WO2005049306A1 - Procede de compactage assiste par ultrasons utilisant un dispositif de compactage a base de metal et de plastique - Google Patents

Procede de compactage assiste par ultrasons utilisant un dispositif de compactage a base de metal et de plastique Download PDF

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Publication number
WO2005049306A1
WO2005049306A1 PCT/EP2004/052990 EP2004052990W WO2005049306A1 WO 2005049306 A1 WO2005049306 A1 WO 2005049306A1 EP 2004052990 W EP2004052990 W EP 2004052990W WO 2005049306 A1 WO2005049306 A1 WO 2005049306A1
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WO
WIPO (PCT)
Prior art keywords
drug
process according
matrix
ultrasound
compacted
Prior art date
Application number
PCT/EP2004/052990
Other languages
English (en)
Inventor
Stefano Kirchmayer
Massimo Bresciani
Luca Dobetti
Original Assignee
Eurand Pharmaceuticals Limited
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 Eurand Pharmaceuticals Limited filed Critical Eurand Pharmaceuticals Limited
Publication of WO2005049306A1 publication Critical patent/WO2005049306A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B30—PRESSES
    • B30B—PRESSES IN GENERAL
    • B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
    • B30B11/022—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space whereby the material is subjected to vibrations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B30—PRESSES
    • B30B—PRESSES IN GENERAL
    • B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
    • B30B15/02—Dies; Inserts therefor; Mounting thereof; Moulds
    • B30B15/022—Moulds for compacting material in powder, granular of pasta form
    • B30B15/024—Moulds for compacting material in powder, granular of pasta form using elastic mould parts

