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WO1995008987A1 - Procede de preparation de dispersions solides et de depots notamment comme medicaments solides a l'aide d'antagonistes du calcium du genre dihydropyridine - Google Patents

Procede de preparation de dispersions solides et de depots notamment comme medicaments solides a l'aide d'antagonistes du calcium du genre dihydropyridine Download PDF

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Publication number
WO1995008987A1
WO1995008987A1 PCT/SI1994/000017 SI9400017W WO9508987A1 WO 1995008987 A1 WO1995008987 A1 WO 1995008987A1 SI 9400017 W SI9400017 W SI 9400017W WO 9508987 A1 WO9508987 A1 WO 9508987A1
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WO
WIPO (PCT)
Prior art keywords
water
process according
solid
solvent
mono
Prior art date
Application number
PCT/SI1994/000017
Other languages
English (en)
Inventor
Franc VREC^¿ER
Marija FILIPC^¿IC^¿-MOC^¿NIK
Jozica Gustin
Original Assignee
Krka Tovarna Zdravil, P.O.
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 Krka Tovarna Zdravil, P.O. filed Critical Krka Tovarna Zdravil, P.O.
Priority to EP94927147A priority Critical patent/EP0721329A1/fr
Priority to SK379-96A priority patent/SK37996A3/sk
Publication of WO1995008987A1 publication Critical patent/WO1995008987A1/fr
Priority to FI961394A priority patent/FI961394A0/fi
Priority to NO961242A priority patent/NO961242L/no

