US20050058705A1 - Immediate release pharmaceutical granule compositions and a continuous process for making them - Google Patents

Immediate release pharmaceutical granule compositions and a continuous process for making them Download PDF

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US20050058705A1
US20050058705A1 US10/933,674 US93367404A US2005058705A1 US 20050058705 A1 US20050058705 A1 US 20050058705A1 US 93367404 A US93367404 A US 93367404A US 2005058705 A1 US2005058705 A1 US 2005058705A1
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drug
excipient
weight
immediate
composition
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Jean Remon
Chris Vervaet
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Universiteit Gent
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Assigned to UNIVERSITEIT GENT reassignment UNIVERSITEIT GENT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VERVAET, CHRIS, REMON, JEAN PAUL
Publication of US20050058705A1 publication Critical patent/US20050058705A1/en
Priority to US11/276,577 priority Critical patent/US20070009592A1/en
Priority to US12/815,715 priority patent/US8349366B2/en
Priority to US12/815,781 priority patent/US8337897B2/en
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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

Definitions

  • the present invention is in the field of drug delivery systems and immediate release technology.
  • the invention is in the field of immediate or fast release pharmaceutical solid, preferably granule, compositions. More specifically, the invention relates to such compositions with low to moderate and even high drug loading for immediate or fast release of drugs which have low or very low solubility in water.
  • the invention also relates to various solid pharmaceutical dosage forms such as sachets, gelules and tablets including such immediate or fast release pharmaceutical granule compositions. Still more specifically, the invention relates to immediate or fast release water-soluble granule veterinary compositions which can readily be administered to animals together with drinking water. Finally the invention relates to a continuous process for manufacturing said immediate or fast release pharmaceutical or veterinary granule compositions.
  • Tablets and capsules are generally unsuitable for administering high doses of biologically active ingredients since individual large dosage forms are difficult to swallow or necessitate the administration of several tablets or capsules at a time, leading to impaired patient compliance.
  • Hard gelatin capsules are known as a conventional pharmaceutical dosage form. Their sizes have been standard since the start of industrial manufacture of drug compositions, ranging from 5 (corresponding to a volume of 0.13 ml) up to 000 (corresponding to a volume of 1.36 ml). Thus, when a large amount of ingredient is required for each dosage unit, depending on the bulk density of the formulation, it may be necessary to use large size capsules which are too large to swallow or, even worse, a size 000 capsule may be too small to receive the said amount. Pellets and granules have been filled into hard gelatin capsules to be used as conventional or controlled release dosage forms, however the latter are rather difficult to manufacture.
  • tablettetting coated active ingredient particles is therefore of major interest. Attempts have been made to produce tablets comprising microcapsules because of the advantages resulting from the microencapsulated substance being protected from external influences and vice-versa, e.g. increased stability, reduced chances of irritations or undesirable reactions with other components in a mixture, ability to mask unpleasant tastes and smells, etc. However, compaction of coated beads or pellets for making tablets encounters many difficulties and problems. As is well known in the pharmaceutical industry, beads or pellets are quite distinguishable from granules. Beads can be defined as small, free-flowing spherical or sphere-like particulates manufactured by pelletization, i.e. the agglomeration of fine powders or granules of drug substances and excipients using appropriate processing equipment. As opposed to the process of granulation, the production of beads by pelletization results in a larger average size and a narrower size-range distribution.
  • U.S. Patent Publication No. 2001/0048946 provides solid dosage forms of sparingly water-soluble pharmaceutical agents, i.e. solid or crystalline drugs having a water-solubility of 10 to 33 ⁇ g/ml at 25° C., such as glitazones. More particularly, this document discloses a pharmaceutical composition in the form of a solid particulate dispersion of such a pharmaceutical agent dispersed throughout a matrix of a water-soluble polymer such as polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose.
  • a water-soluble polymer such as polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose.
  • the particulate pharmaceutical agent is dispersed in the water-soluble polymer in a weight ratio of about 10% to about 90% active ingredient to about 90% to about 10% polymer.
  • Other conventional excipients such as glycerin, propylene glycol, Tween, stearic acid salts and the like can be added.
  • U.S. Patent Publication No. 2001/0044409 discloses a process for the preparation of a poorly water soluble drug in solid dispersion comprising the steps of (a) blending the drug with a carrier, (b) dissolving a surfactant and a plasticizer/solubilizer in water, (c) spraying the surfactant-plasticizer/solubilizer solu-tion onto the drug/carrier mixture in a fluid bed granulator, (d) extruding the resulting granulation through a twin screw extruder with at least one heating zone, and (e) milling the extrudate to a powdery mass of the solid drug dispersion.
  • said carrier may be selected from the group consisting of polyvinylpyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, vinyl acetate copolymer, acrylic polymers, succinic acid, sugars and mixtures thereof;
  • the said plasticizer/solubilizer may be selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof
  • the said surfactant may be selected from the group consisting of Tween, Span, Pluronics, polyoxyethylene sorbitol esters, monodiglycerides, polyoxyethylene acid polyoxyethylene alcohol and mixtures thereof.
