EP2376061A1 - Aqueous coacervate composition comprising poorly water-soluble biologically-active agents - Google Patents
Aqueous coacervate composition comprising poorly water-soluble biologically-active agentsInfo
- Publication number
- EP2376061A1 EP2376061A1 EP10702263A EP10702263A EP2376061A1 EP 2376061 A1 EP2376061 A1 EP 2376061A1 EP 10702263 A EP10702263 A EP 10702263A EP 10702263 A EP10702263 A EP 10702263A EP 2376061 A1 EP2376061 A1 EP 2376061A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- water
- phase
- coacervate
- soluble
- aqueous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—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.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
This invention relates to an aqueous gelatin-free, egg portion-free, two-phase coacervate composition comprising a coacervate phase and an equilibrium water phase, comprising, per 100 parts by weight, a mixture of: (a) from 2 to 30 parts by weight of a poorly water-soluble bio-active agent, (b) from 5 to 55 parts by weight of a polysaccharide-free tensio-active system with a HLB from 8 to 18 and consisting of non-ionic tensio-active agents, (c) from 2 to 40 parts by weight of one or more water-soluble carriers for said poorly water-soluble bio-active agent, said carriers being selected from the group consisting of maltodextrins with a molecular weight below 1,800, erythritol, xylitol, sorbitol, mannitol, maltitol, isomalt and lactitol, and (d) from 20 to 85 parts by weight of water, wherein the weight ratio (c)/(b) of the water-soluble carriers to the non-ionic tensio- active agents in the said mixture is from 0.005/1 to 3.5/1. Such coacervate compositions may be dried into solid dosage forms from which rapid release of the bio-active agent can be obtained.
Description
AQUEOUS COACERVATE COMPOSITION COMPRISING POORLY WATER-SOLUBLE BIOLOGICALLY-ACTIVE AGENTS
FIELD OF THE INVENTION
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. 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.
BACKGROUND OF THE INVENTION
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. The BCS pertains both to the human therapeutic field and to the veterinary art. 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.
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. The main disadvantages of animal mass medication via drinking water are (1 ) possible variations in drug uptake between the animals and (2) the fact that most drugs are not water-soluble or water-dispersible enough or their water-solutions or water-dispersions are not stable enough along time. Because of the practical and organizational importance of drinking water therapy for animals, water-soluble drug formulations have an important contribution in the veterinary industry. The same concern about the poor bioavailability of certain drugs is also more and more applicable to human therapy. This is especially due to the fact that most newly developed human drugs tend to be poorly water-soluble, i.e. belong to Class Il or Class IV of the BCS. The same concern about poor bioavailability is also applicable to new types of pesticides and fertilizers which tend to be poorly water-
soluble and which, if properly dispersed at the locus to be treated in a more water- soluble or water-dispersible form, would highly contribute to improved treatment efficiency and/or decreased damages to the environment.
Different methods to improve water solubility of human or veterinary drugs such as the inclusion of drugs into the cavity of (β-hydroxypropyl)cyclodextrins, or the production of self-emulsifying drug delivery systems, or the use of phospholipid micro-emulsions or water-soluble salts have been described in the literature. However most methods have limited practical application to a small number of drug molecules or do not provide the expected solution at a reasonable additional manufacturing expense. Other techniques to improve the water solubility of poorly water soluble human or veterinary drugs still constitute a global and significant challenge and certainly have an additional value for drug development research and manufacturing industry.
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 useful compositions, said system being prepared from water and non- ionic surfactants and high molecular weight dextran polysaccharides; and
- EP-416.575-A teaches coacervate-based micro-encapsulated compo-sitions 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.
However the 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.
SUMMARY OF THE INVENTION
Unexpectedly, the combination in suitable proportions of a poorly water- soluble biologically-active agent, a non-ionic tensio-active agent and a water- soluble carrier (such as a maltodextrin or a polyol) 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. Furthermore the aqueous biphasic coacervate systems of this invention, as well as solid dosage forms derived from drying, 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.
DETAILED DESCRIPTION OF THE INVENTION
According to a first embodiment, the present invention relates to an aqueous gelatin-free two-phase coacervate composition comprising a coacervate phase and an equilibrium water phase, wherein 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,
(b) from about 5 to about 30 parts by weight of one or more non-ionic tensio- active agents,
(c) from about 5 to about 75 parts by weight of one or more water-soluble carriers for said poorly water-soluble biologically-active agent, and
(d) from about 35 to about 85 parts by weight of water, wherein the weight ratio (c)/(b) of the water-soluble carriers to the non-ionic tensio- active agents in the said mixture is from about 0.5/1 to about 15/1.