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • the present invention relates to the process for the preparation of solid dispersions and deposits as well as of solid medicinal forms with dihydropyridine type calcium antagonists.
  • a too low dissolution rate of medicinal active substances from solid medicinal preparations may lead to an incomplete absorption and to a too low biological availability thereof.
  • micronization Due to the regulative requirements, the most suitable solution in connection with the too slow dissolution rate is represented by the pharmaceutical-technological ap ⁇ proach being realized in the simplest way by micronization.
  • pharmaceutical-technological ap ⁇ proach being realized in the simplest way by micronization.
  • micronization does not always result in an increase of the dissolution rate. Therefore at developing formulations including one or more 1,4-dihydropyridine derivatives characterized by very bad solubility and low dissolution rate in water, this approach could not be used.
  • DE 3419128 there is described a process for the preparation of a formulation with 1,4-dihydropyridine derivatives, wherefrom the active substance is released rapidly and reliably.
  • the cited application protects a classical process of granulation of the active substance selected from 1,4-dihydropyridine derivatives with water-soluble ex- cipients such as lactose, saccharose, fructose, glucose, mannitol, sorbitol, some alkaline and alkaline earth salts of organic acids and other excipients such as starch, cellulose, PVP and colloidal silicon dioxide.
  • water-soluble ex- cipients such as lactose, saccharose, fructose, glucose, mannitol, sorbitol, some alkaline and alkaline earth salts of organic acids and other excipients such as starch, cellulose, PVP and colloidal silicon dioxide.
  • the present invention includes technological processes and methods, which make possible the preparation of solid dispersions and/or deposits of one or more 1,4- dihydropyridine derivatives with appropriate pharmacologically indifferent com ⁇ pounds selected from mono-, di-, oligo- and polysaccharides and the preparation of solid medicinal forms with incorporated dispersions and/or deposits.
  • a dispersion solution or suspension
  • an appropriate carrier selected from mono-, di-, oligo- and polysaccharides, colloidal silicon dioxide or microciystalline cellulose
  • solid compositions in connection with this application are preferably:
  • solid dispersions where the drug (one or more 1,4-dihydropyridines) is homogeneously dispersed in the matrix of pharmacologically inactive sub ⁇ stances which comprise one or more water-soluble mono, di, oligo and/or polysaccharides, surfactants and one or more disintegrators;
  • Solid compositions described above can be, according to our invention, produced by:
  • solid compositions prepared in such a manner and containing a total of 1 to 75% (preferably 2.5 to 25%) of 1,4-dihydropyridine derivatives with antagonistic ac ⁇ tion upon the receptors at calcium channels by the addition of a superdisintegrator selected from sodium starch glycolate, polacrilin potassium, cross-linked carboxy methyl cellulose and cross-linked PVP and of anionic and/or non-ionic surfactants and other known adjuvants, there are formed solid medicinal forms such as capsules, tablets (classic or coated) or dragees.
  • a superdisintegrator selected from sodium starch glycolate, polacrilin potassium, cross-linked carboxy methyl cellulose and cross-linked PVP and of anionic and/or non-ionic surfactants and other known adjuvants
  • the object of the present invention is thus a process for preparing solid compositions containing 1,4-dihydropyridine derivatives, which comprises: (a) preparing a solution or suspension of one or more 1,4-dihydropyridines, one or more water soluble mono, di, oligo or polysaccharides and preferably one or more surfactants in a hydrophilic solvent,
  • a further object of the present invention is a process for preparing solid composi ⁇ tions containing 1,4-dihydropyridine derivatives, which comprises:
  • the surfactant is selected from sodium lauryl sulphate, substitued and unsubstituted polyoxyethylene-polyoxypropylene blockpolymers and polyoxyethylene sorbitan esters of higher fatty acids with 10-18 carbon atoms per molecule and preferably from sodium lauryl sulphate, ⁇ -hydro-o-hydroxypoly(oxyethylene) a -poly(oxy- propylene) b -poly(oxyethylene) a blockpolymer, where a is 80 or 101 and b is 27 or 56, and polyoxyethylene sorbitan monooleate.
  • Soluble starch, lactose, mannitol, sorbitol and/or glucose, preferably sorbital, man- nitol and/or lactose are used as the water soluble saccharide in step (a) and step (i) and as saccharide in step (b).
  • the disintegrator is selected from methacrylic acid-divinyl-benzene copolymer potas ⁇ sium salt (polacrilin potassium), sodium starch glycolate and cross-linked carboxy methyl cellulose and preferably from sodium starch glycolate and cross-linked car ⁇ boxy methyl cellulose.
  • methacrylic acid-divinyl-benzene copolymer potas ⁇ sium salt polycrilin potassium
  • sodium starch glycolate and cross-linked carboxy methyl cellulose preferably from sodium starch glycolate and cross-linked car ⁇ boxy methyl cellulose.
  • nitrendipine, nimodipine and/or lacidipine are used as 1,4-dihydropyridine derivatives.
  • hydrophilic solvent Lower aliphatic alcohols having one to four carbon atoms and containing 0 to 50% by volume of water are used as the hydrophilic solvent.
  • the lower aliphatic alcohols are preferably ethanol and/or 1-propanol.
  • a fluid bed process is used in step (c).
  • the solvent is removed by using spray drying or by drying under reduced pressure and elevated temperature.
  • the technological processes and the used ingredients of the present invention provide a comparable or an even faster release of the active substance from solid medicinal forms than in the case of the formulation according to DE 3419128, whereat at the same time the mentioned processes also dispose of the need for the micronization of the medicinal active substance and of the problems connected therwith. This ensures a lower energy consumption, a smaller loss of the active sub ⁇ stance and a greater homogeneity of the final solid medicinal form.
  • the present invention also includes the preparation of solid medicinal forms such as capsules, tablets (classic or coated) or dragees containing at least one of the following 1,4-dihydropyridine derivatives: nitrendipine, nimodipine and lacidipine in an amount of 2 to 240 mg per dose and provides for a stable and rapid release of the ac ⁇ tive substance from the formulation.
  • solid medicinal forms such as capsules, tablets (classic or coated) or dragees containing at least one of the following 1,4-dihydropyridine derivatives: nitrendipine, nimodipine and lacidipine in an amount of 2 to 240 mg per dose and provides for a stable and rapid release of the ac ⁇ tive substance from the formulation.
  • this invention also includes one or more adjuvants selected from water- soluble carriers selected from mono-, di-, oligo- and polysaccharides, preferably sor- bitol, lactose, water-soluble starch and mannitol in concentrations of 5-90%; one or more substances from the group of disintegrators, preferably sodium starch glycolate, polacrilin potassium, cross-linked sodium carboxy methyl cellulose and/or cross- linked polyvinylpyrrolidone in a concentration of 5 to 20%; one or more anionic or non-ionic surfactants selected from the esters and ethers of sorbitan, polyethylene glycol and polypropylene glycol, poloxamers, alkylsulfonic acid alkali salts in a con ⁇ centration of 0.05 to 10% and other commonly known adjuvants selected from the groups of binders, preferably microciystalline cellulose, and lubricants, preferably magnesium or aluminiumine, preferably magnesium or aluminiumine, adi
  • Nitrendipine was dissolved in ethanol and then mannitol was dispersed into the solu ⁇ tion. The solvent was removed from the dispersion by spraying under a stream of heated air. The final product was sieved through the sieve with 200 ⁇ m openings.
  • Nitrendipine and lactose were dissolved in a mixture of ethanolAvater and then it was proceeded according to the same process as in example 1.
  • nitrendipine 250.0 g lactose 750.0 g mixture ethanol (96% by vol.)/water 2+1 q.s.
  • the above listed ingredients were mixed in a planetary mixer and granulated with a PVP water solution. The granulate was dried until a 4.5% moisture was reached.
  • Example 7 nitrendipine 20 mg tablets
  • Example 8 nimodipine 30 mg tablets
  • Fig. shows a comparison of the dissolution profiles of dis ⁇ persions of examples 2 and 5 vs. the dissolution profile of micronized nitrendipine
  • Fig. 2 shows a comparison of the thermograms of the dispersion of Example 2 vs. the granulate of Example 5
  • Fig. 3 shows a comparison of the dissolution profiles of 20 mg nitrendipine tablets of Examples 6 and 7.

