WO2010081815A1 - Compositions aqueuses coacervées comprenant des agents biologiquement actifs faiblement solubles dans l'eau - Google Patents

Compositions aqueuses coacervées comprenant des agents biologiquement actifs faiblement solubles dans l'eau Download PDF

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Publication number
WO2010081815A1
WO2010081815A1 PCT/EP2010/050330 EP2010050330W WO2010081815A1 WO 2010081815 A1 WO2010081815 A1 WO 2010081815A1 EP 2010050330 W EP2010050330 W EP 2010050330W WO 2010081815 A1 WO2010081815 A1 WO 2010081815A1
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Prior art keywords
water
phase
coacervate
soluble
aqueous
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PCT/EP2010/050330
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English (en)
Inventor
Jean Paul Remon
Chris Vervaet
Andre Bruno Da Fonseca Antunes
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Universiteit Gent
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Priority to EP10702263A priority Critical patent/EP2376061A1/fr
Publication of WO2010081815A1 publication Critical patent/WO2010081815A1/fr
Priority to US13/181,243 priority patent/US20110294864A1/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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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 relates to the formulation of poorly water-soluble biologically-active agents such as therapeutic drugs, pesticides, fertilizers, cosmetics and the like.
  • the present invention especially relates to the formulation of human and veterinary therapeutic drugs belonging to Class Il or Class IV of the Bio Classification System (BCS) showing a low oral bioavailability due to their low water solubility. More specifically the present invention relates to aqueous coacervate systems including poorly water-soluble biologically-active agents such as therapeutic drugs, pesticides, fertilizers, cosmetics and the like.
  • the present invention also relates to biologically-active agent powders and granules that can be produced, e.g.
  • aqueous coacervate systems by drying, from such aqueous coacervate systems and that are easily water-soluble or water-dispersible and that are able to achieve, upon administration to a human or animal (therapeutic drugs and cosmetics) or upon dispersion to a locus to be treated (pesticides and fertilizers), a desired release kinetics e.g. an immediate release.
  • 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 Il and Class IV, and a class of highly soluble drugs, i.e. Class I.
  • BCS pertains both to the human therapeutic field and to the veterinary art. According to M.
  • 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.
  • Human therapeutic drugs or veterinary drugs belonging to class Il or IV of the BCS are known to the skilled person not to be very efficacious after oral administration whatever the oral dosage form (tablets, pellets, liquids, ...) because of a decreased bioavailability at the place of absorption, itself often due to the low aqueous solubility of the drug.
  • Veterinary drugs for pigs, poultry and other cattle or livestock animals are often administered via feed or drinking water because of the fact that a large number of animals can be medicated at the same time (mass medication). Especially drinking water and to a lesser extent feed medication are very popular. Drinking water medication offers several advantages and a few disadvantages in relation to prophylactic and therapeutic treatment. Important advantages are the low cost of organization and the easiness of administration. Immediate therapeutically care of all sick or endangered animals in the flock and - if necessary - a quick change to another drug and/or dose are possible. An important advantage is that all subclinical sick animals and animals in the incubation period are also treated, avoiding further spreading of the disease in the flock.
  • Coacervation can be considered as a phenomenon in which aqueous colloidal solutions separate - upon alteration of the thermodynamic condition of state - into two liquid phases, one being rich in colloid (i.e. the coacervate phase) and the other one containing little colloid (i.e. the equilibrium water phase). Coacervation is readily distinguishable from precipitation, which occurs in colloidally unstable systems and where a coagulum of floes is formed. Certain coacervate systems are already known in the art in relation to therapeutic drugs, e.g.:
  • - US Patent No. 4.596.788 teaches a synthetic whole blood comprising two gelatins having different isoelectric points, water, and sufficient alkaline substance to achieve a basic pH (e.g. within the range of human blood, e.g. from about 7.2 to 7.6), said synthetic whole blood being either a substantially non-polar coacervate phase or a two-phase system wherein said two phases are a substantially non-polar coacervate phase and a polar equilibrium water phase, which can carry therapeutic drugs and may also include 1 to 10% weight to volume of a non-ionic surfactant;
  • - EP-450.141 -A teaches a hydrogel-based or foamed-based aqueous coacervate system including a water-insoluble drug, an amphoteric surfactant and an edible mono- or polysaccharide acting as a rigid ifying agent for the gel or foam material;
  • - US Patent No. 4.794.000 teaches a coacervate-based oral delivery system for medically
  • compositions providing for the delivery of medically useful drugs, said compositions being based on the use of eggs in whole or in part from domestic fowl, and further including non-ionic surfactant agents.
  • the compositions may optionally include high molecular weight dextrins and glycol ethers such as PEG.
  • gelatin-based or hydrogel-based or foamed-based aqueous coacervate systems of the prior art are not practically suitable for most administration modes of human or veterinary poorly water-soluble therapeutic drugs due to the physical characteristics associated with gelified forms.
  • the combination in suitable proportions of a poorly water- soluble biologically-active agent, a non-ionic tensio-active agent and a water- soluble carrier is able to result in the formation of an aqueous two-phase coacervate system.
  • This coacervate system or the coacervate phase thereof which includes the major part of the poorly water-soluble biologically-active agent, can be used for the production of solid dosage forms via spray-drying, freeze-drying or any other drying technique such as, but not limited to, granulation which does not harm the biologically-active agent, to obtain a water soluble or water-dispersible powder, which can be easily applied to a locus to be treated with said biologically-active agent, e.g. a drinking water medication. If desired, this powder can also be further processed into other solid dosage forms such as tablets, capsules, sachets and the like. The obtained powder form has shown ability to provide an immediate release dissolution profile after administration together with water.
