WO2000072828A1 - Procede de fabrication d'unites posologiques de principes actifs en comprimes - Google Patents

Procede de fabrication d'unites posologiques de principes actifs en comprimes Download PDF

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Publication number
WO2000072828A1
WO2000072828A1 PCT/GB2000/002039 GB0002039W WO0072828A1 WO 2000072828 A1 WO2000072828 A1 WO 2000072828A1 GB 0002039 W GB0002039 W GB 0002039W WO 0072828 A1 WO0072828 A1 WO 0072828A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
binder
particles
microparticles
liquid
Prior art date
Application number
PCT/GB2000/002039
Other languages
English (en)
Other versions
WO2000072828B1 (fr
Inventor
Hiran Asoka Malinga Ratwatte
Original Assignee
Hiran Asoka Malinga Ratwatte
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 Hiran Asoka Malinga Ratwatte filed Critical Hiran Asoka Malinga Ratwatte
Priority to AU50892/00A priority Critical patent/AU5089200A/en
Publication of WO2000072828A1 publication Critical patent/WO2000072828A1/fr
Publication of WO2000072828B1 publication Critical patent/WO2000072828B1/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
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying

Definitions

  • This invention relates to a method of tabletting by compression of a mixture of an active agent or agents and excipients using liquid or gelled binder encapsulated in microparticles which disintegrate during tablet compression releasing the liquid or gelled binder and thus causing adhesion and binding of the particles in the tablet mix during the compression operation.
  • a rigid porous tablet with relatively high tensile strength is particularly advantageous.
  • active agents such as pharmaceuticals are formed into unit dose tablets by compression of an agglomerated mixture comprising of the active agent, one more excipients and a suitable binding agent.
  • a process involving direct compression of a mixture of the active agent, excipients is also known. The above processes are designed to be carried out at ambient temperatures using die tooling for tablet compression.
  • More recently low temperature processes have been developed for preparation of tablets and wafers for delivering unit doses of mainly process sensitive pharmaceutical agents. These processes involve the use of moulds and also, die tools for freezing either solutions of the tablet pre-mix or semi-solid mixtures of pre-chilled tablet components containing ice particles respectively, to form frozen unit doses from which the ice is removed by freeze-drying or other conventional means to produce a dry unit dose tablet.
  • the binding agent is added to the tablet pre-mix directly either in liquid form or suspended or dissolved in a suitable carrier material or solvent respectively.
  • a suitable carrier material or solvent for example, such as water, particle size distribution, degree of agglomeration and particle flow characteristics of the tablet mix during the pre-mixing operations prior to tabletting.
  • This can lead to unhomogeneous distribution of the active agent, excipients during mixing and poor compressibility of the tablet pre-mix, in-turn resulting in unacceptable variations in tablet content uniformity, strength and disintegration properties.
  • the above problems are particularly enhanced during preparation of porous freeze-dried tablets which involve semi-solid pre- ixes containing relatively large amounts of interstitial liquid, ice particles, chilled excipients, active agent and liquid binder.
  • the binder should ideally be in a fluid state in order to achieve uniform distribution and effective binding of the active agent, excipients and ice particles in the tablet pre-mix prior to freezing during tabletting and freeze drying.
  • the relatively high amounts of free liquid and binder being present in the interstitial spaces between particles in the tablet pre-mix leads to difficulty with controlling and maintaining the required physical properties of the pre-mix, in particular preventing unacceptable melting of the ice particles resulting in agglomeration, in-turn leading to poor flow properties of the particles in the pre-mix during delivery to the tablet press for compression.
  • the pre-mix should consist of the required particle size distribution and possess free-flowing characteristics.
  • the binder becomes increasingly less fluid and can eventually solidify, preventing effective adhesion of particles in the tablet pre-mix during tabletting.
  • the size of the individual encapsulated microparticles may be 3500 microns or smaller.
  • On rapid compression of the said tablet pre-mix at relatively high pressures and low temperatures (i .e . less than 0°C ) during tabletting the outer ice-layer of the microparticles disintegrates releasing the liquid or gelled binder.
  • This in-turn causes the liquid or gelled binder to be distributed evenly throughout the tablet mass leading to adhesion of the active agent, excipient and ice particles in the tablet pre-mix, forming a network structure of binder within the tablet mass on storage at temperatures less than the freezing point of the binder.
  • the ice in the tablet is removed by freeze-drying or other conventional means to make a rigid dry porous tablet with relatively high tensile strength.
  • the method of the present invention of using encapsulated binder microparticles at temperatures below 0 °C and above the freezing temperature of the encapsulated binder prevents problems caused during processing such as melting of the ice particles, agglomeration and poor flow characteristics of the tablet mix during the pre-mixing phase of the active, excipients and free-flowing ice particles due to prevention of unacceptable particle adhesion and resulting agglomeration encountered during conventional processes.
  • the prevention of unacceptable particle adhesion and agglomeration at the pre-mixing stage is achieved due to the absence of free liquid or gelled binder in the interstitial spaces between particles as the binder is encapsulated by a layer of ice held at temperatures below 0 °C .
  • the other advantages with the present method are that this allows better control over the overall mixing process of the tablet pre-mix preventing unhomogeneous distribution of the active, excipients and ice particles as the individual particles in the pre-mix are free-flowing. Also, the absence of liquid or gel in the pre-mix at this stage of the process allows the tablet pre-mix to be delivered rapidly as a free- flowing mixture to the die tool for compression at temperatures below 0 °C to form the tablet. The rapid release of the liquid or gelled binder as a result of disintegration of the ice-layer encapsulating it during the compression operation directly into the interstitial spaces between the particles of active agent, excipients and ice, enables uniform distribution of the binder within the tablet mass. This results in improved binding of the particles in the frozen tablet mass and the overall result, following removal of ice by freeze drying, is a rigid porous tablet of relatively high tensile strength.
  • the encapsulated liquid or gelled binder microparticles are prepared by spraying a solution of the suitable binder or a mixture of binders dissolved or suspended in a solvent into a bath of liquid Nitrogen to produce fine frozen particles .
  • the resulting fine frozen particles are then passed through a sieve of required size to achieve the correct particle size distribution.