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

Abstract

Procédé de préparation de dispersions solides et de dépôts à l'aide d'antagonistes du calcium du genre dihydropyridine, comportant comme substance active un ou plusieurs dérivés de la 1,4-dihydropyridine tels que la nitrendipine, la nimodipine, et la lacidipine et comme excipient un ou plusieurs dérivés hydrosolubles de mono, di, oligo et polysaccharides, et si nécessaire des polymères gonflant au contact de l'eau choisis parmi la polacriline potassique, un sel sodique de glycolate d'amidon et/ou de la carboxyméthylcellulose réticulée ainsi que des surfactants anionogènes ou non ionogènes choisis parmi le sulfate de sodium laurylé, des poloxamères et/ou des esters polyoxyéthylénés de sorbitan et d'acides gras supérieurs, formant de préférence une solution et/ou une suspension de substances actives, et si nécessaire un ou plusieurs adjuvants hydrosolubles choisis parmi des mono, di, et oligosaccharides et des surfactants choisis parmi, des poloxamères et/ou des esters polyoxyéthyléné de sorbitan et d'acides gras supérieurs présentant de 12 à 18 atomes de carbone, dans un solvant choisi parmi les alcools aliphatiques inférieurs présentant de 1 à 4 atomes de carbone, de préférence éthanol ou 1-propanol, et si nécessaire dans un mélange aqueux, et si nécessaire un excipient choisi parmi un ou plusieurs dérivés hydrosolubles de mono, di, oligo et polysaccharides, et si nécessaire des polymères gonflant au contact de l'eau choisis parmi le groupe des désintégrateurs, et des surfactants anioniques ou non ioniques. L'extraction du solvant se fait par projection de la dispersion dans un courant d'air chaud. Est en outre présenté un procédé de préparation, sous forme de médicaments solides, d'antagonistes du calcium de type dihydropyridine dans lequel les dispersions et/ou dépôts solides sont mélangés idoinement à des désintégrateurs et à des lubrifiants, et si nécessaire à d'autres adjuvants tels que des excipients ou des liants en un mélange servant de préférence à préparer des comprimés ou des capsules.
PCT/SI1994/000017 1993-09-28 1994-09-26 Procede de preparation de dispersions solides et de depots notamment comme medicaments solides a l'aide d'antagonistes du calcium du genre dihydropyridine WO1995008987A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP94927147A EP0721329A1 (fr) 1993-09-28 1994-09-26 Procede de preparation de dispersions solides et de depots notamment comme medicaments solides a l'aide d'antagonistes du calcium du genre dihydropyridine
SK379-96A SK37996A3 (en) 1993-09-28 1994-09-26 Process for preparation of solid dispersions, deposits as well as of solid medicinal forms with dihydropyridine type calcium antagonists
FI961394A FI961394A0 (fi) 1993-09-28 1996-03-27 Menetelmä kiinteiden dispersioiden ja depositioiden sekä kiinteiden lääkemuotojen valmistamiseksi dihydropyridiinityyppisistä kalsiumantagonisteista
NO961242A NO961242L (no) 1993-09-28 1996-03-27 Fremgangsmåte for fremstilling av faste dispersjoner og depoter såvel som faste medisinske former med dihydropyridin-type kalsium-antagonister