  • aqueous biphasic coacervate systems of this invention are stable within a broad temperature range from about 5°C to about 45°C and broad relative humidity conditions, therefore can be stored under such conditions without a loss of their rapid bioactive agent release characteristics.
  • the present invention relates to an aqueous gelatin-free two-phase coacervate composition
  • a coacervate phase and an equilibrium water phase
  • said composition comprises, or consists essentially of, per 100 parts by weight, a mixture of: (a) from about 0.01 to about 30 parts by weight of a poorly water-soluble biologically-active agent,
  • the present invention relates to an aqueous gelatin-free egg-free, two-phase coacervate composition
  • a coacervate phase and an equilibrium water phase
  • said coacervate composition comprises or consists essentially of, per 100 parts by weight, a mixture of:
  • the proportion by weight of the poorly water- soluble biologically-active agent in the mixture of the first embodiment of the present invention may be at least 0.1 part by weight, or at least 0.5 part by weight, or at least 2 parts by weight, or at least 5 parts by weight.
  • the proportion by weight of the poorly water-soluble biologically-active agent in the mixture may be at most 25 parts by weight, or at most 20 parts by weight, or at most 10 parts by weight, or at most 5 parts by weight.
  • the proportion by weight of the poorly water-soluble biologically-active agent in the mixture of the other broad embodiment of the present invention may be at least 5 parts by weight, or at least 10 parts by weight, and/or may be at most 25 parts by weight, or at most 20 parts by weight, or at most 15 parts by weight.
  • the proportion by weight of the poorly water-soluble biologically-active agent in the mixture of the other broad embodiment of the present invention may be at least 5 parts by weight, or at least 10 parts by weight, and/or may be at most 25 parts by weight, or at most 20 parts by weight, or at most 15 parts by weight.
  • the specific type i.e.
  • the proportion by weight of the non-ionic tensio-active agent(s) in the mixture of both embodiments of the present invention may be at least 5 parts by weight, or at least 10 parts by weight, or at least 15 parts by weight.
  • the specific type i.e.
  • the proportion by weight of the non-ionic tensio-active agent(s) in the mixture of the first embodiment of the present invention may be at most 30 parts by weight, or at most 25 parts by weight, or at most 20 parts by weight.
  • the proportion by weight of the non-ionic tensio-active agent(s) in the mixture of the other broad embodiment of the present invention may be at most 50 parts by weight, or at most 30 parts by weight, or at most 20 parts by weight. Contrary to the teachings of US Patent No.
  • the tensio-active system used in the present invention is preferably free from high molecular weight polysaccharides.
  • the one or more non-ionic tensio- active agent(s) of the other broad embodiment of the present invention build up a polyssaccharide-free tensio-active system with a hydrophilic-lipophilic balance (HLB) from 8 to 18, for instance from 10 to 16.
  • HLB hydrophilic-lipophilic balance
  • the proportion by weight of the water-soluble carher(s) in the mixture of both embodiments of the present invention may be at least 10 parts by weight, or at least 20 parts by weight, or at least 30 parts by weight.
  • the specific type i.e.
  • the proportion by weight of the water-soluble carher(s) in the mixture of the first embodiment of the present invention may be at most 60 parts by weight, or at most 50 parts by weight, or at most 40 parts by weight.
  • the proportion by weight of water (d) in the mixture of the two-phase coacervate compositions of both embodiments of this invention is adjusted to complete to 100 parts by weight of mixture, after accounting for the weight amounts of the other required components (a), (b) and (c).
  • the proportion by weight of water in the mixture of both embodiments of the present invention may be at least 35 parts by weight, or at least 45 parts by weight, or at least 60 parts by weight.
  • the proportion by weight of water in the mixture of both embodiments of the present invention may be at most 85 parts by weight, or at most 70 parts by weight, or at most 60 parts by weight.
  • the poorly water-soluble biologically-active agent present in the aqueous two- phase coacervate composition according to both embodiments of the present invention may be a therapeutic drug for human or veterinary use, a cosmetic agent, a pesticide, a fertiliser, a herbicide, a plant growth regulator, a crop treatment agent, an anti-microbial agent (in particular a fungicide or a bactericide), admissible for use in plants, animals and/or humans.
  • the biologically active compositions according to this invention may be for pharmaceutical use, cosmetic use, veterinary use or for plant treatment.
  • the poorly water-soluble biologically-active agent is a poorly soluble drug or a cosmetic agent, it preferably belongs to Class Il or Class IV of the BCS.
  • such human or veterinary drugs belong to various therapeutic classes including, but not limited to, ⁇ -blockers, calcium antagonists, ACE inhibitors, sympatho-mimetic agents, hypoglycaemic agents, contraceptives, ⁇ -blockers, diuretics, anti-hypertensive agents, anti-psohatics, bronchodilators, cortisones, anti-mycotic agents, salicylates, cytostatic agents, antibiotic agents, virustatic agents, antihistamines, UV-absorbers, chemotherapeutics (e.g.
  • antiproliferative agents include antiseptics, estrogens, scar treatment agents, anti-fungal agents, antibacterial agents, anticoccidials, antifolate agents, cardiovascular agents, nutritional agents, antispasmodics, analgesics, antipyretics, antiinflammatory agents, coronary vasodilators, peripheral vasodilators, anti-tussive agents, muscle relaxants, tranquilisers, antiarrythmic agents, anticoagulants, antiemetics, anthelmintic agents, expectorants, anti-diabetic agents, immunosuppressants, central nervous system agents (e.g. against Alzheimer or Parkinson diseases) and the like.