According to another broad embodiment, the present invention relates to an aqueous gelatin-free egg-free, two-phase coacervate composition comprising a coacervate phase and an equilibrium water phase, wherein said coacervate composition comprises or consists essentially of, per 100 parts by weight, a mixture of:
(a) from 2 to 30 parts by weight of a poorly water-soluble biologically-active agent,
(b) from 5 to 55 parts by weight of a polysaccharide-free tensio-active system with a HLB from 8 to 18 and consisting of one or more non-ionic tensio- active agents,
(c) from 2 to 40 parts by weight of one or more water-soluble carriers for said poorly water-soluble biologically-active agent, said carrier being selected from the group consisting of maltodextrins with a molecular weight below 1 ,800, erythritol, xylitol, sorbitol, mannitol, maltitol, isomalt, lactitol and mixtures thereof, and
(d) from 20 to 85 parts by weight of water, wherein the weight ratio (c)/(b) of the water-soluble carriers to the non-ionic tensio- active agents in the said mixture is from 0.005/1 to 3.5/1. By egg-free within the context of this embodiment, it is intended a composition which is free from egg portions such as egg yolk and/or egg white.
Within the framework of the above definitions of the first embodiment and the broad other embodiment of the present invention, and using the more specific teachings detailed below, the skilled person will be able to determine, without inventive contribution and simply performing routine experimental optimisation work, which specific weight proportions of the four required components (a), (b), (c) and (d) are more suitable for achieving a two-phase coacervate composition, depending upon the type (i.e. chemical nature and/or physical characteristics, such as water-solubility) of biologically-active agent to be formulated.
Depending upon the intended route of administration or application of the biologically-active agent formulation, 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. Depending upon the intended route of administration or application of the biologically-active agent formulation, 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. Depending upon the specific type (i.e. chemical nature and/or tensio-active characteristics) of the non-ionic tensio-active agent(s) present in the mixture, and upon the specific other components (a), (c) and (d) in the mixture, 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. Depending upon the specific type (i.e. chemical nature and/or tensio-active characteristics) of the non-ionic tensio-active agent(s) present in the mixture, and upon the specific other components (a), (c) and (d) in the mixture, 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. 4.794.000 and EP-416.575-A, the tensio-active system used in the present invention is preferably free from high molecular weight polysaccharides. Preferably 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. Depending upon the specific type (i.e. chemical nature and/or physical characteristics) of the water-soluble carher(s) present in the mixture, and upon the specific other components (a), (b) and (d) in the mixture, 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. Depending upon the specific type (i.e. chemical nature
and/or physical characteristics) of the water-soluble carrier(s) present in the mixture, and upon the specific other components (a), (b) and (d) in the mixture, 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). Depending upon parameters such as the exact water-solubility in particular of the water-soluble carher(s) and of the poorly water-soluble biologically-active agent, 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. Depending upon these parameters, 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. Thus the biologically active compositions according to this invention may be for pharmaceutical use, cosmetic use, veterinary use or for plant treatment. When 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. As known to those skilled in the art, such human or veterinary drugs belong to various therapeutic classes including, but not limited to, β-blockers, calcium antagonists, ACE inhibitors, sympatho-mimetic agents, hypoglycaemic agents, contraceptives, α-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), 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.
For instance 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, beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, bipehden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalosporins, cetihzine, chloramphenicol, chlordiazepoxide, chlorhexidine, chlorpheniramine, chlortalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, citalopram, clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphen, d i a ze pa m , diclofenac, digoxin, dihydrocodeine,
dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavine mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil, Ginkgo biloba, glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylpredni-solone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, paroxetine, penicillins, phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, physostigmine, piroxicam, polymyxin B, povidone iodine, pravastatin, prazepam, praziquantel, prazosin, prednisolone, prednisone, bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, risperidone, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatotropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracaine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, triazolam, trimethoprim, troxerutin, uracil,
valproic acid, verapamil, vitamins, folinic acid, zidovudine and zopiclone, including enantiomers thereof, organic and inorganic addition salts (including acid salts and base salts) thereof, and solvates (such as, but not limited to, hydrates and alcoholates) thereof. 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 μg/ml and may even have a water-solubility as low as about 0.2 μg/ml, at room temperature and physiological pH. 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.
