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US20090311414A1 - Process for producing a solid dispersion of an active ingredient - Google Patents

Process for producing a solid dispersion of an active ingredient Download PDF

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Publication number
US20090311414A1
US20090311414A1 US12/279,415 US27941507A US2009311414A1 US 20090311414 A1 US20090311414 A1 US 20090311414A1 US 27941507 A US27941507 A US 27941507A US 2009311414 A1 US2009311414 A1 US 2009311414A1
Authority
US
United States
Prior art keywords
extruder
mixing
section
screw
active ingredient
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.)
Abandoned
Application number
US12/279,415
Other languages
English (en)
Inventor
Thomas Kessler
Jörg Breitenbach
Christoph Schmidt
Matthias Degenhardt
Jörg Rosenberg
Harald Krull
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.)
AbbVie Deutschland GmbH and Co KG
Original Assignee
Abbott GmbH and Co KG
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36754000&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20090311414(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Abbott GmbH and Co KG filed Critical Abbott GmbH and Co KG
Priority to US12/279,415 priority Critical patent/US20090311414A1/en
Assigned to ABBOTT GMBH & CO. KG reassignment ABBOTT GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KRULL, HARALD, DEGENHARDT, MATTHIAS, BREITENBACH, JORG, KESSLER, THOMAS, ROSENBERG, JORG, SCHMIDT, CHRISTOPH
Publication of US20090311414A1 publication Critical patent/US20090311414A1/en
Assigned to ABBVIE DEUTSCHLAND GMBH & CO KG reassignment ABBVIE DEUTSCHLAND GMBH & CO KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABBOTT GMBH & CO KG
Abandoned legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/03—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor characterised by the shape of the extruded material at extrusion
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
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    • B29C48/285—Feeding the extrusion material to the extruder
    • B29C48/288—Feeding the extrusion material to the extruder in solid form, e.g. powder or granules
    • B29C48/2886—Feeding the extrusion material to the extruder in solid form, e.g. powder or granules of fillers or of fibrous materials, e.g. short-fibre reinforcements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29C48/29—Feeding the extrusion material to the extruder in liquid form
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    • B29C48/395—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders
    • B29C48/40—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders using two or more parallel screws or at least two parallel non-intermeshing screws, e.g. twin screw extruders
    • B29C48/404—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders using two or more parallel screws or at least two parallel non-intermeshing screws, e.g. twin screw extruders the screws having non-intermeshing parts
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B29C48/25—Component parts, details or accessories; Auxiliary operations
    • B29C48/36—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die
    • B29C48/50—Details of extruders
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B29C48/78—Thermal treatment of the extrusion moulding material or of preformed parts or layers, e.g. by heating or cooling
    • B29C48/80—Thermal treatment of the extrusion moulding material or of preformed parts or layers, e.g. by heating or cooling at the plasticising zone, e.g. by heating cylinders
    • B29C48/83—Heating or cooling the cylinders
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29C48/25—Component parts, details or accessories; Auxiliary operations
    • B29C48/88—Thermal treatment of the stream of extruded material, e.g. cooling
    • B29C48/90—Thermal treatment of the stream of extruded material, e.g. cooling with calibration or sizing, i.e. combined with fixing or setting of the final dimensions of the extruded article
    • B29C48/906—Thermal treatment of the stream of extruded material, e.g. cooling with calibration or sizing, i.e. combined with fixing or setting of the final dimensions of the extruded article using roller calibration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
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    • B29C48/88—Thermal treatment of the stream of extruded material, e.g. cooling
    • B29C48/911—Cooling
    • B29C48/9135—Cooling of flat articles, e.g. using specially adapted supporting means
    • B29C48/914—Cooling drums
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
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    • B29K2105/0035—Medical or pharmaceutical agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0005—Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
    • B29K2105/0038—Plasticisers
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0058—Liquid or visquous
    • B29K2105/0064—Latex, emulsion or dispersion
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/06—Condition, form or state of moulded material or of the material to be shaped containing reinforcements, fillers or inserts
    • B29K2105/16—Fillers

Definitions

  • the present invention relates to a process for producing a solid dispersion of an active ingredient which comprises feeding the active ingredient and a matrix-forming agent to an extruder and forming a uniform extrudate.
  • a continuous process for producing solid pharmaceutical forms, including solid solution products, has been known for some time and entails converting a melt of polymeric binder which contains active ingredients into the required drug form by injection molding or extrusion and subsequent shaping (see, for example, EP-A-240 904, EP-A-240 906 and EP-A-337 256). Satisfactory results are obtained in this process when the active ingredient has a low melting point and/or a high solubility in the molten polymeric binder. Active ingredients having a low melting point are liquefied upon contact with the polymeric binder melt, and the liquefied active ingredient can be readily dispersed in the polymeric binder melt. Alternatively, active ingredients having a high solubility in the molten polymeric binder readily dissolve in the polymeric binder melt.
  • EP 0 580 860 B2 describes a process for producing a solid dispersion of a drug dissolved in a polymer, wherein a twin-screw extruder equipped with paddle means or kneading blocks is employed.