  • the present invention is suitable for formulating therapeutically active drugs or cosmetic agents belonging to various chemical or therapeutic classes such as, but not limited to, the following: febantel, fenbendazole, oxfendazole, paclitaxel, florfenicol, benzimidazoles, acebutolol, acetohexamide, acetylcysteine, acetylsalicylic acid, acyclovir, ajamaline, alendronate, alfuzosine, alprazolam, alfacalcidol, allantoin, allopurinol, alverine, ambroxol, amikacin, amlodipine, amilohde, aminoacetic acid, amiodarone, amithptyline, amlodipine, amoxicillin, ampicillin, amylobarbitone, ascorbic acid, aspartame, astemizole, atenolol, beclomethas
  • the present invention is especially suitable for the formulation of therapeutically active ingredients (drugs) having a water-solubility below about 2.5 mg/ml, even between 0.1 and 1 mg/ml (i.e. " very slightly soluble " as defined in the United States Pharmacopeia), even below 0.1 mg/ml (i.e. " practically insoluble " as defined in the United States Pharmacopeia) or below 0.02 mg/ml, 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.
  • drugs having a water-solubility below about 2.5 mg/ml, even between 0.1 and 1 mg/ml (i.e. " very slightly soluble " as defined in the United States Pharmacopeia), even below 0.1 mg/ml (i.e. " practically insoluble " as defined in the United States Pharmacopeia) or below 0.02 mg/ml, even below about 5 ⁇ g/ml and may even
  • Non-limiting examples of such drugs include for instance febantel, hydrochlorothiazide, nimodipine, flufenamic acid, mefenamic acid, bendroflumethiazide, benzthiazide, ethachnic acid, nitrendipine and diaminopyhmidines, including enantiomers thereof, organic and inorganic addition salts (including acid salts and base salts) thereof, and solvates (such as hydrates and alcoholates) thereof.
  • Suitable examples of such poorly soluble diaminopyhmidines include, without limitation, 2,4-diamino-5-(3,4,5-thmethoxy- benzyl) pyrimidine (trimethoprim), 2,4-diamino-5-(3,4-dimethoxy-benzyl) pyhmidine (diavehdine), 2,4 diamino-5-(3,4,6-trimethoxybenzyl) pyrimidine, 2,4-diamino-5-(2- methyl-4,5-dimethoxybenzyl) pyri m id i n e (ormeto-phm), 2,4-diamino-5-(3,4- dimethoxy-5-bromobenzyl) pyrimidine, 2,4-diamino-5-(4-chloro-phenyl)-6- ethylpyhmidine(pyhmethamine), and analogues thereof.
  • the major part of the poorly water- soluble biologically-active agent (a) is advantageously included in the coacervate phase of the aqueous two-phase coacervate composition of the present invention.
  • the proportion of the poorly water-soluble biologically-active agent which is included in the coacervate phase may be at least about 70%, or at least about 80%, or at least about 90%.
  • the weight ratio (c)/(b) of the water-soluble carher(s) to the non-ionic tensio- active agent(s) in the mixture is a parameter which may influence the easiness of formation or the behaviour of the aqueous two-phase coacervate composition according to the present invention.
  • this weight ratio (c)/(b) may be at least
  • this weight ratio (c)/(b) may be at most 15/1 , or at most 10/1 , or at most 6/1 , or at most 3.5/1.
  • this weight ratio (c)/(b) may be at least 0.01/1 , or at least 0.05/1 , or at least 0.2/1 , or may be at most 2/1 , or at most 1/1 , or at most 0.5/1.
  • the non-ionic tensio-active agent(s) present as component (b) in the aqueous two-phase coacervate compositions of both embodiments of the present invention may be selected from a broad class of chemical compounds well known to the skilled person, e.g. from the group consisting of cholesterol esters, ethylene glycol fatty acid esters, ethoxylated esters, (poly)glycerol fatty acid esters, mono- and diglycehdes of fatty acids, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, propyleneglycol esters, sorbitan fatty acid esters, and mixtures thereof.
  • a broad class of chemical compounds well known to the skilled person e.g. from the group consisting of cholesterol esters, ethylene glycol fatty acid esters, ethoxylated esters, (poly)glycerol fatty acid esters, mono- and digly
  • any biocompatible or pharmaceutically acceptable grade of the above-mentioned non- ionic tensio-active agent(s) may be used as component (b) in the aqueous two- phase coacervate composition of the present invention.
  • a non-limiting suitable example is Cremophor EL, a polyethoxylated castor oil commercially available from BASF Corporation prepared by reacting about 35 moles of ethylene oxide with each mole of castor oil and which may include minor amounts of the polyethylene glycol esters of ricinoleic acid and polyethylene glycol ethers of glycerol.
  • the water-soluble carrier(s) present as component (c) in the aqueous two- phase coacervate composition of the present invention may be selected from a broad class of chemical compounds well known to the skilled person, e.g. from the group consisting of maltodextrins and polyols.
  • Suitable examples include polyols having from 3 to 12 carbon atoms and from 3 to 9 hydroxyl groups such as, but not limited to, erythritol (2R,3S-butane-1 ,2,3,4-tetraol), xylitol (2R,3R,4S-pentane- 1 ,2,3,4,5-pentanol), sorbitol (2R,3S,4S,5S-hexane-1 ,2,3,4,5,6-hexol), mannitol (2R,3R,4R,5R-hexane-1 ,2,3,4,5,6-hexol), maltitol (4-O- ⁇ -D-gluco-pyranosyl-D- glucitol), isomaltitol, lactitol (4-O- ⁇ -D-galactopyranosyl-D-glucitol), glycerol (propan- 1 ,2,3-triol) and mixtures
  • maltodextrins may be used as component (c) in the aqueous two-phase coacervate compositions of the present invention.
