WO2007114797A1 - Comprimés poreux destinés à être ultérieurement remplis avec un ingrédient pharmaceutique actif - Google Patents

Comprimés poreux destinés à être ultérieurement remplis avec un ingrédient pharmaceutique actif Download PDF

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Publication number
WO2007114797A1
WO2007114797A1 PCT/SI2007/000013 SI2007000013W WO2007114797A1 WO 2007114797 A1 WO2007114797 A1 WO 2007114797A1 SI 2007000013 W SI2007000013 W SI 2007000013W WO 2007114797 A1 WO2007114797 A1 WO 2007114797A1
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WO
WIPO (PCT)
Prior art keywords
active pharmaceutical
pharmaceutical ingredient
tablet
acetate
solution
Prior art date
Application number
PCT/SI2007/000013
Other languages
English (en)
Inventor
Odon Planinsek
Original Assignee
Igc Center D.O.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 Igc Center D.O.O. filed Critical Igc Center D.O.O.
Publication of WO2007114797A1 publication Critical patent/WO2007114797A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/2009—Inorganic 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the objects of the invention are porous tablets for subsequent filling with active pharmaceutical ingredient.
  • Tablets according to the invention are made with direct tabletting using excipients that enable subsequent filling of thereof with organic solution of active pharmaceutical ingredient.
  • active pharmaceutical ingredient has to be incorporated into appropriate therapeutical system or medicine.
  • tablet bases consist only of excipients used in pharmacy, active pharmaceutical ingredient is added subsequently as organic solvent solution.
  • Tablets one of the most often used pharmaceutical solid dosage forms are preparations that consist of s single dose of one or more active ingredients. Usually are made in a way that a uniform volume of particles is compressed into a tablet.
  • solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimetoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4- dioxane, 2-etoyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methohyethanol, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, tetrahydrofuran, toluenea and xylene.
  • Class 3 solvents have low toxic potential.
  • Amount of of daily consumption of these solvents are 50 mg or more with lower risk to human health.
  • These solvents are: heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butabol, 2-butanol, buthyl acetate, tert- butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate and formic acid.
  • Formulation contains beside active pharmaceutical ingredient also many different excipients that must be homogenously mixed, which is often difficult task. Compatibility of every excipient with the active pharmaceutical ingredient must be studied. Active pharmaceutical ingredient can adsorb onto equipment surfaces during the production process that can influence the content uniformity and decrease its amount in the tablets. Beside fillers, lubricants are added for improvement of flow properties, antiadhesives for prevention of adhesion onto dye and number of tablet components is rapidly increased. Water with high boiling enthalpy and heat capacity is used for granulation.
  • excipinets microcristalline cellulose treated with SiO 2
  • These excipients are multifunctional which means that they don't possess only one function as lubricants, glidants, antiadhesives, binders or dissintegrants.
  • One component possess two or more properties that enable direct tabletting by use of lower number of excipients.
  • High functionality excipients have good flow properties and good compressibility. However, it is in any case not possible to avoid dusting, especially with active pharmaceutical ingredient and to ensure drag content uniformity at low dosage tablets wich is in correlation with problems for ensuring homogenous tabletting mass. Nonhomogenous distribution of lubricant can decrease drag dissolution rate and influence compressibility of tabletting mass.
  • Nonhomogenous active pharmaceutical ingredient distribution in granulate can be influenced by nonhomogenous distribution of a binder during granulation. Beside that, both procedures demand cleaning of equipment, because it has to be proven that traces of active pharmaceutical ingredient that could contaminate next batch of a product containing new active pharmaceutical ingredient, have been removed. It is necessary to find an appropriate excipients for every active pharmaceutical ingredient separately for tabletting which is of great pretension and retardatory.
  • drag can be sprayed in the form of solution or suspension onto the appropriate carrier or with absorption of drag solution into porous carrier particles (for example porous silicone dioxide) and drying which increase production costs. After the drying, for improvement of flow properties and compressibility excipients should be added to particles loaded with the drag, and homogenous distribution of the active pharmaceutical ingredient in the tabletting mass should be ensured.
  • porous carrier particles for example porous silicone dioxide
  • Invention task is to reduce or dispatch problems related to known procedures of tablet production.
  • porous tablets for subsequent filling with active pharmaceutical ingredient where fore prepared porous tablets are filled with organic solvent solution and subsequent dried.
  • Figure 3 Content of ketoprofen in tablet after one and multiple fillings from ethanol solution.
  • Bases of porous tablets according to the invention do not contain active pharmaceutical ingredient and consist only of excipients used in pharmacy that are not soluble in organic solvents and do not disintegrate in contact with these solvents.
  • excipients are lactose, SiO 2 and with SiO 2 treated microcrystalline cellulose (commercial name PROSOLV HD 90).
  • Tablets without active pharmaceutical ingredient according to the invention are made with direct tabletting of lactose, SiO 2 or with SiO 2 treated microcrystalline cellulose or any combination of these excipients and are meant for filling by use of organic solvent or combination of solvents in which active pharmaceutical ingredient dissolve.