  • kneading blocks consist of, e.g. disk cams disposed offset in the manner of a spiral staircase. The substance is pressed through a narrow tapered gap between the disk cams and the extruder housing. During the passage through the extruder, the material is thus subjected to high local shear forces, which may lead to excessive degradation of the active ingredient and/or the polymer. Shearing may also cause excessive wear of the extrusion equipment.
  • the present invention provides a process for producing a solid dispersion of an active ingredient which comprises feeding the active ingredient and a matrix-forming agent to an extruder and forming a uniform extrudate.
  • the extruder comprises at least two rotating shafts, each of the shafts carrying a plurality of processing elements disposed axially one behind the other.
  • the processing elements define (i) a feeding and conveying section, (ii) at least one mixing section, and (iii) a discharging section.
  • the feeding and conveying section is positioned farthest upstream, close to the hopper of the extruder, the at least one mixing section is positioned downstream of the feeding and conveying section, and the discharging section is positioned farthest downstream, close to the discharge opening of the extruder.
  • downstream refers to direction in which the material is being conveyed in the extruder.
  • the processing elements may be formed separately. They may be strung, one behind the other, along the shaft of the extruder. However, it may also be possible that the processing elements are formed integrally. In this case, the surface structure of the element forms said processing elements.
  • the processing element(s) defining the mixing section comprise(s) a mixing element that is derived from a screw type element.
  • a mixing element “being derived from a screw type element” is intended to mean an element whose basic shape is that of a screw element, but which has been modified such that it exerts a compounding or mixing effect in addition to a conveying effect.
  • the underlying screw type element is a positive-feed (or “right-handed”) screw element. It is believed that the mode of mixing exerted by the inventive mixing elements is predominantly distributive rather than dispersive mixing.
  • paddle means or kneading blocks have conventionally been employed in kneading and plasticizing pharmaceutical mixtures.
  • These kneading blocks consist of cam disks mutually offset at an angle in a peripheral direction.
  • the cam disks have abutting faces that are perpendicular to the general conveying direction in the extruder.
  • these kneading blocks provide effective kneading and homogenization, high local shear occurs at the edges of the cam disks. This local shear is believed to be detrimental to the active ingredient or other components.
  • Preferred mixing elements do not have a plane surface area with a normal parallel and opposite to the general conveying direction.
  • the mixing elements may have no face that is perpendicular to the general conveying direction.
  • the mixing elements used in accordance with the invention do not have abutting faces that are perpendicular to the general conveying direction.
  • the mixing element used in accordance with the invention has recesses formed in the screw flight of a screw type element.
  • Mixing elements of this type are known as such and, for example, described in WO 2004/009326 A1, U.S. Pat. No. 5,318,358 and U.S. Pat. No. 6,106,142.
  • a preferred mixing element has a plurality of concentric ring portions formed by grooves turned into a screw type element. Therefore, the mixing element has a continuous screw flight, which is interrupted only by turned grooves with ring portions.
  • these mixing elements enable a sufficient degree of mixing or homogenization with less degradation of the active ingredient or formation of other ingredients, compared to a conventional process employing paddle means or kneading blocks. Furthermore, a lower temperature of the barrel of the extruder may be chosen while still obtaining an extrudate of the same quality. Additionally, it has been found, surprisingly, that the inventive mixing elements provide a better self-cleaning effect. This self-cleaning effect prevents that residues of the extruded material remain within the extruder over extended periods of time.
  • the extruder comprises at least two axis-parallel shafts and, in preferred embodiments, is a twin-screw extruder.
  • the shafts may be co-rotating or counter-rotating, but are preferably co-rotating.
  • the extruder may comprise more than two and, e.g., up to six shafts. Processing elements disposed on adjacent shafts closely intermesh.
  • the feeding and conveying section as well as the discharging section allow for a smooth passage of the material fed to the extruder from the feed end to the discharge end of the extruder.
  • the processing elements employed in the feeding and conveying section or the discharging section are typically in the form of an endless screw element, i.e. an element characterized by an essentially continuous screw flight.
  • the processing elements additionally comprise at least one backpressure element.
  • the backpressure element is positioned downstream of the mixing section.
  • Backpressure elements serve to create sufficient back-pressure to allow for a desired degree of mixing and/or homogenization.
  • the backpressure elements are designed to stow the material conveyed in the extruder. They may be derived from a screw type element having a reduced pitch flight, relative to the conveying elements. Alternatively, they may be derived from a reverse-flight screw, such that they convey the material in an opposite direction relative to the general conveying direction of the extruder.
  • the backpressure element may be formed separately from the mixing element or integrally with the mixing element.
  • the processing elements define
  • the processing elements additionally comprise a backpressure element positioned downstream of and adjacent to the second mixing section.
  • the length of the feeding and conveying section is suitably selected such that the material which is fed into the extruder has undergone significant softening or is nearly melting when the material enters the (first) mixing section.
  • the feeding and conveying section corresponds to from about 20 to about 40% of the entire length of the shaft.
