethyl methacrylate chloride) (Eudragit RSI 00, manufactured by Rohm) 11 g Lactose 176 g
  • Felodipine and sucrose monopalmitate were added to about 40ml of ethanol and heated to about 60 ° C with stirring to obtain a clear solution.
  • poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) was added and stirred at about 60 ° C to give a clear solution.
  • lactose was added, and the resulting mixture was combined and granulated, followed by drying. The dried granules were milled in a certain size and mixed with magnesium stearate as a lubricant.
  • controlled release tablets containing 5 mg of felodipine per a tablet were obtained.
  • Controlled release tablets containing the following composition were prepared according to the procedure of Example 1.
  • Sucrose monopalmitate (SUCRO ESTER 15, manufactured by Gattefosse) 5 g
  • Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (Eudragit RS 100, manufactured by Rohm) 15 g
  • Example 3 Controlled release tablets containing the following composition were prepared according to the procedure of Example 1.
  • Sucrose monopalmitate (SUCRO ESTER 15, manufactured by Gattefosse) 5 g Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (Eudragit RSI 00, manufactured by Rohm) 17 g Lactose 170 g Magnesium stearate 3g
  • Controlled release tablets containing the following composition were prepared according to the procedure of Example 1.
  • Controlled release tablets containing the following composition were prepared according to the procedure of Example 1.
  • Controlled release tablets containing the following composition were prepared as follows.
  • Sucrose monopalmitate (SUCRO ESTER 15, manufactured by Gattefosse) 5 g Lactose 190 g
  • Felodipine and sucrose monopalmitate were added to about 40ml of ethanol and heated to about 60 ° C with stirring to obtain a clear solution. Then, lactose was added to the solution and the resulting mixture was combined and granulated, followed by drying. The dried granules were passed through a No. 20 sieve (Tyler sieve) to have a uniform size.
  • Preparation Example 2 The procedure of Preparation Example 1 was repeated, except that sucrose mono-distearate (SUCRO ESTER 11, manufactured by Gattefosse) was used as a fatty acid ester of sucrose instead of sucrose monopalmitate.
  • sucrose mono-distearate SUCRO ESTER 11, manufactured by Gattefosse
  • sucrose distearate SUCRO ESTER 7, manufactured by Gattefosse
  • sucrose monopalmitate sucrose distearate
  • Preparation Example 5 The procedure of Preparation Example 1 was repeated, except that 10 g of sucrose monopalmitate (SUCRO ESTER 15, manufactured by Gattefosse) was used.
  • Felodipine and PEG 20000 were added to about 40ml of ethanol and heated to about 60 ° C with stirring to obtain a clear solution. Then, lactose was added to the solution and the resulting mixture was combined and granulated, followed by drying. The dried granules were passed tlirough a No. 20 sieve (Tyler sieve) to have a uniform size.
  • Solid dispersions were prepared according to the procedure of Comparative Example 1, except that 5 g of Poloxamer 407 was used instead of PEG 20000.
  • Solid dispersions were prepared according to the procedure of Comparative Example 1, except that 5 g of Cremophor RH40 was used instead of PEG 20000.
  • Solid dispersions were prepared according to the procedure of Comparative Example 1, except that 5 g of polyvinylpyrrolidone K30 was used instead of PEG 20000.
  • Solid dispersions were prepared according to the procedure of Comparative Example 1, except that 5 g of polyvinylpyrrolidone K90 was used instead of PEG 20000.
  • the granules prepared in Preparation Examples 1, 2 and 3 respectively containing 5 mg of felodipine and the same amount of raw felodipine were subjected to a dissolution test.
  • the used dissolution solution was a buffer of pH 6.5 containing 1 M dihydrogen sodium phosphate, 0.5 M monohydrogen sodium phosphate and Cetyl trimethyl ammonium bromide.
  • the content of felodipine was determined by high performance liquid chromatography.
  • the tablets prepared in Examples 1, 2, 3, 4 and 5 were subjected to a dissolution test.
  • the used dissolution solution was a buffer of pH 6.5 containing 1 M dihydrogen sodium phosphate, 0.5 M monohydrogen sodium phosphate and Cetyl trimethyl ammonium bromide.
  • the content of felodipine was determined by high performance liquid chromatography.
  • the composition according to the present invention can effectively increase the solubility of felodipine, and the method according to the present invention, comprising the steps of dissolving felodipine, a fatty acid ester of sucrose and a copolymer of methacryhc acid in an organic solvent and uniformly combining with an excipient, followed by drying, can effectively solve the problems involved in using the conventional solid dispersions, such as residual organic solvent, difficulty in stirring due to a high viscosity of the solid dispersion at the end phase of drying, and ununiformity of content. Also, it makes possible to achieve controlled release of drug in a desired form without an additional process for dosage formulation, resulting in simplifying the production process. Further, since only altering the content of a copolymer of methaciylic acid can control the drug release rate, it leads to provide controlled release compositions of felodipine having an advantage in quality control of products.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition à libération contrôlée contenant de la felodipine, un ester d'acide gras de sucrose et un copolymère d'acide méthacrylique ; et un procédé de préparation de celle-ci. Cette composition accroît efficacement la solubilité de la felodipine. Le procédé comporte les étapes consistant à dissoudre la felodipine, un ester d'acide gras de sucrose et un copolymère d'acide méthacrylique dans un solvant organique, à combiner uniformément la solution avec un excipient, et à sécher le solvant. Le procédé permet de résoudre efficacement les problèmes qu'implique l'utilisation de dispersions solides classiques, telles qu'un solvant organique résiduel, les difficultés de mélange dus à la viscosité élevée de la dispersion solide à la phase terminale de séchage, et d'assurer l'uniformité des quantités de composants.
PCT/KR2003/000552 2002-06-12 2003-03-21 Composition a liberation controlee contenant de la felodipine et procede de preparation de celle-ci Ceased WO2003105905A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003215947A AU2003215947A1 (en) 2002-06-12 2003-03-21 Controlled release composition comprising felodipine and method of preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020020032876A KR20030095600A (ko) 2002-06-12 2002-06-12 펠로디핀을 포함하는 제어방출형 조성물 및 그 제조방법
KR10-2002-0032876 2002-06-12