  • solventcs can be heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl -1-butanol, methylethylketone, methylisobutylketone, 2-methyl-l-propanol, pentane, 1/pentanol, 1- propanol, 2-propanol, propyl acetate, acetic acid, acetone, anisole, 1-butanol, 2-butanol, buthyl acetate, tert-butylmethyl ether, cumene, dimethyl sulphoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, acetonitrile, chlorobenzene, chloroform, cyclohexane 1,2- dichloroethene, dichloromethane, 1,2-dimetoxyethane, N,N-dimethylacet
  • Invention comprehend two procedures of filling. Bases of tablets can be immersed in a surplus of organic solution of active pharmaceutical ingredient. Every tablet from the same batch due to capillary effect absorbs same mass of the solution. According to second procedure active pharmaceutical ingredient solution is added separately into every tablet with appropriate dosing device, for example pipette in the way where whole solution amount added is absorbed into the tablet. Both examples enable reproducible and accurate dosing of active pharmaceutical ingredient into each tablet. Drying until removal of a solvent from the tablet follows to the limit permitted by regulations of official Pharmacopoeia. Active pharmaceutical ingredient has to be soluble in the organic solvent or in solvent mixture to the extent that enable by one, two, three or multiple filling procedure of the same tablet, assurance of therapeutical dose content.
  • Tablets according to the invention can be of any colour, texture or shape, for example round, oval, biconcave, rectangular, square, polygonal etc. Tablet mass can vary from 50 mg to 1000 mg preferentially from 50 mg to 500 mg.
  • Tablets are prepared with direct tabletting of microcrystalline cellulose treated with SiO 2 with diameter of 12 mm and mass of 440 mg. After immersion of tablets in organic solvent for several minutes disintegration or retention of their shape is checked.
  • Tablets are prepared with direct tabletting of lactose monohydrate /SiO 2 / microcrystalline cellulose treated with SiO 2 in proportion 30/20/50 with diameter of 10 mm and mass of 440 mg. After immersion of tablets in organic solvent for several minutes disintegration or retention of their shape is checked.
  • Tablets are prepared by direct tabletting of microcrystalline cellulose treated with SiO 2 with diameter of 10 mm and mass of 440 mg. Tablets are filled by immersion in solution of ketoprofen in ethyl acetate (20 % weight/volume concentration) for one minute and drying
  • Ketoprofen content in the tablet is determined spectrophotometrically by dissolving in ethanol and concentration determination at wavelength of257 nm.
  • ketoprofen (g) mass in the tablet (g) mass in the tablet (g)
  • Tablets are made with direct tabletting of silicified microcrystalline cellulose (PROSOLV ® -HD90) with diameter of 10 mm, mass of 240 and 455 mg filled with diclofenac in the way that from the both sides of the tablet 75 microliter of tetrahydrofurane solution (20% weight/volume concentration) of diclofenac is added with a pipette.
  • Diclofenac content in the tablet is determined by dissolution in methanol and spectrophotometical determination of concentration at wavelength of 282 nm.
  • Tablets according to the invention enable faster and cheaper development of formulation for production of drugs in comparison to conventional tablet production methods. Les equipment and components for tablet production is needed. There is no dusting and equiplent contamination of equipment that is used for granulation and tabletting eith active pharmaceutical ingredient, cleaning of equipment is less demanding in comparison to conventional methods of tablet production where traces of active pharmaceutical ingredient have to be removed. In comparison to granulation energy consumption is less because there is no water evaporation that has high heat of evaporation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Bases de comprimés poreux destinés à être ultérieurement remplis avec un ingrédient pharmaceutique actif sont fabriquées avec des procédés connus qui sont composées seulement d'excipients utilisés en pharmacie qui ne sont pas solubles dans des solvants organiques, ne se désagrègent pas au contact de ces solvants et sont ensuite remplies en utilisant une solution de solvant organique d'un ingrédient pharmaceutique actif puis séchées. Les excipients sont le lactose et/ou SiO2 et/ou de la cellulose microcristalline modifiée avec SiO2 en différentes proportions. Les solvants organiques dans lesquels l'ingrédient pharmaceutique actif est dissous sont l'heptane, l'acétate d'isobutyle, l'acétate d'isopropyle, l'acétate de méthyle, le 3-méthyl-1-butanol, la méthyléthylcétone, la méthylisobutylcétone, le 2-méthyl-1-propanol, le pentane, le 1-pentanol, le 1-propanol, le 2-propanol, l'acétate de propyle, l'acide acétique, l'acétone, l'anisole, le 1-butanol, le 2-butanol, l'acétate de butyle, l'oxyde de tert-butyle et de méthyle, le cumène, le diméthylsulfoxyde, l'éthanol, l'acétate d'éthyle, l'éther d'éthyle, le formiate d'éthyle, l'acide formique, l'acétonitrile, le chlorobenzène, le chloroforme, le cyclohexane, le 1,2-dichloroéthane, le dichlorométhane, le 1,2-diméthoxyéthane, le N,N-diméthylacétamide, le N,N-diméthylformamide, le 1,4-dioxane, le 2-éthoxyéthanol, l'éthylèneglycol, le formamide, l'hexane, le méthanol, le 2-methoxyéthanol, le méthylcyclohexane, la N-méthylpyrrolidone, le nitrométhane, la pyridine, le tétrahydrofurane, le toluène, le xylène ou des mélanges de deux de ces liquides ou plus. Les bases de comprimés sont immergées dans un excès de solution organique d'ingrédient pharmaceutique actif. Cette solution peut également être ajoutée à chaque comprimé séparément en utilisant un appareil de dosage approprié de préférence une pipette de façon à ce que le comprimé absorbe la totalité de la quantité de solution ajoutée.
PCT/SI2007/000013 2006-04-06 2007-03-21 Comprimés poreux destinés à être ultérieurement remplis avec un ingrédient pharmaceutique actif WO2007114797A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SIP-200600081 2006-04-06
SI200600081A SI22237A (sl) 2006-04-06 2006-04-06 Porozne tablete za naknadno polnjenje z zdravilnouäśinkovino