Definitions

  • a way to enhance the solubility of poorly soluble or insoluble drugs is to thermodynamically activate them by forming an amorphous phase and/or nanocrystalline structures from the original crystalline state. This results in drug solubilisation kinetic, having dissolution rate and supersaturation concentrations, that is much higher than that obtainable with differently formulated drug in crystalline state. As a consequence, a strong increase of the drug effects "in vivo" is allowed by enhancing the bioavailability, reducing the onset of action (t ma ⁇ ) and decreasing the variability between subjects.
  • a technique to enhance the solubility of poorly soluble or insoluble drugs of reduced particle size consists in incorporating them into water-swellable but insoluble polymer by means of polymer swelling with a solution of the drug in a solvent; the solvent is thus removed and the drug precipitates in small particles within the polymer network.
  • An example of this processes is described in US 5,225,192, which deals with the loading of thermodynamically activated drug into particles of inert crosslinked polymers.
  • the mechanochemical activation by high-energy, co-grinding of crystalline drugs with inert substances (carriers) is a technique that allows modification of the chemical-physical properties of drugs by destructuring of the crystal and forming an amorphous phase and/or nanocrystalline structures inside the carrier (Nakai et al.
  • Mechanochemical activation offers the advantage of carrying out the process in solid state, avoiding the use of solvents with the related limitations (e.g. residual amount of solvents in the final product, drug degradation in a liquid state).
  • Ultrasounds or other heat treatments by means of waves can also be used to produce solid dispersions of thermodynamically activated drugs.
  • US 6,462,093 deals with a process for producing solid dispersion of sparingly water soluble drugs comprising an amorphous state-inducing agent and an amorphous state-stabilising agent.
  • Homogeneous physical mixtures comprising a crystalline drug and a suitable carrier have been treated according to US 5,662,935 by means of an ultrasound- assisted tabletting machine, equipped with a compaction device (die chamber and punch) in stainless steel.
  • the mixture of the drug and one or more excipients is exposed to mechanical or electromechanical actions of frequency between 1 kHz and 2MHz .
  • the obtained controlled release forms have a delayed or rapid release.
  • This ultrasound-assisted compaction has shown to bring improvements in the compacting of pharmaceutical solids with respect of the classical compaction processes such as reducing the energy required for compaction, increasing the efficiency in the control of release, improving the uniformity of the original mixture in the obtained tablets.
  • FIGURE 1 shows the scheme of the ultrasound-assisted tabletting machine.
  • Ultrasound-assisted compaction is a technique that uses ultrasounds that are sound waves with high frequency (from 16 KHz up to 200 MHz ) usually generated exploiting the inverse piezoelectric effect of special materials such as quartz or ceramics.
  • the application of a voltage between the faces of a piezoelectric crystal causes a mechanical distortion of the material. If the frequency of the applied voltage is equal to the typical frequency to whom the crystal is distorted, the result is a sound wave.
  • the ultrasonic wave is therefore generated by a piezoelectric transducer. Then, it passes through a horn (or booster), where the original amplitude of the wave is amplified, and is addressed to the powder material to be compressed.
  • the ultrasound-assisted machine combines the actions of pressure and ultrasounds to generate compacted matrices having throughout dispersed the active compound in a thermodynamically activated form (amorphous form).
  • the compaction pressure is lower than that normally required in standard compaction machines (e.g. roll compactors, tabletting machines), since the ultrasounds enhance the compaction of the powder bed by means of their energy.
  • the present invention provides an improved process for preparing a compacted matrix containing an amorphous active compound comprising the step of compacting a powder mixture comprising one or more active compounds and one or more inactive components in a modified ultrasound-assisted compacting device whose die chamber and punch made of a different material one from the other, chosen from plastic and metal.
  • the active and the inactive compounds are mixed my means of conventional methods and the obtained physical mixture is then exposed to ultrasound-assisted compaction.
  • the mixing is preferably carried out in the absence of any solvents so as to obtain a dry physical mixture.
  • Preferred plastic materials are DELRIN ® , an acetal resin trademark of DuPont Co., fluoropolymer resins (TEFLON ® ), polybutylene terephtalate resins as CRASTIN ® , polyamide resins as ZYTEL ® , polyethylene terephtalate, or glass reinforced copolyesther resins as THERMX ® .
  • Other plastic materials having high toughness and chemical resistance can also be used.
  • the plastic material is an acetal resin and the metal is stainless steel.
  • the ultrasound-assisted compaction device can be applied to any ultrasound- assisted compactor such as a tabletting machine or a roll compactor.
  • Tablets, mono or multilayered films, rod-shaped matrices are easily produced, but more complicated geometries can also be prepared.
  • the basic operation conditions of the compactor comprising the device of the invention correspond to usual practice.