  • Maltodexthn is a polysaccharide that is produced from starch and usually found as a hygroscopic powder.
  • Maltodextrins are typically constituted of mixtures of chains that vary from 3 to 19 glucose units long and have a molecular weight below 1 ,800.
  • Maltodextrins can be derived from any starch, e.g. from rice, corn, potato or wheat, and may contain traces of amino acids, including glutamic acid, or monosodium glutamate, as a manufacturing by-product.
  • maltodextrins As is well known to the skilled person, the different commercially available types of maltodextrins are mainly defined with respect to the two following parameters:
  • amylose and amylopectin contents of maltodextrin in practice the amylose content commonly ranges from about 0.1 to about 70% by weight of maltodextrin and the amylopectin content commonly ranges from about 30 to about 99.9% by weight of maltodextrin;
  • DE dextrose equ ivalent
  • the present invention relates to the coacervate phase of an aqueous two-phase coacervate composition as defined in any of the specific embodi merits described hereinabove.
  • This coacervate phase can readily be separated (using techniques known in the art for liquid separation), if desired for further handling such as drying into a powder form, from the equilibrium water phase and is of major industrial interest since, as noted above, it includes the major part of the poorly water-soluble biologically-active agent (a).
  • from 70% to 100% of the bio-active agent (a) is dissolved in the coacervate phase.
  • the present invention relates to the equilibrium water phase of an aqueous two-phase coacervate composition as defined in any of the specific embodiments described hereinabove, which can readily be separated (using techniques known in the art for liquid separation) from the coacervate phase of said two-phase coacervate composition.
  • the equilibrium water phase includes a minor part, usually a very minor part (about 1 to 10%), of the poorly water-soluble biologically-active agent (a), it may be useful as such under special circumstances.
  • the present invention relates to a powder being a dried form of the coacervate phase of an aqueous two- phase coacervate composition as defined in any of the specific embodiments described hereinabove. According to yet another aspect, the present invention relates to a powder being a dried form of the aqueous two-phase coacervate composition itself, as defined in any of the specific embodiments described hereinabove.
  • Spray drying suitable for this invention includes drying the aqueous two-phase coacervate composition as defined in any of the specific embodiments described hereinabove, or the coacervate phase thereof, through a hot gas.
  • this hot gas may be air or, if oxygen-free drying is required, nitrogen gas.
  • This spray-drying is a one step rapid process which eliminates the need for additional processing.
  • the coacervate composition is pumped through an atomizer device that produces fine droplets into the main drying chamber.
  • Atomizers vary with rotary, single fluid, two-fluid, and Ultrasonic Nozzle designs.
  • the hot drying gas may be passed as a co-current or counter-current flow to the atomizer direction.
  • a co-current flow usually enables the particles to have a lower residence time within the system and the particle separator (typically a cyclone device) to operate more efficiently.
  • a counter-current flow enables a greater residence time of the particles in the chamber and may be paired with a fluidized bed system.
  • any type of spray-dryer taking the aqueous liquid stream and quickly separating the solute or suspension as a solid (which may be collected in a drum or cyclone) and water into a vapor may be used.
  • the liquid input stream is sprayed through a nozzle to make the droplets as small (e.g. from about 20 ⁇ m to about 200 ⁇ m) as possible, thus maximizing heat transfer and the rate of water vaporization.
  • Suitable nozzle types include, but are not limited to, the following: - the Rotary atomizer: located in the centre of the chamber roof.
  • An air turbine drive operating from a sixbar compressed air source, supplies power to the atomizer wheel.
  • a vaned atomizer wheel is used for non-abrasive feeds and an atomizer wheel with carbide bushings for atomizing abrasive feeds. Particles in the particle size range of 5-25 ⁇ m are created;
  • the co-current two-fluid nozzle located also in the centre of the chamber roof.
  • the atomization is created by compressed air at a pressure of 0.5-2.0 bar.
  • the feed and atomizing gas are passed separately to the nozzle head where the atomization takes place.
  • Two-fluid nozzles have the advantage of handling more viscous feeds.
  • the co-current mode is selected for drying heat sensitive products to fine particles in the particle size range of 5-25 ⁇ m;
  • Freeze-drying suitable for this invention includes freezing the aqueous two- phase coacervate composition as defined in any of the specific embodiments described hereinabove, or the coacervate phase thereof, and then reducing the surrounding pressure and adding enough heat to allow the frozen water in the coacervate to sublime directly from the solid phase to gas. There are usually three steps in the complete freeze-drying process of this invention: freezing, primary drying, and secondary drying.
  • the freezing step consists of cooling the coacervate below its eutectic point, i.e. the lowest temperature at which the solid and liquid phases of the coacervate can coexist, to ensure that sublimation rather than melting will occur in the following steps.
  • the coacervate may be frozen slowly, or can be cycled up and down in temperature (annealing).
  • the freezing temperature may be between about -50 0 C and -80 0 C.
  • pressure is decreased (e.g. to a few millibars), and enough heat is supplied to the frozen coacervate for its water to sublimate.
  • this step may be slow (up to several days on industrial scale) in order to avoid alteration of the material's structure.
  • pressure is controlled through the application of partial vacuum. The vacuum speeds sublimation, making it useful as a deliberate drying process.
  • a cold condenser chamber and/or condenser plates (typically below -50 0 C) provide a surface for the water vapor to re-solidify on, and prevents water vapor from reaching the vacuum pump, which could degrade the pump's performance.
  • the secondary drying step aims to remove any unfrozen water molecules, since ice was removed in the primary drying step.
  • the temperature is raised higher than in the primary drying step, and can even be above 0 0 C, to break any physico-chemical interactions between the water molecules and the frozen material.