As is demonstrated in one example below, 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. Depending upon parameters such as the particular poorly water-soluble biologically-active agent, the type and proportions of the other required components (b) and (c), 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. Depending upon the specific type (i.e. chemical nature and/or physical characteristics) of water-soluble carher(s) present in the mixture, and upon the specific type (i.e. chemical nature and/or tensio-active characteristics) of the non-ionic tensio-active agent(s) present in the mixture, in the first embodiment of the present invention this weight ratio (c)/(b) may be at least
0.5/1 , or at least 1/1 , or at least 2/1. Depending upon such parameters, 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.
In the other embodiment of the present invention 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. 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-α-D-gluco-pyranosyl-D- glucitol), isomaltitol, lactitol (4-O-α-D-galactopyranosyl-D-glucitol), glycerol (propan- 1 ,2,3-triol) and mixtures thereof in any suitable proportions.
Any bio-compatible or pharmaceutically acceptable grade of 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.
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:
- the 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; and
- the dextrose equ ivalent (herein referred as DE) of maltodextrin, which commonly ranges from about 1 to about 30, e.g. from 5 to 20, or from 9 to 27, or from 13 to 20.
According to another aspect, 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). According to a preferred embodiment of this invention, from 70% to 100% of the bio-active agent (a) is dissolved in the coacervate phase.
According to another aspect, 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. Although, as noted above, 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.
In many situations, especially due to the easiness and cost-effectiveness of handling, long-term storage and transportation, it may be desirable to provide the formulation of the poorly water-soluble biologically-active agent in solid form rather than in liquid form. Therefore, according to another aspect 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. It has been unexpectedly found that these solid forms can be produced as free-flowing powders which will not cause handling problems after a substantial storage period. These solid forms can be produced using standard drying technology in the art such as, but not limited to, spray-drying or freeze- drying.
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. Typically, 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 μm to about 200 μm) 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 μm 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 5-25μm;
- the fountain two-fluid nozzle: located in the cone of the drying chamber, spraying upwards. The fountain mode is selected to meet a more coarse and free-flowing powder specification. Often used for fine ceramics and other non- heat-sensitive products. The counter-current flow offers a dryer performance with excellent heat utilisation and provides the longer powder residence time in the drying chamber required to complete the drying to larger particles in the particle size range of 15 - 80μm. 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). Usually, the freezing temperature may be between about -50 0C and -80 0C.
During the primary drying step, pressure is decreased (e.g. to a few millibars), and enough heat is supplied to the frozen coacervate for its water to sublimate. In this initial drying phase, about 95% of the water in the frozen coacervate is sublimated. This step may be slow (up to several days on industrial scale) in order to avoid alteration of the material's structure. In this step, 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 0C) 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. In this step, the temperature is raised higher than in the primary drying step, and can even be above 00C, 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. After the freeze-drying process is complete, 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.
With each powder production method, the bio-active agent proportion in the composition is raised due to the removal of water. Advantageously 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. 40° to 600C) for a shorter period of time (ranging for instance from about 1 to 6 hours). 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;
- starch and pre-gelatinized starch;
- dicalcium phosphate and monocalcium phosphate; - saccharose;
- fructose;
- sorbitol; and
- mannitol.
The respective 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.
In many situations including, but not limited to, situations where 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.
Unless exceptional circumstances where the 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. Therefore, according to yet another aspect, 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. When 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. When the biologically-active agent (a) is a veterinary drug, 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. When 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.
According to yet another aspect, 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:
(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.
According to yet another aspect, 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
(iϋ) adding of the liquid solution or dispersion obtained in step (ii) to the solution prepared in step (i) under mixing.
As is readily understandable by the skilled person, the two above methods distinguish from each other by the order in which the required components of the aqueous coacervate composition are mixed. Depending upon parameters such as, but not limited to, the exact nature and the respective amounts of the poorly water- soluble biologically-active agent (a), the non-ionic tensio-active agents (b) and the
water-soluble carriers (c), 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.
Since both methods are suitable for producing aqueous coacervate compositions as defined in any of the specific embodiments described hereinabove with respect to the first aspect of this invention, 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.