  • U.S. Pat. No. 3,639,637 discloses oestrogen compositions for the preparation of stable aqueous suspensions that can be sprayed onto animal feed, comprising (by weight) 70-95% of water-dispersible gel-forming microcrystalline cellulose and 5-30% of finely-divided diethylstilbestrol (a compound which is virtually insoluble in water) and optionally further up to one third of the weight of the composition of a hydrocolloid selected from the group consisting of sodium carboxy-methylcellulose, methylcellulose and hydroxyethylcellulose.
  • the two latter cellulose compounds are known, namely from EP-A-403,383, to contribute to an extended linear drug release rate.
  • EP-A-352,190 discloses a solid pharmaceutical unit with a delayed dissolution of the active ingredient, i.e. allowing retention of the active ingredient and avoiding its complete and immediate availability by a simple contact with an aqueous liquid medium. It further discloses in example 9 paracetamol microgranules obtained from a mixture of 182 g paracetamol (a drug belonging to class 1 of the Biopharmaceutical Classification System and having a water-solubility of 14 mg/ml), 728 g microcrystalline cellulose (AVICEL PH 101) and 90 g sodium carboxymethylcellulose.
  • EP-A-352,190 however does not teach using a cyclodextrin compound as a drug dissolution enhancer.
  • U.S. Pat. No. 5,362,860 discloses (see table VI, example C) a composition with improved storage stability comprising (by weight) 0.05% of a pyridine based oxime (a drug undergoing hydrolysis into an aldehyde in an acidic environment), 70% cyclodextrin, 3% crosscarmellose (a crosslinked polymer) and 20.95% microcrystalline cellulose.
  • WO-A-99/12,524 solves the problem of drug formulations with both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time, by providing an oral modified release multiple-units composition wherein the unit dosage form comprises at least (i) a first fraction being able to release at least 50% of the drug within the first 20 minutes of a certain dissolution method, and (ii) a second fraction for delayed and extended release of the drug.
  • the multipleunits of the first fraction may be granulates or, provided that a surfactant is added to the formulation, coated or uncoated pellets. Formulation of the first fraction depends on the specific drug but typically includes wet-granulation, and an antacid-like or other alkaline substance was found to have a pronounced increasing effect on the release rate.
  • U.S. Pat. No. 5,646,131 discloses (example 4) rapidly dissolving capsules containing a granulate formulation of a water-insoluble or sparingly soluble drug, such as terfenadine (less than 0.01 mg/ml water-solubility), surfactants (Tween 80 and sodium lauryl sulfate), cyclodextrin, Avicel PH 101 (microcrystalline cellulose) and a disintegrant/swelling agent (Primojel®, i.e. sodium carboxymethyl starch) in a weight ratio of 10:72 to Avicel.
  • a water-insoluble or sparingly soluble drug such as terfenadine (less than 0.01 mg/ml water-solubility), surfactants (Tween 80 and sodium lauryl sulfate), cyclodextrin, Avicel PH 101 (microcrystalline cellulose) and a disintegrant/swelling agent (Primojel®,
  • Elbers et al. in Drug Development and Industrial Pharmacy (1992) 18(5):501-517 discloses theophylline pellets with a drug loading from 10 to 50% obtained by extrusion-spheronization with AVICEL 581 (a blend of microcrystalline cellulose and sodium carboxymethylcellulose).
  • Theophylline is a drug with a water-solubility of 8 mg/ml (according to Merck Index, 12 th edition 1996) and high permeability (according to FDA Guidance to Industry, 2000), thus belonging to class I of the Biopharmaceutical Classification System.
  • U.S. Pat. No. 4,235,892 discloses a series of 1-aryl-2-acylamido-3-fluoro-1-propanol antibacterial agents including D-(threo)-1-p-methylsulfonyl phenyl-2-dichloroacetamido-3-fluoro-I-propanol, an antibacterial agent known as florfenicol and useful for veterinary purposes.
  • Florfenicol has low solubility in water (about 1.3 mg/ml), as well as in many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin, and benzyl alcohol.
  • these 1-aryl-2-acylamido-3-fluoro-1-propanol may be compounded in the form of tablets, or may even be admixed with animal feed.
  • U.S. Pat. No. 4,235,892 therefore discloses making tablets by compressing granules of a composition comprising the said 1-aryl-2-acylamido-3-fluoro-1-propanol (in a drug loading range from 8.3% to 41.7% by weight), lactose, microcrystalline cellulose, starch and magnesium stearate.
  • the Biopharmaceutical Classification System (hereinafter referred as BCS) according to G. Amidon et al. in Pharm. Res . (1995) 12:413-420 provides for two classes of poorly soluble drugs, i.e. Class II and Class IV, and a class of highly soluble drugs, i.e. Class I. According to M. Martinez et al., Applying the Biopharmaceutical Classification System to Veterinary Pharmaceutical Products (Part I: Biopharmaceutics and Formulation Consideration) in Advanced Drug Delivery Reviews (2002) 54:805-824, a drug substance should be classified as highly soluble when the highest dose strength is soluble in at most 250 ml of aqueous media over the pH range 1-7.5.