  • the physical mixture is preferably exposed to the ultrasound-assisted compaction process of the invention at the frequency of the ultrasounds ranging from 16 to 100 KHz, more preferably from 20 to 60KHz and at a range of amplitude of the ultrasonic waves ranging preferably from 10 to 100 ⁇ m, more preferably from 15 to 40 ⁇ m.
  • the ultrasound action on the powder bed is preferably applied for a brief period of time, usually from 0.1 to 100 seconds, more preferably from 0.2 to 10 seconds.
  • the total amount of energy supplied to the powder is usually between 10 and 10000 J, preferably from 100 to 2000 J.
  • the resulting compacted matrix is a tablet.
  • said tablet has a diameter from 2 to 25 mm or a mono or multi layered film having a size from 4 to 50 cm and thickness from 0.1 to 20 mm.
  • the powder mixture to be compacted by means of the process of the present invention is a pharmaceutical powder mixture comprising at least one drug and at least one excipient.
  • said drug is a poorly water-soluble or water-insoluble drug.
  • Illustrative examples of therapeutic classes to which said drug may belong are antibiotics, diuretics, sedatives, analgesics, bronchodilators, beta-blockers, anti- inflammatories, anti-depressants, anti-diabetics, anti-hyperlipidemic agents, anti- hypertensives, vasodilators, vasoconstrictors, hormones, steroids, anti-histamines, anti-pyretics, anti-microbial agents, amphetamines, barbiturates, anti-Parkinson agents, anti-spastics, ophthalmic drugs, anti-cancer drugs, immunosuppresants, anti-HIV agents, anti-psoriasis.
  • Preferred drugs according to the present invention are nimesulide, piroxicam, naproxene, ketoprofen, ibuprofen, diacereine, griseofulvin, itraconazole, fluconazole, miconazole, ketonazole, zafrilukast, salbutamol, beclomethasone, flunisolide, clenbuterol, salmeterol, budesonide, estradiol, estriol, progesterone, megestrol acetate, medroxyprogesterone acetate, nefedipine, nicergoline, nicardipine, lisinopril, enalapril, nicorandil, celiprolol, verapamil, temazepam, diazepam, lorazepam, fluidiazepam, medazepam, oxazolam, zolmitriptan, sumatriptan, f
  • the matrix of the present invention contains as an excipient at least one pharmaceutically acceptable polymer .
  • Particularly preferred polymers which can be utilised alone or any mixture thereof, comprise cellulose and derivatives thereof such as methyl cellulose, ethyl cellulose, hydroxylpropyl cellulose, hydroxylpropylmethyl cellulose and sodium crosscarmellose, starch and derivatives thereof such as pre-gelatinised starch and sodium starch glycolate, linear and crosslinked polyvinylpyrrolidones, cyclodextrins such as alpha-, beta- and gamma-cyclodextrin, polysaccharides such as carrageenans, alginates, pectates, hyaluronates, chitosan, chitin, scleroglucans, dextrans and beta-glucans, acrylic polymers such as polymethacrylates as Eudragit L, S, RL, RS, polyethylene glycols, polyvinylpyrroline, polyvinylacetate, polylactic and polyglycolic polymers.
  • cellulose and derivatives thereof such as methyl
  • a further object of the present invention are also compacted matrices obtained with the process of the invention.
  • said matrices are in the form of a tablet.
  • the matrices of the invention contain at least one drug and at least one excipient.
  • a further object of the present invention is a method to increase the amorphous fraction of a water insoluble or slightly soluble drug characterised in that a powder mixture comprising said drug is compacted in a device according to the invention.
  • the present invention is not restricted to the used active compounds or inactive ingredients described in the examples below.
  • the equipment is a Saitec (Castelguelfo (BO), Italy) ultrasound-assisted tabletting machine ( Figure 1) having the compaction device reported in Figure 2.
  • the compaction die chamber is loaded with the powder (that has been previously homogeneously obtained by mixing the drug and excipient) and the punch presses the powder against the horn.
  • the punch pressure is very low (20-80 kg/cm 2 ) .
  • the ultrasonic wave is generated by a piezoelectric transducer and then passed through the horn (or booster) where the original amplitude of the wave is amplified.
  • the simultaneous action of pressure and ultrasounds shapes the tablet and activates the drug inside it.
  • a Teflon ® sheet avoids sticking of tablets on the horn , so tablets can be easily ejected.
  • the assay of the amount of drug sampled in the different parts (bottom, centre, periphery) of the matrix is determined by means of a HPLC method.
  • the sampling spots in the matrix are performed according to the scheme reported in Figure 3.
  • the amount of amorphous drug present in the different spots (bottom, centre, periphery) of the matrix is determined, as a complementary part of the crystalline form of the drug, by means of Differential Scanning Calorimetry (DSC).
  • the fraction of crystalline form is determined by comparing the enthalpy relative to the melting of the crystals in the polymer ( ⁇ H me ⁇ ting) to that of pure drug ( ⁇ H 0 ).
  • the ⁇ Hmeiting/ ⁇ Ho ratio normalized in accordance with the drug assayed in the polymer, is then considered equal to the fraction of crystalline form.
  • the amount of amorphous form is then:
  • Compaction device Die chamber Stainless steel Punch: Delrin ®
  • Compaction device Die chamber stainless steel internally coated with Teflon 1
  • Punch stainless steel internally coated with Teflon ®
  • the illustrative examples show an increase of homogeneity of the distribution of the amorphous form (complementary to crystalline form) in the matrices compressed in the coupled plastic-metal parts of the compaction device.
  • the standard deviation values of the crystallinity are much lower in samples compressed in devices made of coupled plastic and metal parts (examples B) compared to those of samples compressed either in metal (reference examples A) or in plastic (reference example C) parts.