  • Pressure may also be lowered (typically in the range of microbars) in this step to encourage desorption.
  • the vacuum is usually broken with an inert gas, such as nitrogen, before the resulting powder (with final residual water content typically around 1 % to 4%) is sealed.
  • the bio-active agent proportion in the composition is raised due to the removal of water.
  • the weight proportion of the poorly water-soluble biologically-active agent in the powder may ranges from 2.5% to 20%, e.g. from 5% to 20% or from 15% to 20%.
  • the solid dosage form of the present invention may, especially when the poorly water-soluble biologically-active agent is a therapeutic drug for human or veterinary use, also be in the form of granules which may be obtained by a method comprising a step of separating the coacervate phase from the equilibrium water phase of the aqueous two-phase coacervate composition, and using said coacervate phase as a granulating liquid for wet granulating a biologically-inactive carrier prior to a drying step which may be carried out at moderate temperature (including room temperature) under low relative humidity conditions for a relatively long period of time (ranging for instance from about 6 to 30 hours), or at a higher temperature (e.g.
  • Exemplary but non-limiting biologically-inactive, pharmaceutically or veterinary acceptable carriers suitable for this purpose include one or more of the following: - microcrystalline cellulose; - lactose; - maltodextrins with a molecular weight below 1800 and/or a dextrose equivalent from 1 to 30;
  • weight proportions of the coacervate phase and the biologically- inactive carrier(s) in the above granule dosage form embodiment of the present invention may vary within relatively broad limits depending upon parameters such as, but not limited to, the type of therapeutic drug, and the type of biologically- inactive carrier. In any circumstance, such weight proportions may be determined by the skilled person without inventive effort and merely performing routine experimentation.
  • Both the powder solid dosage form and the granule solid dosage form described herein-above for the first embodiment and the broad other embodiment of the invention are able to provide optimal release of the poorly water-soluble biologically-active agent from an aqueous medium within a short period of time, e.g. within no more than about 4 hours in vivo, or within no more than 10 minutes in vitro.
  • the poorly water-soluble biologically-active agent (a) is a veterinary drug intended for mass medication, it may be desirable to provide the drug formulation in a drinking liquid form.
  • aqueous two-phase coacervate composition can be produced at the place of bio-active agent consumption and soon or immediately before consumption, providing the biologically-active agent formulation in a liquid form may usually be suitably effected by dissolving or dispersing in water (or an essentially aqueous medium) a powder form that was previously obtained by drying, e.g. spray-drying or freeze-drying, or a granule solid dosage form as explained above, the aqueous two-phase coacervate composition as defined in any of the specific embodiments described hereinabove, or the coacervate phase thereof.
  • the present invention relates to a water-soluble or water-dispersible formulation comprising a water-soluble amount, respectively a water-dispersible amount, of a powder or granule being a dried form of the aqueous two-phase coacervate composition as defined in any of the specific embodiments described hereinabove, or the coacervate phase thereof.
  • One critical advantage of the present invention is the ability to turn a poorly water-soluble biologically-active agent (a) into a solid form, e.g. a free-flowing powder form or a granule form, which is at least easily water-dispersible and even most often water-soluble.
  • the water-soluble amount according to this embodiment of the present invention depends upon parameters such as the exact nature and type of the poorly water-soluble biologically-active agent (a), the weight proportions of said biologically-active agent (a) and the other components (b), (c) and (d) in the coacervate-forming mixture, the average particle size and/or the size polydispersity of the powder form, the type and operating conditions (e.g. temperature, pressure, and/or residence time) of the drying process used, and the temperature at which dissolution is performed.
  • the determination of this water-soluble amount is, in all situations, a trivial exercise for the skilled person using routine experimentation.
  • Water-soluble or water-dispersible formulations as defined hereinabove are highly suitable for administration or application to a wide range of living species where the biologically-active agent (a) is potentially useful for treating or preventing a d isorder or d isease condition or for improving health status.
  • the biologically-active agent (a) is a therapeutic drug or a cosmetic agent
  • the coacervate powder or granule form, or the water-soluble or water-dispersible formulation obtained therefrom may be administered to human beings.
  • the coacervate powder or granule form, or the water-soluble or water-dispersible formulation obtained therefrom may be administered to animals such as a mammal, a fish, a reptile or a bird.
  • the biologically-active agent (a) is a pesticide, a fertiliser or a herbicide
  • the coacervate powder or granule form, or the water-soluble or water-dispersible formulation obtained therefrom may be applied onto plants such as crops, e.g. using spraying techniques well known in agriculture and horticulture.
  • the present invention relates to a first method for producing an aqueous coacervate composition as defined in the first embodiment of the present invention, said method comprising the steps of:
  • step (i) dissolving or dispersing the poorly water-soluble biologically-active agent (a) into the one or more non-ion ic tensio-active agents (b) at a temperature not below the melting point of said poorly water-soluble biologically-active agent (or a salt thereof or a complex thereof); (ii) adding the liquid solution obtained in step (i) to water under mixing, and (iii) adding the one or more water-soluble carriers (c) to the mixture obtained in step (ii) under mixing.
  • the present invention relates to an alternative method for producing an aqueous coacervate composition as defined in the first embodiment of the present invention, said method comprising the steps of : (i) dissolving one or more water-soluble carriers (c) into water; (ii) dissolving or dispersing the poorly water-soluble biologically-active agent (a) into the one or more non-ionic tensio-active agents (b) at a temperature not below the melting point of said poorly water-soluble biologically-active agent (or a salt thereof or a complex thereof), and
  • step (i ⁇ ) adding of the liquid solution or dispersion obtained in step (ii) to the solution prepared in step (i) under mixing.