Publications (1)

Publication Number Publication Date
WO2007114797A1 true WO2007114797A1 (fr) 2007-10-11

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PCT/SI2007/000013 WO2007114797A1 (fr) 2006-04-06 2007-03-21 Comprimés poreux destinés à être ultérieurement remplis avec un ingrédient pharmaceutique actif

Country Status (2)

Country Link
SI (1) SI22237A (fr)
WO (1) WO2007114797A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010028843A1 (fr) * 2008-09-11 2010-03-18 Univerza V Ljubljani Comprimés pour un remplissage ultérieur de suspension de nanoparticules à l'aide d'ultrasons
RU2483715C2 (ru) * 2010-12-30 2013-06-10 Общество с ограниченной ответственностью "АКАДЕМФАРМ" Твердая лекарственная форма препаратов мемантина и его солей

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5558880A (en) * 1989-12-22 1996-09-24 Janssen Pharmaceutica Inc. Pharmaceutical and other dosage forms
US6399591B1 (en) * 2000-01-19 2002-06-04 Yung-Shin Pharmaceutical Ind. Co., Ltd. Chargeable pharmaceutical tablets
WO2006000229A2 (fr) * 2004-06-28 2006-01-05 Lifecycle Pharma A/S Comprimes poreux utilises comme excipients de formulations liquides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5558880A (en) * 1989-12-22 1996-09-24 Janssen Pharmaceutica Inc. Pharmaceutical and other dosage forms
US6399591B1 (en) * 2000-01-19 2002-06-04 Yung-Shin Pharmaceutical Ind. Co., Ltd. Chargeable pharmaceutical tablets
WO2006000229A2 (fr) * 2004-06-28 2006-01-05 Lifecycle Pharma A/S Comprimes poreux utilises comme excipients de formulations liquides

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010028843A1 (fr) * 2008-09-11 2010-03-18 Univerza V Ljubljani Comprimés pour un remplissage ultérieur de suspension de nanoparticules à l'aide d'ultrasons
RU2483715C2 (ru) * 2010-12-30 2013-06-10 Общество с ограниченной ответственностью "АКАДЕМФАРМ" Твердая лекарственная форма препаратов мемантина и его солей

Also Published As

Publication number Publication date
SI22237A (sl) 2007-10-31

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