  • the discharging section corresponds to from about 15 to about 30% of the entire length of the shaft.
  • a twin-screw extruder is used. It has at least two parallel co-rotating shafts. In the mixing section or in the mixing sections the shafts are equipped with intermeshing mixing elements. The face of the mixing elements is limited by circular arcs corresponding to the outside screw diameter, the screw core diameter and at most the centre distance of the mixing elements. The shafts are guided on circular segments of the extruder housing that are parallel to the shafts.
  • the mixing element comprises screw portions between the ring portions which first cause a pressure buildup that forces the substance through the annular gap between the extruder housing and the ring portions with shearing action and elongation; the pressure is then reduced again.
  • the recurring sequence of shear gap passage, pressure buildup, shear gap passage, etc., on the mixing elements causes a defined stress on the substance and thus a uniform stress, without unduly stressing in particular the active ingredient.
  • the screw portions between the ring portions of a mixing element may have the same pitch flight. However, the pitch flight of these screw portions may also be different. According to an advantageous embodiment of the present invention, the screw portions of at least one mixing element on each shaft have partly a positive screw flight and partly a reverse-screw flight.
  • the annular and/or shear gap between the ring portions and the concave circular segments of the extruder housing can have a different height to produce a sufficient mixing effect for the active ingredient in the matrix-forming agent.
  • the ring portion might correspond only to the core diameter of the screw shaft.
  • the annular gap may also have a height of from 10 percent to 90 percent of the flight depth of the screw.
  • the diameter of the ring portions may correspond approximately to the center distance of two adjacent shafts.
  • the screw portions located between two adjacent ring portions generally have a length of at least 1/10, preferably at least 1 ⁇ 5, of the screw diameter.
  • the turned grooves of the ring portions preferably have a depth of, for example, 1 ⁇ 2 or less of the flight depth.
  • the angle of the flanks of the turned grooves can be, for example, 30 to 90 degrees.
  • oblique grooves are turned, in particular at an angle of about 60 degrees, to the shaft axis.
  • the mixing element can be provided with further portions.
  • a mixing section with substantially neutral conveying action can be provided by stock removal.
  • the screw flight can continue at the same pitch angle. That is, the screw portions of the mixing element can form a continuous screw flight apart from the turned interruptions in the area of the ring portions.
  • the ring portions permit additional dispersing surfaces to be gained.
  • a substantial enlargement of the dispersing surface can moreover be obtained if the screw portions between the ring portions are disposed at a progressive angular offset from each other with the same direction of rotation, for example, at an angular offset by half the flight angle.
  • the angularly offset screw portions form faces angularly offset in step-like fashion as additional dispersing surfaces.
  • FIGS. 2 and 5 of WO 2004/009326 A1 show preferred mixing elements used in accordance with the invention. Further examples are described below with reference to the accompanied drawings.
  • the solid dispersions manufactured by the process of the present invention contain one or more active ingredient and, optionally, additives. Additives may be used to impart desirable properties to the solid dispersions or to facilitate the manufacture thereof. Although the actives and additives may be incorporated into the extruded mixture at any appropriate stage of the process, it may be preferred to introduce a part or all of the active ingredients or additives into the extruder separately from the matrix-forming agent and/or other components.
  • At least part of the matrix-forming agent is fed to the hopper of the extruder and at least one component selected from
  • the at least one component is introduced into the extruder at a position at or close to the junction of the feeding and conveying section and a mixing section.
  • the component may be solid, e.g. powdered, but preferably is liquid or liquefied.
  • the at least one component comprises a pharmaceutically acceptable surfactant.
  • Melting means transition into a liquid or rubbery state in which it is possible for one component to be homogeneously embedded in the other. Melting usually involves heating above the softening point of the polymer. Usually, the maximum melt temperature is in the range of 70 to 250° C., preferably 80 to 180° C., most preferably 100 to 140° C.
  • the extruder housing is heated in order to form a melt from the substances fed to the extruder. It will be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used. A part of the energy needed to melt, mix and dissolve the components in the extruder can be provided by heating elements, while the friction and shearing of the material in the extruder can also provide the mixture with a substantial amount of energy and aid in the formation of a homogeneous melt of the components.
  • the active ingredient-containing melt is kept in the heated barrel of the melt extruder for a sufficient length of time.
  • the extruder barrel comprises several heating zones.
  • the portion of the barrel upstream of the first mixing element is maintained at a lower temperature than the portion of the barrel downstream of the first mixing element. It has been found that this temperature distribution leads to a homogeneous, smooth and transparent extrudate which, in particular, has not been damaged by temperatures too high for the active ingredient.
  • one or more active ingredients are dispersed evenly throughout the polymer. This encompasses systems having small particles, typically of less than 1 ⁇ m in diameter, of active ingredient in the polymer phase. These systems do not contain any significant amounts of active ingredients in their crystalline or microcrystalline state, as evidenced by thermal analysis (DSC) or X-ray diffraction analysis (WAXS). Typically, at least 98% by weight of the total amount of active ingredients is present in an amorphous state.