With respect to the production of coacervate compositions according to the other broad embodiment of the present invention, the following methods are available:
- a method comprising the steps of:
(i) 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 300C below the melting point and 500C above the melting point of said poorly water-soluble biologically-active agent (a);
(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.
- a method comprising the steps of : (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 300C below the melting point and 500C 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.
Although in some situations, 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. Depending upon parameters such as, but not limited to, the respective 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), 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.
Since in each production method the three designated steps have proven to be sufficient for achieving aqueous coacervate compositions with suitable behaviour, 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
150 g Cremophor® EL (a polyoxyl 35 castor oil non-ionic tensio-active agent commercially available from BASF Corporation) was heated to 1500C and 60 g febantel (melting point: 127-132°C) was dissolved in the heated liquid. When the drug was visually dissolved, 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. Thereafter, 300 g 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 2 - production and water-dissolution of a febantel powder
After dispersing the coacervate phase into the equilibrium water phase of the coacervate composition prepared in example 1 by shaking and/or stirring, 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 1300C and the resulting outlet temperature was 58 0C.
A dissolution test in water was performed for the spray-dried free-flowing powder formulation at room temperature (20 - 25°C). The test showed that the drug powder formulation was completely dissolved within 5 minutes.
Example 3 - preparation of an aqueous gel-free coacervate system based on Tween 80
200 g Tween® 80 was heated to 1500C and 60 g febantel was dissolved in the heated liquid. When the drug was visually dissolved, 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 conditions (using a Silverson L4R device operated at 6000-8000 RPM) and after addition, mixing was continued during 5 minutes. Thereafter, 400 g maltodexthn (dextrose equivalent 18, commercially available as C*PharmDry 01983 from Cargill, France) was slowly added to the liquid under high-shear forces (using a Silverson L4R device operated at 6000 - 8000 RPM) and mixed during 5 minutes and stirred afterwards. An upper coacervate phase and a lower equilibrium water phase were obtained.
Example 4 - production and water-dissolution of a febantel powder
After dispersing the coacervate phase into the equilibrium water phase of the coacervate composition prepared in example 3 by means of shaking and/or stirring, 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 1300C and the resulting outlet temperature was 60 °C.
A dissolution test in water was performed at room temperature (20 - 25°C). The test showed that the drug powder formulation was completely dissolved within 5 minutes.
Example 5 (comparative) - preparation of a physical mixture based on Cremophor EL
6 g febantel was mixed with 30 g maltodextrin (dextrose equivalent 18, commercially available as_C*PharmDry 01983 from Cargill, France) by using the geometric dilution method, i.e. an equal amount (6 g) of maltodextrin was mixed with the total amount of febantel. An equal amount (12 g) of maltodextrin was mixed with the first mixture and so on. Thereafter, 15 g Cremophor® EL (a polyoxyl
35 castor oil non-ionic tensio-active agent commercially available from BASF
Corporation) was used as a granulation liquid for the mixture of febantel and maltodextrin.
Example 6 - comparison of aqueous dispersions of a spray-dried coacervate powder and a physical mixture based on Cremophor EL
When the spray-dried powder of example 2 was dispersed in water under stirring, a clear liquid was observed. The particles were floating in water and a very small amount of particles was precipitated on the bottom of the beaker. After 5 minutes the liquid was completely clear and all floating and precipitated particles were disappeared.
When the physical mixture of example 5 was dispersed in water under stirring, a clear liquid was observed. The particles were floating in the water and a significant amount of particles was precipitated on the bottom of the beaker. The floating particles disappeared after 5 minutes but, in contrast to the previous observation, a fraction of precipitated particles was still observed even after 60 minutes. The same dissolution test in water was performed at room temperature (20-
25°C) as in example 2. The test showed that only 3% of drug from the physical mixture was dissolved after 60 minutes, while (as noted in example 2) the spray dried formulation was completely dissolved within 5 minutes.
Example 7 - storage stability of a coacervate formulation
This example illustrates the stability of the coacervate powder formulation of example 2 at 7°C. A dissolution test was performed in water at room temperature (T = 20,9 0C). Afterwards, the samples were stored at 7°C and samples were taken immediately after dissolution, and 1 , 7 or 14 days after storage of the dissolved formulation at 7 0C. The percentage of drug recovered from the samples remains constant even after 14 days of storage 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.