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SIP-9300504 1993-09-28
SI9300504A SI9300504A (en) 1993-09-28 1993-09-28 Process for preparation solid dispersions and deposits of calcium antagonist dihidropyrimidine derivates and pharmaceutical compositions comprising the same

Publications (1)

Publication Number Publication Date
WO1995008987A1 true WO1995008987A1 (fr) 1995-04-06

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Application Number Title Priority Date Filing Date
PCT/SI1994/000017 WO1995008987A1 (fr) 1993-09-28 1994-09-26 Procede de preparation de dispersions solides et de depots notamment comme medicaments solides a l'aide d'antagonistes du calcium du genre dihydropyridine

Country Status (11)

Country Link
EP (1) EP0721329A1 (fr)
CZ (1) CZ90096A3 (fr)
FI (1) FI961394A0 (fr)
HR (1) HRP940611A2 (fr)
HU (1) HUT75643A (fr)
NO (1) NO961242L (fr)
PL (1) PL313712A1 (fr)
SI (1) SI9300504A (fr)
SK (1) SK37996A3 (fr)
WO (1) WO1995008987A1 (fr)
YU (1) YU56494A (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2133052A1 (es) * 1996-04-29 1999-08-16 Almirall Prodesfarma Sa Nuevas formulaciones farmaceuticas liquidas para la via oral.
EP0884054A3 (fr) * 1997-05-13 2000-08-23 Vita-Invest, S.A. Association à dosage fixe comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine et un antagoniste des canaux à calcium pour le traitement de maladies cardiovasculaires
WO2004010976A1 (fr) * 2002-07-30 2004-02-05 Whan In Pharm. Co., Ltd Dispersion solide contenant de l'amlodipine, procede de preparation et composition pharmaceutique contenant la dispersion solide
WO2003082247A3 (fr) * 2002-03-26 2004-02-05 Teva Pharma Microparticules medicamenteuses
EP0951300A4 (fr) * 1996-12-31 2006-07-26 Nektar Therapeutics Procedes permettant de secher par pulverisation des solutions de medicaments hydrophobes et d'excipients hydrophiles et compositions preparees selon ces procedes
EP2705839A1 (fr) 2012-09-10 2014-03-12 Rivopharm SA Composition pharmaceutique contenant de la lacidipine et procédé de préparation
CN104095811A (zh) * 2013-04-09 2014-10-15 上海信谊药厂有限公司 尼莫地平纳米混悬剂及其制备方法
CN109010288A (zh) * 2018-07-27 2018-12-18 洛阳瑞华动物保健品有限公司 一种提高二氢吡啶固体制剂稳定性工艺