  • Solid solutions of active ingredients are preferred physical systems.
  • the polymer does not contain significant amounts of volatile solvents.
  • volatile solvent is intended to encompass water and any compound that is liquid at ambient temperature and has a higher volatility than water.
  • the matrix contains less than 25%, preferably less than 6%, and most preferably less than 3% by weight of a volatile solvent.
  • Preferred extrudates formed by the process according to the invention comprise:
  • the matrix-forming agent may be any agent capable of setting or gelling from a liquified state, e.g. from a molten state, to form a continuous matrix. Mixtures of matrix-forming agents can, of course, be used.
  • Useful matrix-forming agents are selected from polyols (i.e. sugar alcohols, sugar alcohol derivatives, or maltodextrines), waxes and lipids.
  • Suitable sugar alcohols include mannitol, sorbitol, xylitol; sugar alcohol derivatives include isomalt, or hydrogenated condensed palatinose (as described in DE-A 10262005); further matrix-forming agents are maltodextrines.
  • the matrix-forming agent includes a pharmaceutically acceptable polymer or a mixture of pharmaceutically acceptable polymers.
  • pharmaceutically acceptable polymers are water-soluble or at least water-dispersible.
  • the pharmaceutically acceptable polymer employed in the invention has a Tg of at least about +10° C., preferably at least about +25° C., most preferably from about 40° to 180° C.
  • Tg means glass transition temperature.
  • Methods for determining the Tg values of organic polymers are described in “Introduction to Physical Polymer Science”, 2nd Edition by L. H. Sperling, published by John Wiley & Sons, Inc., 1992.
  • the Tg value can be calculated as the weighted sum of the Tg values for homopolymers derived from each of the individual monomers i that make up the polymer, i.e.
  • Tg ⁇ W i X i
  • W is the weight percent of monomer i in the organic polymer
  • X is the Tg value for the homopolymer derived from monomer i.
  • Tg values for the homopolymers are indicated in “Polymer Handbook”, 2nd Edition by J. Brandrup and E. H. Immergut, Editors, published by John Wiley & Sons, Inc., 1975.
  • compositions having a Tg as defined above allow the preparation of solid dispersions that are mechanically stable and, within ordinary temperature ranges, sufficiently temperature stable so that said solid dispersions may be used as dosage forms without further processing or can be compacted to tablets with only a small amount of tabletting aids.
  • Dosage forms are, e.g., tablets, capsules, implants, films, foams, suppositories.
  • the pharmaceutically acceptable polymer comprised in the composition is a polymer that, when dissolved at 20° C. in an aqueous solution at 2% (w/v), preferably has an apparent viscosity of 1 to 50 000 mPa ⁇ s, more preferably of 1 to 10 000 mPa ⁇ s, and most preferably of 5 to 100 mPa ⁇ s.
  • preferred pharmaceutically acceptable polymers can be selected from the group comprising:
  • N-vinyl lactams especially polyvinylpyrrolidone (PVP), copolymers of a N-vinyl lactam and one or more comonomers copolymerizable therewith, the comonomers being selected from nitrogen-containing monomers and oxygen-containing monomers; especially a copolymer of N-vinyl pyrrolidone and a vinyl carboxylate, preferred examples being a copolymer of N-vinyl pyrrolidone and vinyl acetate or a copolymer of N-vinyl pyrrolidone and vinyl propionate; cellulose esters and cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkyl-alkylcelluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate
  • homopolymers or copolymers of N-vinyl pyrrolidone in particular a copolymer of N-vinyl pyrrolidone and vinyl acetate, are preferred.
  • a particularly preferred polymer is a copolymer of 60% by weight of the copolymer N-vinyl pyrrolidone and 40% by weight of the copolymer vinyl acetate.
  • Hydroxypropylcellulose is another example of a particularly preferred polymer.
  • Active ingredients used in the process according to the present invention are biologically active agents and include those which exert a local physiological effect, as well as those which exert a systemic effect, after oral administration.
  • the invention is particularly useful for water-insoluble or poorly water-soluble (or “lipophilic”) compounds.
  • Compounds are considered water-insoluble or poorly water-soluble when their solubility in water at 25° C. is less than 1 g/100 ml.
  • suitable active substances include, but are not limited to:
  • analgesic and anti-inflammatory drugs such as fentanyl, indomethacin, ibuprofen, naproxene, diclofenac, diclofenac sodium, fenoprofen, acetylsalicylic acid, ketoprofen, nabumetone, paracetamol, piroxicam, meloxicam, tramadol, and COX-2 inhibitors such as celecoxib and rofecoxib; anti-arrhythmic drugs such as procainamide, quinidine and verapamil; antibacterial and antiprotozoal agents such as amoxicillin, ampicillin, benzathine penicillin, benzylpenicillin, cefaclor, cefadroxil, cefprozil, cefuroxime axetil, cephalexin, chloramphenicol, chloroquine, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, doxyxyc
  • cyclophosphamide chlorambucil, chiormethine, iphosphamide, melphalan, or the nitrosoureas, e.g. carmustine, lomustine, or other alkylating agents, e.g.