  • the size of the frozen particles may be reduced by mechanical means at temperatures not higher than the freezing point of the binder prior to sieving.
  • the prepared frozen particles are then coated with a layer of ice by passing high humidity air through the particle mass by conventional means, such as by using a fluid-bed mixing chamber or by any other mechanical mixing means familiar to those skilled in the art.
  • Any suitable binder or a mixture of one or more binders dissolved in a solvent or a mixture of solvents which has a freezing point below 0 °C, preferably -5°C to -20 °C below 0 °C may be used. This prevents melting of the surface ice-layer of the microparticles as the binder in the core of the microparticles is converted to a liquid or gelled state by holding the microparticles at a suitable temperature below the freezing point of water (i.e. 0 °C) but, above the melting point of the solid core of binder.
  • microparticles with a liquid or gelled core of binder can then be stored under the above conditions prior to addition into the tablet pre-mix for further mixing and compression.
  • binder microparticles coated with a suitable inorganic or organic material and or a polymer or mixture of polymers in a carrier material at low processing temperature can be used.
  • These binder microparticles with cores containing liquid or gelled binder may be prepared by any conventional means such as by spray freezing of mixtures of binder and polymer in a carrier material or by polymer coating of pre-formed solid binder particles of which the cores are subsequently allowed to fully or partially melt.
  • polymer coated microparticles containing liquid or gelled binder in the central core and prepared at temperatures above 0 °C by conventional means such as spray drying, spray cooling and microencapsulation may be used.
  • Any suitable coating material or a mixture of coating materials may be used, such as an inorganic or organic material, a polymer, for example sugars, starches, celluloses, poly-acrylates can be used which is relatively brittle and would fracture during compression. Multiple layers of coating material or materials can be used for encapsulation.
  • Any suitable binder or mixtures of binders and or binder or mixtures of binder in a carrier material or materials such as a solvent can be used.
  • Suitable binders include polyvinylpyrrolidone, polyacrylamides, polyvinylalcohols, methylcellulose, ethylcellulose, carboxymethylcellulose, sodium-carboxymethylcellulose, hydroxypropylmethylcellulose, gelatine and starches.
  • Any suitable solvent or a mixture of solvents for example such as water, ethanol and methanol can be used.
  • excipients known to those skilled in the art may be used for example fillers, surfactants, lubricants, disintegrants, effervescing agents, colourings, sweeteners and preservatives.
  • the active agent may be a pharmaceutically active agent, vitamin, flavour, a microbiological or biological material or an agent for use in nutraceuticals, food additives, consumer goods such as detergents or cosmetics .
  • the active agent may be selected from either water soluble or insoluble materials and added in powdered form.
  • the active agent is a drug for human or veterinary use.
  • Each tablet may contain a unit dose amount of the drug.
  • EXAMPLE lOg of hydroxypropylmethylcellulose was mixed with 500ml of a 40% (volume/volume) solution of ethanol and deionised water. The above mixture was sprayed into a bath of liquid Nitrogen to form fine frozen particles of the binder. The particles were passed through a sieve of pore size of 100 microns.
  • the frozen particles of the binder were suspended in an air mix fluidised bed chamber maintained at a temperature less than the freezing point of the binder and air with a humidity content between 40% to 70% passed through the chamber until a substantial layer of ice was deposited on the surface of the individual particles covering and sealing the binder particles in the central core .
  • Free-flowing ice particles were prepared by passing air having a high humidity content in juxtaposition with a chilled metal surface at a temperature between -20 °C to -30 °C, so that ice seeds grow on the surface.
  • the free-flowing ice particles were removed by mechanical scraping and passed through a 70 micron sieve whilst maintaining a temperature of less than 0 °C to prevent melting of the frozen particles.
  • Fine free-flowing ice particles may also be made by spraying water into a bath of liquid Nitrogen using an atomising nozzle.
  • Measured quantities of the free-flowing ice particles and the frozen gelatine, mannitol particles were mixed in an air mix fluid bed chamber to homogeneity and a measured quantity of the ice-encapsulated microparticles added to the above mix, whilst continuing to mix and maintaining the chamber temperature not higher than the freezing point of the entrapped binder particles so, that a homogeneous premix of free-flowing ice, gelatine/mannitol and encapsulated binder particles were obtained.
  • the chamber temperature was warmed to a temperature not lower than the freezing point of the encapsulated binder mix but, lower than 0 °C to cause melting of the binder in the core of the binder particles and whilst maintaining the outer layer of ice in a solid state entrapping the melted liquid binder.
  • pre-chilled calcitonin was added to the particle mixture and mixed to homogeneity.
  • the resulting free-flowing pre-mix was transferred to a chilled die tool at a temperature not higher than 0 °C and not lower than the freezing point of the binder solution, and compressed at high pressures to allow disintegration of the encapsulated binder particles releasing the liquid binder into the interstitial spaces within the tablet mass.
  • the resulting tablets were stored at a temperature not higher than the freezing point of the binder mix and the ice removed by freeze-drying .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé de fabrication de comprimés consistant à former un mélange d'un principe actif, d'excipients et de microparticules contenant un liquide ou un gel de liaison encapsulés dans le noyau, puis à comprimer ledit mélange, ce qui provoque la désintégration des microparticules liantes et libère ainsi le liant liquide ou gélifié directement dans les interstices entre les particules du mélange du comprimé, formant un réseau de liant après séchage du comprimé. Les microparticules ont une taille individuelle inférieure à 3500 microns et peuvent être obtenues par encapsulation du liant dans un matériau relativement cassant comme la glace, un matériau organique ou inorganique ou un polymère cassant sous l'effet de la pression appliquée lors de la compression du comprimé. Ce procédé peut être utilisé dans la production de mélanges pour comprimés à écoulement libre et homogènes, à des températures supérieures et inférieures à 0 °C, et des comprimés rigides, poreux et possédant une résistance élevée à la rupture.
PCT/GB2000/002039 1999-06-01 2000-05-26 Procede de fabrication d'unites posologiques de principes actifs en comprimes WO2000072828A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50892/00A AU5089200A (en) 1999-06-01 2000-05-26 A method of tabletting dose units of active agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9912683.1 1999-06-01
GB9912683A GB2350582A (en) 1999-06-01 1999-06-01 A method of tableting