Abstract

L'invention concerne un dispositif de compactage assisté par ultrasons destiné au compactage d'un mélange pulvérulent, se caractérisant par le fait que la matrice et le poinçon du dispositif sont fabriqués à partir d'un matériau différent, du plastique ou du métal.
PCT/EP2004/052990 2003-11-18 2004-11-17 Procede de compactage assiste par ultrasons utilisant un dispositif de compactage a base de metal et de plastique WO2005049306A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IE2003/0861 2003-11-18
IE20030861 2003-11-18

Publications (1)

Publication Number Publication Date
WO2005049306A1 true WO2005049306A1 (fr) 2005-06-02

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WO (1) WO2005049306A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO337576B1 (no) * 2014-04-03 2016-05-09 Badger Explorer Asa Sonisk/ultrasonisk assistert fremgangsmåte for kompaktering og injeksjon av granulære oppslemminger og masser i undergrunnen

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB821282A (en) * 1956-03-26 1959-10-07 Production Tool Alloy Company Improvements in or relating to the production of shaped articles from powders
JPS5722899A (en) * 1980-07-14 1982-02-05 Inoue Japax Res Inc Magnetic field pressing apparatus
JPS63275511A (ja) * 1987-05-07 1988-11-14 Kobayashi Kooc:Kk 粉体化粧料の成型法
JPH01151507A (ja) * 1987-12-09 1989-06-14 Erusoru Prod Kk 粉状化粧料の圧縮成形方法
US5662935A (en) * 1992-12-23 1997-09-02 Saitec S.R.L. Process for preparing controlled release pharmaceutical forms and the forms thus obtained
WO2001021388A1 (fr) * 1999-09-21 2001-03-29 Medsym Ärtzeservice-Informations-Und Veranstaltungsdienst Gmbh Procede de production d'un medicament
DE10030518C1 (de) * 2000-06-21 2001-11-29 Peter Goericke Preßwerkzeug und Verfahren zur Herstellung eines Preßwerkzeugs

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB821282A (en) * 1956-03-26 1959-10-07 Production Tool Alloy Company Improvements in or relating to the production of shaped articles from powders
JPS5722899A (en) * 1980-07-14 1982-02-05 Inoue Japax Res Inc Magnetic field pressing apparatus
JPS63275511A (ja) * 1987-05-07 1988-11-14 Kobayashi Kooc:Kk 粉体化粧料の成型法
JPH01151507A (ja) * 1987-12-09 1989-06-14 Erusoru Prod Kk 粉状化粧料の圧縮成形方法
US5662935A (en) * 1992-12-23 1997-09-02 Saitec S.R.L. Process for preparing controlled release pharmaceutical forms and the forms thus obtained
WO2001021388A1 (fr) * 1999-09-21 2001-03-29 Medsym Ärtzeservice-Informations-Und Veranstaltungsdienst Gmbh Procede de production d'un medicament
DE10030518C1 (de) * 2000-06-21 2001-11-29 Peter Goericke Preßwerkzeug und Verfahren zur Herstellung eines Preßwerkzeugs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 006, no. 086 (M - 131) 25 May 1982 (1982-05-25) *
PATENT ABSTRACTS OF JAPAN vol. 013, no. 095 (C - 573) 6 March 1989 (1989-03-06) *
PATENT ABSTRACTS OF JAPAN vol. 013, no. 414 (C - 635) 13 September 1989 (1989-09-13) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO337576B1 (no) * 2014-04-03 2016-05-09 Badger Explorer Asa Sonisk/ultrasonisk assistert fremgangsmåte for kompaktering og injeksjon av granulære oppslemminger og masser i undergrunnen

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