  • busulphan dacarbazine, procarbazine, thiotepa; antibiotics such as daunorubicin, doxorubicin, idarubicin, epirubicin, bleomycin, dactinomycin and mitomycin; HER 2 antibodies such as trastuzumab; podophyllotoxin derivatives such as etoposide and teniposide; farnesyl transferase inhibitors; anthrachinon derivatives such as mitoxantron; anti-migraine drugs such as alniditan, naratriptan and sumatriptan; anti-Parkinsonian drugs such as bromocryptine mesylate, levodopa and selegiline; antipsychotic, hypnotic and sedating agents such as alprazolam, buspirone, chlordiazepoxide, chlorpromazine, clozapine, diazepam, flupenthixol, fluphenazine, flu
  • Pharmaceutically acceptable acid addition salts comprise the acid addition salt forms which can be obtained conveniently by treating the base form of the active ingredient with appropriate organic and anorganic acids.
  • Active ingredients containing an acidic proton may be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • addition salt also comprises the hydrates and solvent addition forms which the active ingredients are able to form. Examples of such forms are hydrates, alcoholates and the like.
  • the N-oxide forms of the active ingredients comprise those active ingredients in which one or several nitrogen atoms are oxidized to the so-called N-oxide.
  • stereochemically isomeric forms defines all possible stereoisomeric forms which the active ingredients may possess.
  • stereogenic centers may have the R- or S-configuration and active ingredients containing one or more double bonds may have the E- or Z-configuration.
  • pharmaceutically acceptable surfactant refers to a pharmaceutically acceptable ionic or non-ionic surfactant. Incorporation of surfactants is especially preferred for matrices containing poorly water-soluble active ingredients.
  • the surfactant may effectuate an instantaneous emulsification of the active ingredient released from the dosage form and/or prevent precipitation of the active ingredient in the aqueous fluids of the gastrointestinal tract.
  • Preferred surfactants are selected from:
  • polyoxyethylene alkyl ethers e.g. polyoxyethylene ( 3 ) lauryl ether, polyoxyethylene ( 5 ) cetyl ether, polyoxyethylene ( 2 ) stearyl ether, polyoxyethylene ( 5 ) stearyl ether; polyoxyethylene alkylaryl ethers, e.g. polyoxyethylene ( 2 ) nonylphenyl ether, polyoxyethylene ( 3 ) nonylphenyl ether, polyoxyethylene ( 4 ) nonylphenyl ether or polyoxyethylene ( 3 ) octylphenyl ether; polyethylene glycol fatty acid esters, e.g.
  • PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate or PEG-300 dioleate alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); sucrose fatty acid esters, e.g.
  • sucrose monostearate sucrose distearate, sucrose monolaurate or sucrose dilaurate
  • sorbitan fatty acid mono esters such as sorbitan mono laurate (Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span® 40), or sorbitan stearate
  • polyoxyethylene castor oil derivates e.g.
  • polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40; BASF Corp.) or polyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60; BASF Corp.); or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, or Poloxamer® 407 (BASF Corp.); or mono fatty acid esters of polyoxyethylene ( 20 ) sorbitan, e.g.
  • additives may be included in the melt, for example flow regulators such as colloidal silica; lubricants, fillers, disintegrants, or plasticizers, stabilizers or preservatives.
  • additives for example dyes such as azo dyes, organic or inorganic pigments such as iron oxides or titanium dioxide, or dyes of natural origin; stabilizers such as antioxidants, light stabilizers, radical scavengers and stabilizers against microbial attack.
  • dyes such as azo dyes, organic or inorganic pigments such as iron oxides or titanium dioxide, or dyes of natural origin
  • stabilizers such as antioxidants, light stabilizers, radical scavengers and stabilizers against microbial attack.
  • additives may be incorporated into the mixture of active ingredient and polymer at any appropriate stage of the process. For ease of handling it is, however, convenient to include such additives in a powdery mixture of the matrix-forming agent and the active ingredient that is being fed into the extruder.
  • the extrudate exiting from the extruder ranges from pasty to viscous.
  • the extrudate Before allowing the extrudate to solidify, the extrudate may be directly shaped into virtually any desired shape. Shaping of the extrudate may be conveniently carried out by a calender with two counter-rotating rollers with mutually matching depressions on their surface. A broad range of tablet forms can be attained by using rollers with different forms of depressions. If the rollers do not have depressions on their surface, films can be obtained.
  • the extrudate is moulded into the desired shape by injection-moulding.
  • the extrudate is subjected to profile extrusion and cut into pieces, either before (hot-cut) or after solidification (cold-cut).
  • foams can be formed if the extrudate contains a propellant such as a gas, e.g. carbon dioxide, or a volatile compound, e.g. a low molecular weight hydrocarbon, or a compound that is thermally decomposable to a gas.
  • a propellant such as a gas, e.g. carbon dioxide, or a volatile compound, e.g. a low molecular weight hydrocarbon, or a compound that is thermally decomposable to a gas.