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2822882A1 (de) * 1977-06-07 1978-12-21 Yamanouchi Pharma Co Ltd Nifedipine-enthaltende feste praeparatzusammensetzung, verfahren zu ihrer herstellung und ihre verwendung
EP0001247A1 (fr) * 1977-09-14 1979-04-04 Kanebo, Ltd. Composition pharmaceutique contenant de la nifédipine et procédé pour sa préparation.
EP0176773A1 (fr) * 1984-09-11 1986-04-09 Bayer Ag Préparation pharmaceutique solide contenant de la nitrendipine et procédé pour sa préparation
EP0287488A1 (fr) * 1987-04-07 1988-10-19 Recherche Informatique Et Pharmacie R.I.Ph., Sarl Médicament, produit diététique et produit d'hygiène sous la forme d'une composition pulvérulente obtenue par adsorption de principes actifs sur un sucre à dissolution rapide et procédé d'obtention de ladite composition
WO1992011001A1 (fr) * 1990-12-19 1992-07-09 Solvay (Societe Anonyme) Composition pharmaceutique a administration par voie orale
EP0521310A2 (fr) * 1991-06-05 1993-01-07 FUJIREBIO Inc. Comprimés de type dispersion solide contenant des dérivés de 1,4-dihydropyridine et procédé pour leur préparation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2822882A1 (de) * 1977-06-07 1978-12-21 Yamanouchi Pharma Co Ltd Nifedipine-enthaltende feste praeparatzusammensetzung, verfahren zu ihrer herstellung und ihre verwendung
EP0001247A1 (fr) * 1977-09-14 1979-04-04 Kanebo, Ltd. Composition pharmaceutique contenant de la nifédipine et procédé pour sa préparation.
EP0176773A1 (fr) * 1984-09-11 1986-04-09 Bayer Ag Préparation pharmaceutique solide contenant de la nitrendipine et procédé pour sa préparation
EP0287488A1 (fr) * 1987-04-07 1988-10-19 Recherche Informatique Et Pharmacie R.I.Ph., Sarl Médicament, produit diététique et produit d'hygiène sous la forme d'une composition pulvérulente obtenue par adsorption de principes actifs sur un sucre à dissolution rapide et procédé d'obtention de ladite composition
WO1992011001A1 (fr) * 1990-12-19 1992-07-09 Solvay (Societe Anonyme) Composition pharmaceutique a administration par voie orale
EP0521310A2 (fr) * 1991-06-05 1993-01-07 FUJIREBIO Inc. Comprimés de type dispersion solide contenant des dérivés de 1,4-dihydropyridine et procédé pour leur préparation

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2133052A1 (es) * 1996-04-29 1999-08-16 Almirall Prodesfarma Sa Nuevas formulaciones farmaceuticas liquidas para la via oral.
EP0951300A4 (fr) * 1996-12-31 2006-07-26 Nektar Therapeutics Procedes permettant de secher par pulverisation des solutions de medicaments hydrophobes et d'excipients hydrophiles et compositions preparees selon ces procedes
EP0884054A3 (fr) * 1997-05-13 2000-08-23 Vita-Invest, S.A. Association à dosage fixe comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine et un antagoniste des canaux à calcium pour le traitement de maladies cardiovasculaires
WO2003082247A3 (fr) * 2002-03-26 2004-02-05 Teva Pharma Microparticules medicamenteuses
AU2003226021B2 (en) * 2002-03-26 2008-07-17 Teva Pharmaceutical Industries Ltd. Drug microparticles
US9107832B2 (en) 2002-03-26 2015-08-18 Teva Pharmaceutical Industries, Ltd. Risperidone microparticles formed by sublimation
WO2004010976A1 (fr) * 2002-07-30 2004-02-05 Whan In Pharm. Co., Ltd Dispersion solide contenant de l'amlodipine, procede de preparation et composition pharmaceutique contenant la dispersion solide
EP2705839A1 (fr) 2012-09-10 2014-03-12 Rivopharm SA Composition pharmaceutique contenant de la lacidipine et procédé de préparation
CN104095811A (zh) * 2013-04-09 2014-10-15 上海信谊药厂有限公司 尼莫地平纳米混悬剂及其制备方法
CN109010288A (zh) * 2018-07-27 2018-12-18 洛阳瑞华动物保健品有限公司 一种提高二氢吡啶固体制剂稳定性工艺

Also Published As

Publication number Publication date
YU56494A (sh) 1997-03-07
EP0721329A1 (fr) 1996-07-17
SI9300504A (en) 1995-04-30
HUT75643A (en) 1997-05-28
FI961394A7 (fi) 1996-03-27
HU9600741D0 (en) 1996-05-28
NO961242L (no) 1996-05-09
SK37996A3 (en) 1997-02-05
FI961394A0 (fi) 1996-03-27
NO961242D0 (no) 1996-03-27
PL313712A1 (en) 1996-07-22
CZ90096A3 (en) 1996-09-11
HRP940611A2 (en) 1996-10-31

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