  • U.S. Pat. No. 6,368,634 discloses a solid preparation suitable for a substantially immediate release of an active agent having a low or very low solubility, for example wherein more than 80% of the active agent is released within 2 hours, preferably within 1 hour or less from the administration.
  • This solid preparation is obtained by pelletisation, i.e. an agglomeration process whereby fine powders or granules are shaped into fine, free-flowing units (pellets) with a particle size above 250 ⁇ m.
  • the pellets of this solid preparation comprise one or more carriers (which may be polymers, or inorganic carriers such as talc, montmorillonite, bentonite, clay or calcium phosphate) and an active ingredient dissolved in a liquid phase (liquid as such or to be liquified for example by means of shear or temperature) which may be an oil or fat, a tensio-active agent or a polar co-solvent (such as polyethylene glycol, glycerol or propylene glycol).
  • carriers which may be polymers, or inorganic carriers such as talc, montmorillonite, bentonite, clay or calcium phosphate
  • an active ingredient dissolved in a liquid phase liquid as such or to be liquified for example by means of shear or temperature
  • a liquid phase liquid as such or to be liquified for example by means of shear or temperature
  • a tensio-active agent such as polyethylene glycol, glycerol or propylene glycol
  • the active ingredient is dissolved in a liquid solubilizer (the weight ratio solubilizer/active agent being greater than 4) which is fixed on solid carrier particles preferably with a particle size below 500 ⁇ m such as microcrystalline cellulose, the resulting mixture being then transformed into pellets using a suitable batch technique such as extrusion/spheronisation, fluid-bed technology, rotary granulation.
  • a suitable batch technique such as extrusion/spheronisation, fluid-bed technology, rotary granulation.
  • the active ingredient is already in solution inside the dosage form (i.e. pellets) and hence is very quickly released from the dosage form upon contact with aqueous media. Therefore according to U.S. Pat. No. 6,368,634 it is essential to have a liquid phase in which the active ingredient can dissolve to obtain the reported dissolution profiles.
  • FIGS. 6 and 7 of U.S. Pat. No. 6,368,634 clearly illustrate that the active ingredient is no longer in its crystalline form inside the dosage form, but has gone into solution in the solubilizer.
  • HCT hydrochlorothiazide
  • FIGS. 6B and 6C The importance of the active agent being dissolved in the liquid solubilizer is clearly shown in example 4 in combination with FIGS. 5 and 7 of U.S. Pat. No. 6,368,634.
  • a limitation of the technology disclosed in U.S. Pat. No. 6,368,634 is that it only allows to increase the dissolution rate of formulations containing a low content of active ingredient (i.e. drug loading) since the amount of liquid phase (solubilizer) that can be fixed onto the solid carrier particles is limited to a weight ratio solubilizer/particles from 1:5 to 1:2, and the active ingredient further needs to dissolve into the solubilizer.
  • This limitation is well illustrated in U.S. Pat. No. 6,368,634 teaching drug loadings in a range from about 1% by weight (examples 1 and 9) to about 6.7% by weight (example 5). This limitation was confirmed by our experiments performed while preparing a pellet formulation based on the teachings of U.S. Pat.
  • U.S. Pat. No. 6,368,634 describes the dosage form as pellets which are produced by a suitable batch technique such as fluid-bed technology, rotary granulation or, preferably, extrusion-spheronisation.
  • the extrusion-spheronisation process is a multi-step process capable of making uniformly sized preferably spherical particles (pellets). The following steps are required: (a) dry mixing, (b) wet granulation (i.e. formation of a wet mass, e.g. in U.S. Pat. No. 6,368,634 through the addition of a liquid phase and water (in order to get sufficient plasticity for extrusion), (c) extrusion (i.e.
  • Florfenicol is a drug for administration to warm-blooded animals, such as cattle with naturally-occurring bovine respiratory disease, swine, sheep, goats and poultry, which at present is mainly available in the form of injectable solutions.
  • a solid formulation of florfenicol which can further be admixed with animal feed if necessary.
  • a florfenicol formulation in the form of a water-soluble granulate for administration to animals together with drinking water.
  • a solid formulation for many low solubility drugs for human and veterinary therapies are examples of many low solubility drugs for human and veterinary therapies.
  • the present invention is based on the unexpected finding that drugs classifiable as or belonging to Class 11 (poorly soluble, highly permeable) or Class IV (poorly soluble, poorly permeable) of the Biopharmaceutical Classification System, including drugs having very low water-solubility, can be successfully formulated into immediate or fast release pharmaceutical solid dosage forms provided that:
  • FIG. 1 represents the release, as a function of time, of hydrochloro-thiazide from a granule composition according to one embodiment of the invention.
  • FIG. 2 represents the release, as a function of time, of florfenicol from a granule composition according to one embodiment of the invention.
  • FIG. 3 shows a twin screw extruder useful for manufacturing granule compositions according to one embodiment of the present invention.
  • FIG. 4 shows the release, as a function of time, of florfenicol from a pellet composition according to the prior art.