  • the propellant is dissolved in the extrudate under the relatively high pressure conditions within the extruder and, when the extrudate emerges from the extruder die, the pressure is suddenly released. Thus the solvability of the propellant is decreased and/or the propellant vaporises so that a foam is formed.
  • the resulting solid dispersion product is milled or ground to granules.
  • the granules may then be compacted.
  • Compacting means a process whereby a powder mass comprising the granules is condensed under high pressure in order to obtain a compact with low porosity, e.g. a tablet. Compression of the powder mass is usually done in a tablet press, more specifically in a steel die between two moving punches.
  • At least one additive selected from flow regulators, disintegrants, bulking agents (fillers) and lubricants is used in compacting the granules.
  • Disintegrants promote a rapid disintegration of the compact in the stomach and keep the granules which are liberated separate from one another.
  • Suitable disintegrants are crosslinked polymers such as crosslinked polyvinyl pyrrolidone and crosslinked sodium carboxymethylcellulose.
  • Suitable bulking agents also referred to as “fillers” are selected from lactose, calcium hydrogenphosphate, microcrystalline cellulose (Avicel®), silicates, in particular silicium dioxide, talc, potato or corn starch, and isomalt.
  • Suitable flow regulators are selected from highly dispersed silica (Aerosil®), and animal or vegetable fats or waxes.
  • a lubricant is preferably used in compacting the granules.
  • Suitable lubricants are selected from polyethylene glycol (e.g., having a Mw of from 1000 to 6000), magnesium and calcium stearates, sodium stearyl fumarate, and the like.
  • FIG. 1 shows schematically a sectional view of the extruder comprising screws comprising paddle means or kneading blocks that was used for the comparative examples;
  • FIG. 2 shows schematically a sectional view of the extruder that was used for the examples in accordance with the process according to the present invention
  • FIG. 3 A and FIG. 3 B show one preferred embodiment of a mixing element in accordance with the present invention
  • FIG. 4 A and FIG. 4 B show another preferred embodiment of a mixing element in accordance with the present invention.
  • FIG. 5 A and FIG. 5 B show another preferred embodiment of a mixing element in accordance with the present invention.
  • FIGS. 1 and 2 are generally similar, the general arrangement of the extruder is described with reference to FIG. 2 .
  • the extruder is known per se. It has been used for producing a solid dispersion of an active ingredient in a matrix-forming agent.
  • the extruder comprises a housing or barrel 1 divided into several sections in a longitudinal direction.
  • an opening 8 is provided for feeding a powder P of the active ingredient and the matrix-forming agent.
  • a hopper is placed on this opening so that the powder P can be easily fed into the barrel 1 of the extruder.
  • a further opening 9 for dosing a further component L, such as a surfactant is provided in conveying direction X of the extruder.
  • the surfactant is pumped in liquid or liquefied form or dosed in solid form to the inside of barrel 1 .
  • another opening 10 is provided for sucking gas G from the inside of the barrel 1 to the outside of the barrel 1 .
  • the barrel 1 ends in conveying direction X in a die, where the dispersion is expelled.
  • the barrel 1 of the extruder is divided into three heating zones H 1 , H 2 and H 3 .
  • the temperature of the barrel 1 in these heating zones H 1 , H 2 and H 3 can be controlled in order to control the melting of the dispersion of the active ingredient and the matrix-forming agent.
  • two parallel shafts 2 are arranged, one of which is shown in the sectional views of FIGS. 1 and 2 .
  • the shafts 2 are co-rotating.
  • the shafts 2 are equipped with processing elements disposed axially one behind the other.
  • the processing elements are arranged within the extruder barrel 1 so that the radially outermost portions of the processing elements are adjacent to the inner wall of the barrel 1 . Only a very small gap is formed between the outermost portions of the processing element and the inner wall of the barrel 1 .
  • FIGS. 1 and 2 are only schematic representations to show the different zones of the extruder in a longitudinal direction, the shafts 2 with the processing elements and the extruder barrel 1 are shown apart from one another.
  • the shaft 2 with the processing elements is divided in several sections.
  • the section furthermost upstream is a feeding and conveying section A.
  • the upstream side of this section A is adjacent to opening 8 for feeding powder P into the barrel 1 .
  • the opening 9 of the barrel 1 is provided for feeding a surfactant to the inside of the barrel 1 .
  • the processing elements of the feeding and conveying section A are formed by screw-type elements 3 , which form an endless screw having the feed direction X and a uniform pitch flight. Therefore, in section A, the powder P is fed into the extruder 1 and conveyed in the downstream direction X.
  • the heating zones H 1 and H 2 of the extruder 1 are controlled so that the substances within the barrel 1 start to melt at the end of the feeding and conveying section A.
  • a mixing section B Downstream from section A, a mixing section B is arranged downstream from section A. It has been found that the selection of the processing elements in mixing section B is an essential factor for the subsequent quality of the extrudate.
  • the extruder of FIG. 1 showing a conventional arrangement, differs from the extruder of FIG. 2 , which was used in the process of the present invention.
  • the shaft 2 is equipped with so-called paddle means or kneading blocks 4 , which consist of disk cams.