  • the two above methods distinguish from each other by the order in which the required components of the aqueous coacervate composition are mixed.
  • one method may prove to be more time-efficient or more convenient (especially in maximising the amount of biologically-active agent (a) retained in the coacervate phase) than the other, but as shown in illustrative examples below, they both achieve aqueous coacervate compositions with similar behaviour and suitability for drying into solid forms, e.g. free-flowing powder forms.
  • the weight amounts of the poorly water-soluble biologically-active agent (a), the non-ionic tensio-active agents (b), the water-soluble carriers (c) and water (d) introduced in the relevant steps (i), (ii) and (iii) are such that their mixture comprises, per 100 parts by weight, from 0.01 to 30 parts by weight (or any above-specified sub-range thereof) of the poorly water- soluble biologically-active agent (a), from 5 to 30 parts by weight (or any above- specified sub-range thereof) of the non-ionic tensio-active agents (b), from 5 to 75 parts by weight (or any above-specified sub-range thereof) of the water-soluble carriers (c), and from 35 to 85 parts by weight (or any above-specified sub-range thereof) of water.
  • step (ii) adding the liquid solution obtained in step (i) to water under mixing
  • step (iii) adding the one or more water-soluble carriers (c) to the mixture obtained in step (ii) under mixing.
  • step (i) dissolving one or more water-soluble carriers (c) into water; (j) dissolving or dispersing the poorly water-soluble biologically-active agent (a) into the one or more non-ionic tensio-active agents (b) at a temperature comprised between 30 0 C below the melting point and 50 0 C above the melting point of said poorly water-soluble biologically-active agent (a), and (k) adding the liquid solution or dispersion obtained in step (j) to the solution prepared in step (i) under mixing.
  • Both such methods may further comprise a step of cooling down the mixture until the coacervate phase separates from the equilibrium water phase.
  • Such cooling step may be spontaneous or may be accelerated through the use of suitable cooling means.
  • a high shear rate of mixing (e.g. with rotational agitation at a rotation speed of about 5,000 to 10,000 rpm) has proven to be efficient in performing steps (ii) and/or (iii) of the first method, or in step (iii) of the alternative method, this type of mixing is not a requirement of the methods of this invention.
  • both methods may also be performed at lower shear rates.
  • Suitable high shear homogenizers include, but are not limited to, the Silverson Mixer Model L4R, a multi-purpose high shear mixer suitable for the widest range of applications - mixing, emulsifying, homogenising, dissolving - with high efficiency and flexibility, with a capacity up to 12 litres and the ability to mix in-line with various flow rates, and offering a full load speed of 6000 to 8000 rpm.
  • each production method may consist of, rather than comprise, these three steps.
  • the following examples are provided solely for the purpose of illustrating various embodiments of the present invention, and without any intention of limiting the scope thereof.
  • Example 1 preparation of an aqueous gel-free coacervate system based on Cremophor EL
  • Cremophor ® EL a polyoxyl 35 castor oil non-ionic tensio-active agent commercially available from BASF Corporation
  • 60 g febantel melting point: 127-132°C
  • the solution was kept at this temperature for 2 minutes. Thereafter, the warm solution was added to 1000 ml demineralised water under high shear mixing (using a Silverson L4R device operated at 6000-8000 RPM) and after addition, mixing was continued during 5 minutes.
  • maltodextrin (dextrose equivalent 18, commercially available as C * PharmDry 01983 from Cargill, France) was slowly added to the liquid under high-shear conditions (using a Silverson L4R device operated at 6000-8000 RPM) and mixed during 5 minutes. After a cooling down period of 8 hours, an upper coacervate phase and a lower equilibrium water phase were obtained.
  • the formulation was spray-dried to a white free-flowing powder by means of a laboratory scale spray-drying equipment Mobile Minor commercially available from Niro, Copenhagen, Denmark.
  • the feed rate of the dispersed liquid was set at 30 ml/minute, the inlet temperature at 130 0 C and the resulting outlet temperature was 58 0 C.
  • Example 3 preparation of an aqueous gel-free coacervate system based on Tween 80
  • the formulation was spray-dried to a white powder by means of a laboratory scale spray-drying equipment Mobile Minor commercially available from NIRO, Copenhagen, Denmark.
  • the feed rate of the dispersed liquid was set at 28 ml/minute, the inlet temperature at 130 0 C and the resulting outlet temperature was 60 °C.
  • Example 5 (comparative) - preparation of a physical mixture based on Cremophor EL
  • Example 6 comparison of aqueous dispersions of a spray-dried coacervate powder and a physical mixture based on Cremophor EL
  • Example 7 storage stability of a coacervate formulation
  • This example illustrates the stability of the coacervate powder formulation of example 2 at 7°C.
  • Example 8 - X-ray characterization of a spray-dried coacervate formulation of febantel
  • the physical characteristics of the spray-dried powder obtained from the coacervate composition of example 2 was investigated by X-ray diffraction. Due to the absence of peaks in the X-ray diffraction pattern, it can be said that no febantel crystals are present in the spray-dried powder.
  • This example illustrates the amount of drug which can be achieved in the coacervate phase, as measured indirectly onto the coacervate system of example 1.
  • the amount of febantel in the equilibrium water phase was first determined.
  • a sample of 10 ml was taken from the equilibrium water_phase and a volume of 200 ⁇ l was diluted in 20 ml methanol and sonicated for 15 minutes. Thereafter, a test tube of 10 ml was filled with this mixture and centhfuged for 5 minutes at 4000 RPM. Then, a sample of 500 ⁇ l was taken and further diluted to 10 ml with methanol . The absorbance of this sample was measured by UV spectroscopy operating a double beam spectro-photometer (Shimadzu UV-1650 PC, Kyoto, Japan) at a wavelength of 280 nm.