Example 9 - determination of febantel proportion in the coacervate phase
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.
Therefore, a sample of 10 ml was taken from the equilibrium water_phase and a volume of 200 μl 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 μl 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. Based on the absorbance and the total volume of the liquid phase, 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 - alternative production method for the coacervate system This example illustrates an alternative method for producing a coacervate composition of this invention.
30 g maltodextrin (dextrose equivalent 18, commercially available as
C*PharmDry 01983 from Cargill, France) was dissolved in 100 ml of water.
Thereafter 15 g Cremophor® EL (commercially available from BASF Corporation) was heated to 1500C and 6 g febantel was dissolved in the heated Cremophor®
EL. After the drug was visually dissolved, the solution was kept at temperature
(1500C) for 2 minutes. These solution was added to water containing the dissolved maltodextrins under high shear mixing (using a Silverson L4R device operated at
6000-8000 RPM) and after addition, these compounds were mixed during 5 minutes.
In this way of production, a coacervate phase and an equilibrium water phase were obtained as well.
Example 11 - alternative aqueous coacervate composition This example illustrates the influence of using a mixture of water-soluble carriers. 15 g Cremophor® EL (commercially available from BASF Corporation) was heated to 150 °C and 6 g febantel was dissolved in the heated liquid. When the drug was visually dissolved, the solution was kept at temperature for 2 minutes. Thereafter, 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. Thereafter, a mixture of 20 g maltodextrin (dextrose equivalent 18, commercially available as C*PharmDry 01983 from Cargill, France) and 10 g mannitol was slowly added to the liquid under high-shear forces and mixed (using a Silverson L4R device operated at 6000-8000 RPM) during 5
minutes. A coacervate phase and an equilibrium water phase were obtained as well.
Example 12 - preparation of a high drug loading aqueous gel-free coacervate system based on Cremophor EL
150 g Cremophor® EL (a polyoxyl 35 castor oil non-ionic tensio-active agent commercially available from BASF Corporation, New Jersey) was heated to 1500C and 60 g febantel (melting point: 127-132°C) was dissolved in the heated liquid. When the drug was visually dissolved, 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. Thereafter, 10 g 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
Jersey) heated at 1300C. This molten phase was kept at 1300C for 2 minutes before being added to 1 liter of an aqueous solution (30% m/v) of maltodextrin (dextrose equivalent 18, commercially available as C*PharmDry 01983 from
Cargill, France) under homogenization (8000 rpm for 10 minutes) using a high sheer mixer (Silversson L4R, Waterside, UK). A milky liquid system was obtained, which was left to cool down for a period of 8 hours during which a coacervate biphasic system including an upper phase and a lower equilibrium water phase was formed.
Example 14 - determination of febantel proportions in the coacervate system
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 1300C, an outlet temperature of 600C 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.
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 storage stability of the powder and granule formulations of examples 15 and 16 was investigated. Storage at 25°C and 60% relative humidity (RH), or at 400C and 75% RH, did not significantly change the febantel release profile in the dissolution test of example 17. From the spray dried powder formulation of example 15, 100% release was achieved within 10 minutes. No solid state changes of the drug were observed during storage under such conditions.
Example 19 - in vivo evaluation of febantel formulations in pigs
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.
Claims
1. An aqueous gelatin-free, egg portion-free, two-phase coacervate composition comprising a coacervate phase and an equilibrium water phase, wherein said composition comprises, per 100 parts by weight, a mixture of:
(a) from 2 to 30 parts by weight of a poorly water-soluble biologically-active agent,
(b) from 5 to 55 parts by weight of a polysaccharide-free tensio-active system with a HLB from 8 to 18 and consisting of one or more non-ionic tensio- active agents,
(c) from 2 to 40 parts by weight of one or more water-soluble carriers for said poorly water-soluble biologically-active agent, said carrier being selected from the group consisting of maltodextrins with a molecular weight below 1 ,800, erythritol, xylitol, sorbitol, mannitol, maltitol, isomalt, lactitol and mixtures thereof, and
(d) from 20 to 85 parts by weight of water, wherein the weight ratio (c)/(b) of the water-soluble carriers to the non-ionic tensio- active agents in the said mixture is from 0.005/1 to 3.5/1.