  • the shaft 2 is equipped with a particular mixing element 11 which is described in greater detail below with reference to FIGS. 3 to 5 .
  • intermediate conveying section C On the downstream side of mixing section B, an intermediate conveying section C is formed.
  • the processing elements of intermediate section C are the same screw-type elements 3 used in the feeding and conveying section A. Therefore, intermediate conveying section C only conveys the melt from mixing section B to the next section.
  • a second mixing section D Downstream of the intermediate conveying section C, a second mixing section D is arranged downstream of the intermediate conveying section C.
  • the processing elements used in this second mixing section D of the conventional extruder, shown in FIG. 1 again differ from the processing element used in the extruder in accordance with the present invention, which is shown in FIG. 2 .
  • Intermediate conveying section C and second mixing section D are optional.
  • the shaft 2 is equipped with paddle means or kneading blocks 5 and 6 .
  • a backpressure element 7 is positioned on the downstream side of kneading block 6 .
  • the backpressure element 7 serves to create sufficient back-pressure to allow for a desired degree of mixing and/or homogenization. It accumulates the material into mixing sections B and D.
  • the backpressure element 7 is derived from a screw-type element having a reverse-pitch flight, such that it conveys the melt in an opposite direction relative to the general conveying direction X of the extruder.
  • the backpressure element 7 used in the conventional extruder shown in FIG. 1 corresponds to the backpressure element 14 used in the extruder according to the present invention as shown in FIG. 2 ,
  • the use of such a backpressure element 7 in connection with the arrangement of the extruder shown in FIG. 1 is not known per se.
  • the backpressure element 7 has been used in the conventional extruder so that the results of the process in which the conventional extruder has been used are comparable to the results of the process in which the extruder in accordance with the present invention has been used.
  • the shaft is equipped with particular mixing elements 12 , 13 , which are again described in greater detail below with reference to FIGS. 3 to 5 .
  • Mixing elements 12 , 13 may be identical to mixing element 11 of the first mixing section B. However, in the embodiment shown in FIG. 2 , the mixing element is divided into portions 12 and 13 , portion 12 having a positive feeding direction and portion 13 having a negative feeding direction or a reverse flight.
  • a backpressure element 14 is arranged, which corresponds to the backpressure element 7 described above.
  • the length of kneading blocks 4 corresponds to the length of the mixing element 11 and the length of kneading blocks 5 , 6 corresponds to the length of mixing elements 12 , 13 .
  • a discharging section E Downstream from the second mixing section D, a discharging section E is arranged.
  • the shaft 2 of the extruder according to the present invention as well as the shaft 2 of the conventional extruder is equipped with screw-type elements 3 , which are identical to the elements used in sections A and C.
  • discharging section E the melt is only fed to the die of the extruder.
  • a polymer and the matrix-forming agent are fed to the inside of barrel 1 of the extruder through opening 8 .
  • the matrix-forming agent and the active ingredient are conveyed by screw elements 3 to mixing element 11 .
  • Heating zones H 1 and H 2 are heated to a temperature so that the polymer and the matrix-forming agent start to melt just before mixing element 11 .
  • surfactants are fed through opening 9 to the inside of the barrel 1 .
  • the melt then passes mixing element 11 and is conveyed by screw elements 3 of the intermediate conveying section C to the second mixing section D comprising mixing elements 12 , 13 and thereafter backpressure element 14 .
  • the main mixing and melting effect is performed.
  • the uniform extrudate is conveyed by screw elements 3 of discharging section E to the die of the extruder.
  • mixing elements that may be used in mixing sections B and D are described with reference to FIGS. 3 to 5 .
  • the mixing elements 15 , 20 , and 24 shown in FIGS. 3 to 5 and which may be used as mixing elements 11 to 13 on the two shafts 2 have a transverse profile 23 composed of three circular arcs.
  • One circular arc has a diameter corresponding to the diameter of the outer screw
  • another circular arc has a diameter corresponding to the diameter of the screw core
  • a further circular arc has a diameter whose radius corresponds to the center distance of the two elements of the mixing element (cf. EP-B-0002 131).
  • the mixing elements 15 , 20 , and 24 comprise a bore 22 having projections for engagement with grooves of the shaft 2 so that the mixing elements 15 , 20 , and 24 can be rotated together with the shaft 2 .
  • the mixing element 15 has five ring portions 16 that are concentric with the shaft axis and disposed a distance apart from another.
  • the ring portions 16 are obtained by grooves turned into the mixing element 15 .
  • the angle of the flanks 18 of the grooves to the shaft axis is about 60 degrees.
  • the height of the annular gaps 19 between the ring portions 16 and the inner wall of the extruder barrel 1 is about the flight depth, i.e. the difference between the core diameter and the outside screw diameter.
  • the diameter of the ring portions 8 thus corresponds to the core diameter of the screw.
  • a continuous screw flight may be formed which is interrupted only by the turned grooves with ring portions 16 .
  • screw portions of the mixing element 15 between ring portions 16 may also be disposed at a progressive angular offset from each other with the same direction of rotation.