  • the concentration of febantel was calculated, indicating that 10% of the drug was retained in the equilibrium water phase. As a consequence this means that 90 % of febantel was retained in the coacervate phase.
  • Example 10 illustrates an alternative method for producing a coacervate composition of this invention.
  • Cremophor ® EL commercially available from BASF Corporation
  • Example 11 illustrates the influence of using a mixture of water-soluble carriers.
  • 15 g Cremophor ® EL commercially available from BASF Corporation
  • 6 g febantel was dissolved in the heated liquid.
  • the solution was kept at temperature for 2 minutes.
  • the mixture febantel - Cremophor ® E L was added to 1 000 m l demineralised water under high shear mixing conditions (using a Silverson L4R device operated at 6000-8000 RPM) and after addition, these compounds were mixed during 5 minutes.
  • Example 12 preparation of a high drug loading aqueous gel-free coacervate system based on Cremophor EL
  • Cremophor ® EL a polyoxyl 35 castor oil non-ionic tensio-active agent commercially available from BASF Corporation, New Jersey
  • 60 g febantel melting point: 127-132°C
  • the solution was kept at this temperature for 2 minutes. Thereafter, the warm solution was added to 80 ml demineralised water under high shear mixing (using a Silverson L4R device operated at 6000-8000 RPM) and after addition, mixing was continued during 5 minutes.
  • maltodextrin (dextrose equivalent 18, commercially available as C * PharmDry 01983 from Cargill, France) was slowly added to the liquid under high-shear conditions (using a Silverson L4R device operated at 6000-8000 RPM) and mixed during 5 minutes. After a cooling down period of 8 hours, an upper coacervate phase and a lower equilibrium water phase were obtained.
  • Example 13 alternative production method for the coacervate system 60 g febantel, a poorly water-soluble drug (solubility 0.019 mg/mL, melting point 129.5°C), was dissolved in 150 g of a molten polyoxyl 35 castor oil non-ionic surfactant (Cremophor ® EL, commercially available from BASF Corporation, New
  • the lower phase of the biphasic system of example 13 was mainly composed of maltodextrin and febantel (1 % of the drug amount), as quantified by UV spectroscopy operating a double beam spectro-photometer (Shimadzu UV- 1650 PC, Kyoto, Japan) at a wavelength of 280 nm. Maltodextrin was not detected in the coacervate upper layer which was composed of febantel (99% of the drug amount) and Cremophor®EL
  • Example 15 production of a spray dried febantel powder formulation
  • the biphasic coacervate system of example 13 was re-dispersed using a paddle homogenizer (IKAWERK, Germany) and spray dried using a laboratory scale spray-drying equipment Mobile Minor commercially available from NIRO, Copenhagen, Denmark. This equipment was operated in a co-current air flow with a inlet temperature of 130 0 C, an outlet temperature of 60 0 C and a liquid feed rate of 20-30 ml/minute. From this process a free flowing powder of febantel was obtained with a 10% w/w drug loading.
  • a paddle homogenizer IKAWERK, Germany
  • Mobile Minor commercially available from NIRO, Copenhagen, Denmark
  • Example 16 production of a granulated febantel formulation
  • the febantel-hch upper phase of the biphasic coacervate system of example 13 was separated from the lower aqueous phase and used as granulation fluid for the production of microcrystalline cellulose-based granules (160 ml_ coacervate phase mixed with 300 g of microcrystalline cellulose commercially available under the tradename AVICEL PH 101 ).
  • the granules were formed by passing the mixture through a 1400 mesh sieve, then dried for 12 hours in a controlled humidity room ( ⁇ 20% relative humidity).
  • the resulting granules contained 10% by weight febantel.
  • Example 17 - characterization of febantel powder formulations by means of a dissolution test
  • the spray-dried febantel powder formulation of example 15, the granulated febantel formulation of example 16, the comparative physical mixture of example 5, and a commercially available febantel reference formulation were submitted to a dissolution test according to U.S. Pharmacopeia standard 27 on a Vankel VK7010 dissolution tester combined with a VK8000 automatic sampling station. Dissolution testing was performed in water at room temperature. Samples of 5 ml_ were withdrawn from the dissolution vessels at 5, 10, 15, 20, 30, 45 and 60 minutes respectively. Results are shown in figure 1. In contrast with both the comparative physical mixture of example 5 and the commercially available febantel reference formulation, febantel was rapidly released from the powder and granule formulations of examples 15 and 16. Without wihing to be bound by theory, the lower febantel release from the granule formulation may be due to the adsorption of febantel onto microcrystalline cellulose.
  • Example 1 8 storage stabil ity of coacervate formulations under different temperature and humidity conditions
  • the spray-dried febantel powder formulation of example 15 and a commercially available febantel reference formulation were submitted to a crossover study in 6 pigs (20-30 kg, ⁇ 9 weeks old).
  • Febantel-containing formulations were orally administered, and blood samples were taken at 0.5, 1 , 2, 4, 8, 12, 24, 32 hours after administration of the respective formulation.
  • Febantel is known to be metabolized into two active metabolites (fenbendazole and oxfendazole respectively, hereinafter denoted M1 and M2) the plasma concentrations of which were determined. Results are shown in figure 2.
  • the maximum plasma concentrations of both metabolites were much higher after administration of the spray-dried powder formulation of example 15 compared to the commercially available product.