2. An aqueous two-phase coacervate composition according to claim 1 , wherein said poorly water-soluble biologically-active agent (a) is a therapeutically active drug, a pesticide, a cosmetic agent, a fertiliser, a herbicide, a plant growth regulator, a crop treatment agent or an anti-microbial agent.
3. An aqueous two-phase coacervate composition according to claim 1 or claim 2, wherein from 70% to 100% of said poorly water-soluble biologically-active agent (a) is dissolved in the coacervate phase.
4. An aqueous two-phase coacervate composition according to any one of claims 1 to 3, wherein said non-ionic tensio-active agent (a) is selected 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.
5. The coacervate phase of an aqueous two-phase coacervate composition according to any one of claims 1 to 4.
6. The equilibrium water phase of an aqueous two-phase coacervate composition according to any one of claims 1 to 4.
7. A powder being a dried form of the coacervate phase of claim 5 or the coacervate composition of claim 1.
8. A powder according to claim 7, wherein the weight proportion of the poorly water-soluble biologically-active agent ranges from 2.5% to 20%.
9. A water-soluble formulation comprising a water-soluble amount of a powder according to claim 7.
10. A method for producing an aqueous coacervate composition according to claim 1 comprising the steps of:
(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 300C below the melting point and 500C above the melting point of said poorly water-soluble biologically-active agent (a); (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.
11. A method for producing an aqueous coacervate composition according to claim 1 comprising the steps of :
(e) dissolving one or more water-soluble carriers (c) into water;
(f) 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 300C below the melting point and 500C above the melting point of said poorly water-soluble biologically-active agent (a), and
(g) adding the liquid solution or dispersion obtained in step (j) to the solution prepared in step (i) under mixing.
12. A method for producing an aqueous coacervate composition according to claim 10 or claim 1 1 , further comprising the step of cooling down the mixture until the coacervate phase separates from the equilibrium water phase.
13. A method for producing a powder according to claim 7 or claim 8, comprising the steps of : (i) producing an aqueous two-phase coacervate composition according to claim 1 ; (ii) optionally separating the coacervate phase from the equilibrium water phase of said aqueous two-phase coacervate composition, and
(iii) drying the coacervate phase, optionally combined together with the equilibrium water phase, until at least 70% of water contained in said phase(s) is removed.
14. A method according to claim 13, wherein the drying step (iii) is effected by spray-drying or freeze-drying.
15. A method according to claim 13, comprising the step of separating the coacervate phase from the equilibrium water phase of said aqueous two-phase coacervate composition, and using said coacervate phase as a granulating liquid for wet granulating a biologically-inactive carrier prior to the drying step (iii).
16. A method for producing a water-soluble formulation according to claim 9, comprising producing a powder according to claim 7 or claim 8, and re-dispersing or re-suspending said powder into water until the water-solubility limit of said powder is achieved.
17. An aqueous gelatin-free two-phase coacervate composition comprising a coacervate phase and an equilibrium water phase, wherein said composition comprises, per 100 parts by weight, a mixture of:
(a) from 0.01 to 30 parts by weight of a poorly water-soluble biologically-active agent,
(b) from 5 to 30 parts by weight of one or more non-ionic tensio-active agents,
(c) from 5 to 75 parts by weight of one or more water-soluble carriers for said poorly water-soluble biologically-active agent, said carrier being selected from the group consisting of maltodextrins with a dextrose equivalent of 1 to 30, erythritol, xylitol, sorbitol, mannitol, maltitol, isomalt, lactitol and mixtures thereof, and
(d) from 35 to 85 parts by weight of water, wherein the weight ratio (c)/(b) of the water-soluble carriers to the non-ionic tensio- active agents in the said mixture is from 0.5/1 to 15/1.
18. An aqueous two-phase coacervate composition according to claim 17, wherein said poorly water-soluble biologically-active agent is a therapeutic drug, a pesticide, a cosmetic agent, a fertiliser, a herbicide, a plant growth regulator, a crop treatment agent or an anti-microbial agent.
19. An aqueous two-phase coacervate composition according to claim 17 or claim 18, wherein at least about 70% of said poorly water-soluble biologically-active agent is included in the coacervate phase.
20. An aqueous two-phase coacervate composition according to any one of claims 17 to 19, wherein said non-ionic tensio-active agent is selected from the group consisting of cholesterol esters, ethylene glycol fatty acid esters, ethoxylated esters, (poly)glycerol fatty acid esters, mono- and diglycerides 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.