Publications (2)

Publication Number Publication Date
WO2000072828A1 true WO2000072828A1 (fr) 2000-12-07
WO2000072828B1 WO2000072828B1 (fr) 2001-02-08

Family

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Application Number Title Priority Date Filing Date
PCT/GB2000/002039 WO2000072828A1 (fr) 1999-06-01 2000-05-26 Procede de fabrication d'unites posologiques de principes actifs en comprimes

Country Status (3)

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AU (1) AU5089200A (fr)
GB (1) GB2350582A (fr)
WO (1) WO2000072828A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103191023B (zh) * 2013-03-22 2014-06-25 海南卫康制药(潜山)有限公司 一种快速崩解片剂的低温压制方法
CN103191069A (zh) * 2013-03-25 2013-07-10 海南卫康制药(潜山)有限公司 一种快速崩解片剂及其低温压制方法
CN109090319A (zh) * 2018-08-31 2018-12-28 迪拜尔特控股（北京）有限公司 乳矿物盐压片糖果

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4470202A (en) * 1981-12-11 1984-09-11 John Weyeth & Brother Limited Process and apparatus for freezing a liquid medium
US4829783A (en) * 1987-04-02 1989-05-16 Messer Griesheim Gmbh Device for the controlled freezing of viscous liquids
US5560927A (en) * 1995-07-28 1996-10-01 Isp Investments Inc. Co-processing method for making a free-flowing compressible powder and tablet therefrom

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3423489A (en) * 1966-11-01 1969-01-21 Minnesota Mining & Mfg Encapsulation process
DE2261426A1 (de) * 1972-12-15 1974-06-20 Manfred Dipl-Phys Lottermoser Verfahren zum getriggerten haerten von giessereiformteilen
US4978483A (en) * 1987-09-28 1990-12-18 Redding Bruce K Apparatus and method for making microcapsules
JP2640570B2 (ja) * 1992-01-13 1997-08-13 ファイザー インク． 強度が増加した錠剤の製造

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4470202A (en) * 1981-12-11 1984-09-11 John Weyeth & Brother Limited Process and apparatus for freezing a liquid medium
US4829783A (en) * 1987-04-02 1989-05-16 Messer Griesheim Gmbh Device for the controlled freezing of viscous liquids
US5560927A (en) * 1995-07-28 1996-10-01 Isp Investments Inc. Co-processing method for making a free-flowing compressible powder and tablet therefrom

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KNOCH, AXEL: "Cryopelletization", DRUGS PHARM. SCI., vol. 65, 1994, pages 35 - 50, XP000951630 *

Also Published As

Publication number Publication date
GB9912683D0 (en) 1999-07-28
GB2350582A (en) 2000-12-06
WO2000072828B1 (fr) 2001-02-08
AU5089200A (en) 2000-12-18

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