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Abstract

La présente invention concerne une composition aqueuse coacervée biphasique ne contenant ni gélatine ni œuf, mais comprenant une phase coacervée et une phase aqueuse à l'équilibre. Ladite composition comporte, pour 100 parties en poids, un mélange associant (a) de 2 à 30 parties en poids d'un agent bioactif peu soluble dans l'eau, (b) de 5 à 55 parties en poids d'un système tensioactif sans polysaccharides, caractérisé par un équilibre hydrophile-lipophile compris entre 8 et 18 et constitué de tensioactifs non ioniques, (c) de 2 à 40 parties en poids d'un ou plusieurs supports solubles dans l'eau pour ledit agent bioactif peu soluble dans l'eau, lesdits agents étant choisis dans le groupe constitué des maltodextrines d'une masse moléculaire inférieure à 1 800, de l'érythritol, du xylitol, du sorbitol, du mannitol, du maltitol, de l'isomalt et du lactitol, et (d) de 20 à 85 parties en poids d'eau, le rapport pondéral (c)/(b) entre les supports solubles dans l'eau et les tensioactifs non ioniques dans ledit mélange étant compris entre 0,005/1 et 3,5/1. Lesdites compositions coacervées peuvent être déshydratées pour donner des formes pharmaceutiques solides à partir desquelles on peut obtenir une libération rapide de l'agent bioactif.
PCT/EP2010/050330 2009-01-13 2010-01-13 Compositions aqueuses coacervées comprenant des agents biologiquement actifs faiblement solubles dans l'eau WO2010081815A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2407156A3 (fr) * 2010-07-14 2012-07-11 Universiteit Gent Compositions coacervatées aqueuses adaptées à la fabrication de poudres et formulations solubles dans l'eau d'agents actifs biologiques
WO2016131853A1 (fr) 2015-02-17 2016-08-25 Universiteit Gent Forme pharmaceutique solide adaptée pour utilisation en tant que médication dans l'eau de boisson
WO2020182994A1 (fr) * 2019-03-13 2020-09-17 Certis Europe B.V. Composition

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0156277A2 (fr) * 1984-03-29 1985-10-02 Bayer Ag Formulations anthelmintiques stabilisées
US4596788A (en) 1983-02-07 1986-06-24 Neomed, Inc. Gelatin and lecithin based synthetic whole blood and a method of making the same
US4794000A (en) 1987-01-08 1988-12-27 Synthetic Blood Corporation Coacervate-based oral delivery system for medically useful compositions
EP0416575A2 (fr) 1989-09-05 1991-03-13 Neophore Technologies, Inc. Compositions pour la délivrance de médicaments à base de substances biologiques et procédé de préparation de telles compositions
EP0450141A1 (fr) 1989-08-14 1991-10-09 Janssen Pharmaceutica Inc. Matériau support pour l'administration de médicaments
WO1995023590A1 (fr) * 1994-03-03 1995-09-08 Bomac Laboratories Limited Preparation antihelmintique
WO2000064575A1 (fr) * 1999-04-26 2000-11-02 Eurand International S.P.A. Production de microcapsules
DE10314976A1 (de) * 2003-04-02 2004-10-14 Bayer Healthcare Ag Verbesserte Penetration von Wirkstoffen in Zellen und Organe
WO2005074914A1 (fr) * 2004-02-03 2005-08-18 Wyeth Composition anthelminthique

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4596788A (en) 1983-02-07 1986-06-24 Neomed, Inc. Gelatin and lecithin based synthetic whole blood and a method of making the same
EP0156277A2 (fr) * 1984-03-29 1985-10-02 Bayer Ag Formulations anthelmintiques stabilisées
US4794000A (en) 1987-01-08 1988-12-27 Synthetic Blood Corporation Coacervate-based oral delivery system for medically useful compositions
EP0450141A1 (fr) 1989-08-14 1991-10-09 Janssen Pharmaceutica Inc. Matériau support pour l'administration de médicaments
EP0416575A2 (fr) 1989-09-05 1991-03-13 Neophore Technologies, Inc. Compositions pour la délivrance de médicaments à base de substances biologiques et procédé de préparation de telles compositions
WO1995023590A1 (fr) * 1994-03-03 1995-09-08 Bomac Laboratories Limited Preparation antihelmintique
WO2000064575A1 (fr) * 1999-04-26 2000-11-02 Eurand International S.P.A. Production de microcapsules
DE10314976A1 (de) * 2003-04-02 2004-10-14 Bayer Healthcare Ag Verbesserte Penetration von Wirkstoffen in Zellen und Organe
WO2005074914A1 (fr) * 2004-02-03 2005-08-18 Wyeth Composition anthelminthique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
G. AMIDON ET AL., PHARM. RES., vol. 12, 1995, pages 413 - 420
M. MARTINEZ ET AL.: "Applying the Biopharmaceutical Classification System to Veterinary Pharmaceutical Products (Part I: Biopharmaceutics and Formulation Consideration)", ADVANCED DRUG DELIVERY REVIEWS, vol. 54, 2002, pages 805 - 824

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2407156A3 (fr) * 2010-07-14 2012-07-11 Universiteit Gent Compositions coacervatées aqueuses adaptées à la fabrication de poudres et formulations solubles dans l'eau d'agents actifs biologiques
WO2016131853A1 (fr) 2015-02-17 2016-08-25 Universiteit Gent Forme pharmaceutique solide adaptée pour utilisation en tant que médication dans l'eau de boisson
US10335371B2 (en) 2015-02-17 2019-07-02 Universiteit Gent Solid pharmaceutical dosage form suitable for use as drinking water medication
AU2016221774B2 (en) * 2015-02-17 2020-09-17 Orotech Nv Solid pharmaceutical dosage form suitable for use as drinking water medication
WO2020182994A1 (fr) * 2019-03-13 2020-09-17 Certis Europe B.V. Composition

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