  • the screw sections 17 a , 17 b , 17 c , 17 d between the ring portion 16 of mixing element 15 in the embodiment shown in FIGS. 3A and 3B have the same screw pitch.
  • the mixing element 15 shown in FIGS. 3A and 3B may be used in particular as mixing element 11 in mixing section B as shown in FIG. 2 .
  • FIGS. 4A and 4B A further example of a mixing element 20 is shown in FIGS. 4A and 4B .
  • Mixing element 20 differs from mixing element 15 in screw sections 21 a , 21 b , 21 c , 21 d between ring portions 16 .
  • Screw sections 21 a and 21 b may correspond to 17 a and 17 b of mixing element 15 .
  • screw sections 21 c and 21 d of mixing element 20 differ from screw sections 17 c and 17 d of mixing element 15 .
  • screw sections 21 c and 21 d have a reverse-flight screw so that these sections 21 c and 21 d convey the melt in an opposite direction relative to the general conveying direction X of the extruder and the conveying direction of screw sections 21 a and 21 b.
  • Screw sections 21 a and 21 b may be formed integrally with screw sections 21 c and 21 d as shown in FIGS. 4A and 4B .
  • two mixing elements may also be provided, one comprising screw sections 21 a and 21 b and the other comprising screw sections 21 c and 21 d .
  • Mixing element 20 may correspond to mixing elements 12 , 13 of the second mixing section D shown in FIG. 2 .
  • FIGS. 5A and 5B A further example of a mixing element 24 is shown in FIGS. 5A and 5B .
  • the mixing element 24 is similar to mixing element 20 shown in FIGS. 4A and 4B .
  • Screw section 26 a and 26 b have a positive screw flight and screw section 26 c and 26 d have a negative screw flight or reverse-flight screw.
  • mixing element 24 differs from mixing elements 20 and 15 in the annular gap 27 between the ring portions 25 and the extruder barrel 1 .
  • the height of the annular gaps 27 is about half of the flight depth, i.e. half the difference between the core diameter and the outside screw diameter.
  • the diameter of the ring portions 8 thus corresponds approximately to the center distance of the two shafts from each other.
  • the larger diameter of ring portions 25 relative to the diameter of ring portions 16 of mixing elements 20 and 15 provides a barrier for the melt. It has been found that such a barrier is advantageous if the mixing element 24 is used as mixing elements 12 , 13 in the second mixing section D as shown in FIG. 2 .
  • the barrier provides a compacting zone within the extruder in which the pressure of the extrudate is raised on the substance supply side.
  • the following provides examples in which the same solid dispersion of an active ingredient in a polymer has been produced by, first, the extruder with the screw arrangement shown in FIG. 1 as a comparative example and, second, the extruder with the screw arrangement shown in FIG. 2 .
  • the active ingredients, the polymer and the glidant were thoroughly mixed and the resulting powder was fed into a twin-screw extruder (ZSK-40, manufactured by Werner & Pfleiderer, Germany).
  • the screw configuration comprised kneading blocks in addition to conveying elements and is shown in FIG. 1 .
  • the emulsifiers were fed into the extruder by means of a liquid dosing pump.
  • the emulsifiers were added at a position immediately before the material in the extruder reaches the first kneading block section.
  • the liquid emulsifiers were blended with the powder and the mixture was melted. Vacuum was applied to the mixture in the last third of the extruder.
  • the process parameters are detailed in Table 2. Subsequent to the extrusion step, the material was formed on a calendar and cooled to reveal a band of lentil-shaped extrudate.
  • Formulation 1 Feeding Rate Powder [g/h] 15.7 15.7 liquid [g/h] 1.0 1.36 Screw speed [rpm] 100 120 Vacuum [mbar] 350 200 Temperature barrel 1 [° C.] 20 20 barrel 2 + 3 [° C.] 80 80 barrel 4-6 [° C.] 100 100 die head [° C.] 125 125 die [° C.] 125 125 Torque 35 35 [% of engine power] Appearance of extrudate Smooth, transparent Smooth, transparent Temperature of extrudate 125 127-128 [° C.]
  • Example 1 was repeated. However, the screws were designed differently: instead of kneading blocks, it comprised mixing elements. The configuration of this screw is depicted in FIG. 2 . The kneading blocks in screw ZSK 40 - 54 ( FIG. 1 ) are replaced by mixing elements with both mixing zones being equivalent in length.
  • the process parameters are given in Table 4, the analytical results are given in Table 5.
  • Formulation 1 Feeding Rate Powder [g/h] 15.7 15.7 liquid [g/h] 1.0 1.36 Screw speed [rpm] 100 120 Vacuum [mbar] 350 200 Temperature barrel 1 [° C.] 20 20 barrel 2 + 3 [° C.] 80 80 barrel 4-6 [° C.] 100 100 die head [° C.] 125 125 die [° C.] 125 125 Torque 36 33 [% of engine power] Appearance of extrudate Smooth, transparent Smooth, transparent Temperature of extrudate 123-124 124 [° C.]

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