  • FIG. 5 shows florfenicol plasma concentrations in chickens after administration of a bolus dose of a florfenicol granule composition according to one embodiment of the invention, compared to intravenous administration of the same dose.
  • FIG. 6 shows florfenicol plasma concentrations in pigs after administration of a bolus dose of a florfenicol granule composition according to one embodiment of the invention, compared to intravenous administration of the same dose.
  • FIG. 7 shows florfenicol plasma concentrations in chickens, as a function of time, after continuous administration of a florfenicol granule composition according to one embodiment of the invention, compared to a florfenicol pellet composition of the prior art.
  • low drug content and “low drug loading” as used herein, unless otherwise stated, are intended to mean a drug content, with respect to the total solid formulation, in a range below about 7% by weight.
  • moderate drug content and “moderate drug loading” as used herein, unless otherwise stated, are intended to mean a drug content, with respect to the total solid formulation, in a range from about 7% by weight to about 20% by weight.
  • high drug content and “high drug loading” as used herein, unless otherwise stated, are intended to mean a drug content, with respect to the total solid formulation, in a range above about 20% by weight.
  • solid shaped article as used herein means any article being in a hard solid state at temperatures not exceeding about 60° C. and having a definite geometrical shape, such as for instance ordinary tablets, effervescent tablets, pills, lozenges and other compressed dosage forms.
  • immediate release means a release of at least about 50% of a drug within 30 minutes in water, preferably a release of at least about 70% of said drug within 10 minutes in water, and more preferably a release of at least about 80% of said drug within 10 minutes in water, under physiological temperature and pH conditions.
  • fast release means a release from about 40% to about 50% of a drug within 30 minutes in water, under physiological temperature and pH conditions.
  • this invention relates to an immediate or fast release pharmaceutical solid composition
  • an immediate or fast release pharmaceutical solid composition comprising at least one drug (i) classifiable as Class II (poorly soluble, highly permeable) or Class IV (poorly soluble, poorly permeable) of the Biopharmaceutical Classification System, e.g. a drug having very low water-solubility such as defined herein, wherein said drug is present in said solid composition in a low drug content, a moderate drug content or a high drug content, i.e.
  • said drug constitutes at least about 0.5% by weight but no more than 50% by weight, for instance from 0.5% to about 20% by weight (low and moderate drug loadings), preferably from 1 to 15% by weight, or alternatively from 20% to 50% by weight (high drug loadings) of the solid composition, wherein said solid composition is in the form of granules comprising one or more pharmaceutically acceptable excipients, wherein said one or more pharmaceutically acceptable excipients comprise
  • this invention relates to a continuous process for manufacturing the aforesaid immediate or fast release solid pharmaceutical composition. More particularly, this invention provides a continuous process for manufacturing a pharmaceutical granule composition comprising at least one drug (i) classifiable as Class II or Class IV of the Biopharma-ceutical Classification System in an amount of no more than about 50% by weight, for instance from 0.5% to about 20% by weight (low and moderate drug loadings), preferably from 1 to 15% by weight, or alternatively from 20% to 50% by weight (high drug loadings), of said pharmaceutical composition, a first excipient (ii) being a dextrin-containing compound in an amount from 40 to 85% by weight of said composition, and a second excipient (iii) comprising a solid fraction and optionally a liquid fraction, said second excipient (iii) being in an amount from 15 to 40% by weight of the composition and being selected from the group consisting of polyethylene glycols and polypropylene glycols having weight number molecular weights between
  • the first excipient (ii) may be a blend of a microcrystalline cellulose and a swellable polymer and the said swellable polymer may be an uncrosslinked carboxyalkylcellulose metal salt such as for instance sodium or calcium carboxymethylcellulose.
  • the first excipient (ii) may be present in the pharmaceutical granule composition in an amount from about 40% to about 85% by weight of the said composition.
  • Microcrystalline cellulose in particular a pharmaceutical grade thereof, is well known in the art of pharmaceutical industry for its high surface porosity and its outstanding capillary character. It is available from a variety of commercial sources, e.g. Avicel® PH 101 (commercially available from FMC Corporation, Philadelphia, Pa.), Emcocel® (Mendell), Vivocel® (JRS) and the like. Microcrystalline cellulose is a partially purified depolymerized form of cellulose and is obtained by treating pulps derived from fibrous plant material with mineral acid. The acid preferentially attacks the less ordered or amorphous regions of the cellulose polymer chain, thereby exposing and freeing the crystalline sites which form cellulose crystallite aggregates.
  • Microcrystalline cellulose is a white, odourless, tasteless, relatively free-flowing powder, insoluble in water, organic solvents, dilute alkalies and dilute acids.
  • a swellable polymer suitable for use in the blend being an embodiment of the first excipient (ii) of the present invention may be defined herein preferably as an ionic hydrocolloid polymer which is easily miscible with microcrystalline cellulose and which, on its own, is able to form a colloidal suspension in an aqueous environment, the colloidal particles e.g. forming a three-dimensional network or grid-like structure throughout the liquid phase.