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WO2003105905A1 true WO2003105905A1 (fr) 2003-12-24

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006089674A3 (fr) * 2005-02-25 2007-02-08 Hoffmann La Roche Comprimés présentant une dispersibilité de substance médicamenteuse améliorée
WO2011031099A3 (fr) * 2009-09-11 2011-07-07 Daewoong Pharmaceutical Co., Ltd. Hybride hydrotalcite-eudragit synthétique comprenant l'acide ursodésoxycholique, composition pharmaceutique le contenant et son procédé de préparation
WO2012070030A1 (fr) * 2010-11-26 2012-05-31 University Of The Witwatersrand, Johannesburg Composition pharmaceutique
US20140100181A1 (en) * 2008-12-23 2014-04-10 Galderma S.A. Topical pharmaceutical composition containing a water-sensitive active principle
RU2710742C1 (ru) * 2019-05-14 2020-01-10 Александра Александровна Савосина Композиция для лечения анальных трещин на основе фелодипина
CN113633616A (zh) * 2020-05-11 2021-11-12 鲁南制药集团股份有限公司 一种生物利用度高的固体制剂

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230332A1 (fr) * 1986-01-13 1987-07-29 N.V. Sanico Composition pharmaceutique à effet prolongé du composé actif et procédé de préparation
EP0311582A1 (fr) * 1987-10-08 1989-04-12 Aktiebolaget Hässle Préparation pharmaceutique à libération prolongée d'une dihydropyridine et un bêta-adrénorécepteur antagoniste et un procédé de production
US6267985B1 (en) * 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US6383471B1 (en) * 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230332A1 (fr) * 1986-01-13 1987-07-29 N.V. Sanico Composition pharmaceutique à effet prolongé du composé actif et procédé de préparation
EP0311582A1 (fr) * 1987-10-08 1989-04-12 Aktiebolaget Hässle Préparation pharmaceutique à libération prolongée d'une dihydropyridine et un bêta-adrénorécepteur antagoniste et un procédé de production
US6383471B1 (en) * 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
US6267985B1 (en) * 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIM B.K. ET AL.: "Preparation and characterization of drug-loaded polymethacrylate microspheres by an emulsion solvent evaporation method", JOURNAL OF MICROENCAPSULATION, TAYLOR&FRANCIS HEALTHSCIENCES, vol. 19, no. 6, 1 November 2002 (2002-11-01), UNITED KINGDOM, pages 811 - 822 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006089674A3 (fr) * 2005-02-25 2007-02-08 Hoffmann La Roche Comprimés présentant une dispersibilité de substance médicamenteuse améliorée
EP2281556A1 (fr) * 2005-02-25 2011-02-09 F. Hoffmann-La Roche AG Comprimés avec une meilleure dispersibilité de substance des médicaments
US20140100181A1 (en) * 2008-12-23 2014-04-10 Galderma S.A. Topical pharmaceutical composition containing a water-sensitive active principle
WO2011031099A3 (fr) * 2009-09-11 2011-07-07 Daewoong Pharmaceutical Co., Ltd. Hybride hydrotalcite-eudragit synthétique comprenant l'acide ursodésoxycholique, composition pharmaceutique le contenant et son procédé de préparation
WO2012070030A1 (fr) * 2010-11-26 2012-05-31 University Of The Witwatersrand, Johannesburg Composition pharmaceutique
RU2710742C1 (ru) * 2019-05-14 2020-01-10 Александра Александровна Савосина Композиция для лечения анальных трещин на основе фелодипина
CN113633616A (zh) * 2020-05-11 2021-11-12 鲁南制药集团股份有限公司 一种生物利用度高的固体制剂

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AU2003215947A1 (en) 2003-12-31
KR20030095600A (ko) 2003-12-24

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