  • Suitable examples of such polymer include pharmaceutical grades of sodium carboxymethylcellulose such as commercially available under the tradenames Nymcel®, Tilose® and Blanose® (Aqualon).
  • the swellable polymer is a low molecular weight and/or low viscosity polymer.
  • the swellable polymer when it is an uncrosslinked carboxyalkylcellulose metal salt, it should preferably have sufficient unsubstituted hydroxyl groups in order to hydrogen bond to the microcrystals of the microcrystalline cellulose upon drying and the substituent groups should have ability to impart water-solubility.
  • the degree of substitution of the carboxyalkyl-cellulose should preferably not exceed about 0.9 and more preferably be within a range of 0.5 to 0.9.
  • the viscosity of a 2% aqueous solution of the swellable polymer at 20° C. should preferably be below 1,000 mPa ⁇ s, more preferably within a range from about 20 to 800 mPa ⁇ s.
  • the swellable polymer and the microcrystalline cellulose being part of the first excipient (ii) may be afforded separately at the time of making the pharmaceutical granule compositions of the present invention or they may be present in the form of a co-processed blend.
  • a co-processed blend of the swellable polymer together with microcrystalline cellulose is readily available, e.g. as Avicel® RC 581 and Avicel® CL 611 (both commercially available from FMC Corporation), both well known in the art in the form of pharmaceutically acceptable grades.
  • This cellulosic blend may alternatively be prepared by bringing the two blend components into intimate contact under suitable conditions, for instance by subjecting the washed filter cake containing microcrystalline solids from the acid degradation of cellulose to intense attritive forces, thus resulting in a further break up of the cellulose crystallite aggregates and an increase in sub-micron particles.
  • a sufficient amount of the swellable polymer e.g. sodium carboxymethyl cellulose
  • the blend is dried and recovered. The dried product is readily redispersible in aqueous media to give gels.
  • this blend is a non-disintegrating water-insoluble water-dispersible powder before it is granulated in admixture with the poorly soluble drug and the second excipient.
  • the weight ratio of the said swellable polymer to the microcrystalline cellulose in this first but less preferred embodiment of the first excipient (ii) for the immediate or fast release pharmaceutical granule composition of the invention, or respectively in the (co-processed) blend as above defined should be above about 2:100 and up to about 30:100, preferably between about 7:100 and 20:100.
  • the first excipient (ii) is a dextrin-containing compound such as described hereinafter.
  • Drug dissolution enhancing agents in particular being dextrin-containing compounds such as maltodextrins, cyclodextrins and related substances such as chemically-modified derivatives thereof, in particular their pharmaceutically acceptable grades, are well known in the art and are available from a variety of commercial sources. They may be collectively referred as starch cyclic linear degradation products containing 6 to 8 glucose residues, or alternatively as cyclic oligosaccharides composed of L-glucose molecules linked by ⁇ or ⁇ osidic bonds having a toric form.
  • Cyclodextrins are crystalline (usually white powder), non-hygroscopic, cyclic oligosaccharides derived from starch.
  • ⁇ -, ⁇ -, and ⁇ -cyclodextrins which have respectively 6, 7, and 8 glucose units.
  • Suitable representative embodiments of cyclodextrin derivative enhancing agents include 2-hydroxypropyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, 2-hydroxyethyl- ⁇ -cyclodextrin, 3-hydroxypropyl- ⁇ -cyclodextrin, and trimethyl- ⁇ -cyclodextrin.
  • Maltodextrins occur as non-sweet, odourless, white powders or granules and are saccharide mixtures of polymers that consist of D-glucose units with a dextrose equivalent less than 20.
  • the amount of the first excipient (ii), particularly in the form of a dextrin-containing compound represents from about 40% by weight to about 85% by weight, more preferably from 50% to 75% by weight of the immediate or fast release pharmaceutical granule composition of the invention, depending on the amounts of the other excipients (such as fillers) that may optionally be present therein.
  • the aforesaid immediate release is a release of at least about 50% of the said drug within 30 minutes in water, preferably a release of at least about 70% of the said drug within 10 minutes in water, and more preferably a release of at least about 80% of the said drug within 10 minutes in water, preferably under physiological temperature and pH conditions.
  • the present invention is also successfully applicable to drugs having low, but not very low, water-solubility but which are relatively highly dosed drugs (i.e. constitute from about 10% to about 20% by weight of the composition) for therapeutic efficiency, such as florfenicol.
  • the immediate or fast release pharmaceutical granule compositions of this invention may further comprise one or more pharmaceutically acceptable fillers.
  • the aforesaid pharmaceutically acceptable fillers may be selected for instance from hydrocolloids (such as xanthan gum), binding agents, glidants, lubricants, surfactants and diluents.
  • hydrocolloids such as xanthan gum
  • binding agents such as xanthan gum
  • glidants such as xanthan gum
  • lubricants such as xanthan gum
  • surfactants and diluents such as xanthan gum
  • pharmaceutically acceptable filler as used herein is intended to refer to any material which is inert in the sense that it does not have any therapeutic and/or prophylactic effect per se but does not adversely interfere with the therapeutic or prophylactic property of the drug or pharmaceutical active ingredient being formulated.
  • the nature and amount of such fillers are not critical to the present invention.
  • binding agents such as starch, gelatin, glucose, alginic acid, sodium and calcium alginates, water-soluble acrylic (co)polymers, polyvinylpyrrolidone, polyamino-acids, ethylene-vinyl acetate copolymers and the like; natural and synthetic mineral fillers or glidants such as fumed (colloidal) silica (e.g.
  • Aerosil® magnesium silicates such as talc, diatomaceous earth, aluminium silicate such as kaolinite, montmorillonite or mica, magnesium aluminium silicate such as attapulgite and vermiculite, carbon such as charcoal, sulphur and highly dispersed silicic acid polymers; water-soluble diluents such as lactose, sorbitol and the like.
  • the nature of fillers is not critical, it is however preferred when the first excipient (ii) is a dextrin-containing compound, that the immediate or fast release pharmaceutical granule composition of the invention be substantially free of micro-crystalline cellulose.
  • the drug (i) is classifiable as Class II or Class IV of the BCS and preferably has a water-solubility below about 2.5 mg/ml, even between 0.1 and 1 mg/ml (i.e. “very slightly soluble” as defined according to the United States Pharmacopeia), even below 0.1 mg/ml (i.e. “practically insoluble” as defined according to the United States Pharmacopeia), even below about 5 ⁇ g/ml and may even have a water-solubility as low as about 0.2 ⁇ g/ml, at room temperature and physiological pH.
  • Non-limiting examples of such drugs include for instance chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide, benzthiazide, ethacrinic acid, nitrendipine, itraconazole, saperconazole, troglitazone, prazosin, atovaquone, danazol, glibenclamide, griseofulvin, ketoconazole, carbamazepine, sulfadiazine, florfenicol, acetohexamide, ajamaline, benzbromarone, benzyl benzoate, beta-methasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, diazepam, dicumarol, digitoxin, ethotoin, glutethimide, hydrocortisone, hydro-flumethi
  • diamino-pyrimidines include, without limitation, 2,4-diamino-5-(3,4,5-trimethoxy-benzyl) pyrimidine (known as trimethoprim), 2,4-diamino-5-(3,4-dimethoxybenzyl) pyrimidine (known as diaveridine), 2,4 diamino-5-(3,4,6-trimethoxybenzyl) pyrmidine, 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine (known as ormetoprim), 2,4-diamino-5-(3,4-dimethoxy-5-bromobenzyl) pyrimidine, and 2,4-diamino-5-(4-chloro-phenyl)-6-ethylpyrimidine (known as pyrimethamine).
  • trimethoprim 2,4-diamino-5-(3,4,5-trimethoxy-benzyl) pyrimidine
  • the above-mentioned drugs are known as belonging to Class II (poorly soluble, highly permeable) or Class IV (poorly soluble, poorly permeable) of the Biopharmaceutical Classification System according to G. Amidon et al. in Pharm. Res . (1995) 12:413-420.
  • these drugs belong to various therapeutic classes, including diuretics, anti-hypertensive agents, anti-viral agents (particularly anti-HIV), antibacterial agents, antifungals, etc, and are not limited to human or veterinary use alone.
  • the granules of the immediate or fast release pharmaceutical granule composition preferably have a diameter ranging from about 100 and 2,500 ⁇ m.
  • the second excipient (iii) of the immediate or fast release pharmaceutical granule composition of this invention is preferably one which will not give rise to difficulties during extrusion and may suitably be selected from the group consisting of polyethyleneglycols and polypropyleneglycols having weight number molecular weights between about 300 and about 10,000, preferably between 300 and 5,000; glycerol; propylene glycol and glycerides (such as mono-, di- and triglycerides of polyethyleneglycol fatty acid esters, including those commercially available under the tradename Gelucire®). Suitable examples of the latter include those having both a portion derived from a glyceride and a portion derived from a polyethylene glycol ester.
  • polyglycosylated glycerides denotes a mixture of mono-, di- and triglycerides with polyethylene glycol (PEG) mono- and diesters of C 8 -C 18 fatty acids with a molecular weight preferably between about 200 and about 600, optionally further including glycerol and/or free PEG, the hydrophilic-lipophilic balance (HLB) value of which is controlled by the chain length of the PEG and the melting point of which is controlled by the chain length of the fatty acids, of the PEG and of the degrees of saturation of the fatty chains, and thus of the starting oil.
  • PEG polyethylene glycol
  • HLB hydrophilic-lipophilic balance
  • C 8 -C 18 fatty acids denotes mixtures in various proportions of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, when these acids are saturated, and the corresponding unsaturated acids. As is well known to the skilled person, the proportions of these fatty acids may vary as a function of the starting oils.
  • saturated polyglycolized C 8 -C 10 glycerides such as the PEG-8 caprylate/caprate glyceride esters sold by Gattefosse Corporation under the tradename Labrasol; PEG-6 caprylic/capric glycerides sold by Huls Aktiengesellschaft under the trade name Softigen 767; PEG-60 corn glycerides sold by Croda under the trade name Crovol M-70; Ceteareth-20 sold by Henkel Corporation under the trade name Emulgin B2; diethyleneglycol monoethylethers sold by Gattefosse Corporation under the trade name Transcutol; a mixture of C 8 -C 18 saturated polyglycosylated glycerides having a melting point within a range of about 42-48° C.
  • a polyethyleneglycol when used for instance, it may comprise a higher molecular weight solid fraction and a lower molecular weight liquid fraction, the latter acting as a plasticizer.
  • the second excipient (iii), particularly when the first excipient (ii) is a dextrin-containing compound, may be present in the immediate or fast release granule composition of this invention in an amount from about 10% to about 40% by weight, more preferably from 15% to 40% by weight, most preferably from 20% to 30% by weight, of the said composition.
  • the weight ratio between the liquid fraction and the solid fraction of the second excipient (iii) may be from 0:1 (no liquid fraction) to about 1:1, more preferably from 0:1 to about 1:2, most preferably not more than 1:3.
  • the weight ratio of the first excipient (ii) to the second excipient (iii) is in a range from about 1:1 to about 5:1.
  • the immediate or fast release pharmaceutical granule composition may optionally further comprise one or more other drugs different from the drug having poor water-solubility, but preferably belonging to the same therapeutic class, in particular when combined drug therapy is desired.
  • the continuous process for manufacturing a pharmaceutical granule composition of the present invention is preferably performed in an apparatus, such as a twin screw extruder, comprising a barrel having a granulation chamber provided with inlets for supplying the drug (i), the first excipient (ii) and the solid fraction of the second excipient (iii), and at least one continuously operated rotating transporting means.
  • the said extruder is preferably operated at a temperature not above about 60° C., more preferably not above 45° C., most preferably at a temperature not above about 35° C., i.e. there is no need to provide a heating zone on the said extruder, therefore no need to provide sophisticated means for controlling and monitoring the temperature of the extruder.
  • the extruder is preferably operated at a rotating speed between about 5 and 450 rpm, for instance between 5 and 300 rpm, depending upon whether low shear, medium shear or high shear is desired.
  • the continuously operated rotating transporting means of the extruder comprises one or more mixing zones and one or more transport zones. The configuration and number of these zones may be widely varied, however at least one mixing zone is most preferred, being very advantageous to induce interaction between the various components of the composition to be extruded.
  • the remaining of the screw may then consist of transportation zones. Single or twin lead discharge screws can be used.
  • the length to diameter ratio of each rotating transporting means may be within a range from about 15 to about 60.
  • the present invention also provides solid shaped articles comprising a core consisting of an immediate or fast release pharmaceutical granule composition as defined herein-above.
  • This solid shaped article may be in the form of a tablet or a hard gelatine capsule. Methods for producing tablets, such as compression, or hard gelatine capsules from pharmaceutical granule compositions are well known to those skilled in the art.
  • the solid shaped article may further comprise a coating, according to standard practice in the art.
  • the solid shaped articles of the present invention may further optionally contain additives typically used in the formulation of such articles, for instance flavoring agents (such as anethole, benzaldehyde, vanillin, ethyl vanillin, ethyl acetate, methyl salicylate and the like), lubricants (such as magnesium stearate), sweeteners (such as sucrose, mannitol, aspartame, saccharin and its salts), colorants and/or buffering agents.
  • flavoring agents such as anethole, benzaldehyde, vanillin, ethyl vanillin, ethyl acetate, methyl salicylate and the like
  • lubricants such as magnesium stearate
  • sweeteners such as sucrose, mannitol, aspartame, saccharin and its salts
  • colorants such as sucrose, mannitol, aspartame, saccharin and its salts
  • the present invention further provides a sachet comprising an immediate or fast release pharmaceutical granule composition as above defined.
  • the present invention provides a number of advantages over the existing formulations of poorly soluble drugs and over the existing methods of making the latter, such as:
  • the present invention provides a solid formulation of florfenicol for oral administration, optionally together with animal feed, to warm-blooded animals such as cattle with naturally-occurring bovine respiratory disease, swine, sheep, goats and poultry.
  • the present invention also provides a solid formulation of trimethoprim, optionally in combination with sulfadiazine (usually in a trimethoprim/sulfadiazine weight ratio of about 1:5), for oral administration to fish as an antibacterial agent effective against both gram-positive and gram-negative bacteria.
  • the present invention also provides a method of treatment of a warm-blooded animal comprising administration to said animal of an effective amount of a pharmaceutical granule composition
  • a pharmaceutical granule composition comprising at least one drug (i) classifiable as Class II or Class IV of the Biopharma-ceutical Classification System in an amount of no more than about 50% by weight of said pharmaceutical composition, a first excipient (ii) being a dextrin-containing compound in an amount from about 40 to about 85% by weight of said composition, and a second excipient (iii) comprising a solid fraction and optionally a liquid fraction, said second excipient (iii) being in an amount from about 10 to about 40% by weight of the composition and being selected from the group consisting of polyethylene glycols and polypropylene glycols having weight number molecular weights between about 300 and 10,000, glycerol, propylene glycol and glycerides.
  • drug (i) used in such a method may be florfen
  • the twin screw extruder used for performing the following pharmaceutical granule preparations is described in FIG. 3 . It consists of seven distinct zones, wherein zones (1), (2), (4) and (6) are three transport zones, zones (3) and (5) are two mixing zones and zone (7) is a densification zone (which could alternatively be omitted, if desired).
  • the extruder is placed within a granulation chamber provided with inlets for supplying the drug and the various excipients.
  • Maltodextrin 01982 is a neutral taste, medium DE maltodextrin with good dispersibility which complies with European and U.S. Pharmacopeia and which is commercially available from Cerestar (Neuilly-sur-Seine, France).
  • the solid fraction of the formulation consisting of hydrochlorothiazide (example 2), PEG 4000, maltodextrin and xanthan gum was homogenised in a planetary mixer. This mixture was fed into the twin screw extruder at a rate of 29.9 g/min.
  • the liquid phase (PEG400) was continuously pumped into the twin screw extruder at a rate of 6.9 g/min. The screw speed during the extrusion was 250 rpm.
  • the temperature of the different zones of the twin screw extruder was set at 25° C., yielding experimental extrusion temperatures of 25° C. in zone (1), 26° C. in zone (2), 26° C. in zone (3) and 25° C. in zones (4) and (5).
  • FIGS. 1 and 2 The extruded granules were collected, sieved and further analysed for drug dissolution (data shown in FIGS. 1 and 2 , formulations B and D).
  • FIG. 1 shows that 72% release of hydrochlorothiazide (example 2) is obtained after 10 minutes, and 90% after 25 minutes.
  • FIG. 2 shows that 80% release of florfenicol (example 3) is already obtained after 10 minutes, and 100% after 20 minutes.
  • the solid fraction of the formulation consisting of hydrochlorothiazide (example 4), PEG 4000, Avicel PH 101/Avicel CL 611 (commercially available from FMC Corporation, Philadelphia, Pa.) was homogenised in a planetary mixer. The homogeneous mixture was then fed into the twin screw extruder at a rate of 27.6 g/min. The liquid phase (PEG 400) was continuously pumped into the twin screw extruder at a rate of 9.2 g/minute. The screw speed during the extrusion was 250 rpm. The temperature of the different zones of the twin screw extruder was set at 25° C. yielding experimental temperatures of 25° C., 28° C., 27° C., 26° C. and 25° C. in zones 1 to 5, respectively.
  • FIGS. 1 and 2 formulations A and C.
  • FIG. 1 shows that 100% release of hydrochlorothiazide (example 4) is obtained after 10 minutes.
  • FIG. 2 shows that 78% release of florfenicol (example 5) is already obtained after 10 minutes, and 100% after 15 minutes.
  • a pharmaceutical pellet formulation was made according to the extrusion-spheronisation process as disclosed in the examples of U.S. Pat. No. 6,368,634, but starting from the following composition (by weight): Florfenicol: 20% Polyethyleneglycol 400: 21% Avicel PH 101: 59%
  • the release rate of florfenicol from these pellets was determined as in the previous examples and, as shown in FIG. 4 , was found to be quite slow: only 11% and 43% of the drug were dissolved after 10 minutes and after 60 minutes, respectively.
  • the comparative formulation used for intravenous administration was Nuflor®, a commercially available injectable preparation with a drug concentration of 300 mg/ml.
  • the granule formulation used for oral administration was prepared according to the procedure of examples 2 and 3, except that the florfenicol content was 20% by weight of the formulation and the maltodextrin content was reduced accordingly.
  • Plasma samples were taken from broilers at the following times after administration: 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h and 12 hours, respectively.
  • Plasma analysis was performed by high performance liquid chromatography (HPLC) with UV detection with chloramphenicol as internal standard.
  • the comparative formulation used for intravenous administration was Nuflor®, a commercially available injectable preparation with a drug concentration of 300 mg/ml.
  • the granule formulation used for oral administration was prepared according to the procedure of examples 2 and 3, except that the florfenicol content was 20% by weight of the formulation and the maltodextrin content was reduced accordingly.
  • Plasma samples were taken from pigs at the following times after administration: 0.33 h, 0.66 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h and 30 hours, respectively.
  • Plasma analysis was performed by high performance liquid chromatography (HPLC) with UV detection with chloramphenicol as internal standard.
  • Plasma samples were taken from broilers at regular intervals, 4 times daily, after administration of said formulations.
  • Plasma analysis was performed by high performance liquid chromatography (HPLC) with UV detection with chloramphenicol as internal standard.
  • Granules Time (hours) 6,368,634) (PCT/BE03/00040) 4 0.11 1.18 8 0.09 1.41 12 0.15 1.38 24 0.38 1.36 28 0.19 1.23 32 0.22 0.98 36 0.28 1.23 48 0.52 1.23 50 0.17 1.46

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