21. The coacervate phase of an aqueous two-phase coacervate composition according to any one of claims 17 to 20.
22. The equilibrium water phase of an aqueous two-phase coacervate composition according to any one of claims 17 to 20.
23. A powder being a dried form of the coacervate phase of claim 21 or the coacervate composition of claim 17.
24. A water-soluble formulation comprising a water-soluble amount of a powder according to claim 23.
25. A method for producing an aqueous coacervate composition according to claim 17 comprising the steps of:
(i) 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 (a); (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.
26. A method for producing an aqueous coacervate composition according to claim 17 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-ion ic tensio-active agents (b) at a temperature not below the melting point of said poorly water-soluble biologically-active agent (a), and
(iϋ) adding the liquid solution or dispersion obtained in step (ii) to the solution prepared in step (i) under mixing.
27. A method for producing a powder according to claim 23, comprising the steps of : (iv) producing an aqueous two-phase coacervate composition according to claim 17;
(v) optionally separating the coacervate phase from the equilibrium water phase, and
(vi) drying the coacervate phase optionally together with the equilibrium water phase.
28. A method according to claim 27, wherein the drying step (vi) is effected by spray-drying or freeze-drying.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0900473A GB0900473D0 (en) | 2009-01-13 | 2009-01-13 | Aqueous coacervate compositions suitable for making powders and water-soluble formulations of biologically-active agents |
PCT/EP2010/050330 WO2010081815A1 (en) | 2009-01-13 | 2010-01-13 | Aqueous coacervate composition comprising poorly water-soluble biologically-active agents |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2376061A1 true EP2376061A1 (en) | 2011-10-19 |
Family
ID=40379479
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10702263A Withdrawn EP2376061A1 (en) | 2009-01-13 | 2010-01-13 | Aqueous coacervate composition comprising poorly water-soluble biologically-active agents |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP2376061A1 (en) |
GB (1) | GB0900473D0 (en) |
WO (1) | WO2010081815A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB201011821D0 (en) * | 2010-07-14 | 2010-09-01 | Univ Gent | Aqueous coacervate compositions suitable for making powders and water-soluble formulations of biologically-active agents |
US10335371B2 (en) | 2015-02-17 | 2019-07-02 | Universiteit Gent | Solid pharmaceutical dosage form suitable for use as drinking water medication |
GB201903406D0 (en) * | 2019-03-13 | 2019-04-24 | Certis Europe Bv | Composition |
Family Cites Families (9)
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 |
DE3411627A1 (en) * | 1984-03-29 | 1985-10-03 | Bayer Ag, 5090 Leverkusen | STABILIZED ANTHELMINTIC FORMULATIONS |
US4794000A (en) | 1987-01-08 | 1988-12-27 | Synthetic Blood Corporation | Coacervate-based oral delivery system for medically useful compositions |
US5079018A (en) | 1989-08-14 | 1992-01-07 | Neophore Technologies, Inc. | Freeze dry composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs |
NO903844L (en) | 1989-09-05 | 1991-03-06 | Neophore Tech Inc | MEDICINAL DELIVERY MIXTURES BASED ON BIOLOGICAL CELLS OR COMPONENTS THEREOF AND PROCEDURES. |
NZ260018A (en) * | 1994-03-03 | 1995-10-26 | Bomac Lab Ltd | Benzimidazole compositions and anthelmintic compositions |
GB9909369D0 (en) * | 1999-04-26 | 1999-06-16 | Eurand Int | Method for production of microcapsules |
DE10314976A1 (en) * | 2003-04-02 | 2004-10-14 | Bayer Healthcare Ag | Improved penetration of drugs into cells and organs |
AU2005210632B2 (en) * | 2004-02-03 | 2011-02-03 | Zoetis Services Llc | Anthelmintic composition |
-
2009
- 2009-01-13 GB GB0900473A patent/GB0900473D0/en not_active Ceased
-
2010
- 2010-01-13 EP EP10702263A patent/EP2376061A1/en not_active Withdrawn
- 2010-01-13 WO PCT/EP2010/050330 patent/WO2010081815A1/en active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2010081815A1 * |
Also Published As
Publication number | Publication date |
---|---|
GB0900473D0 (en) | 2009-02-11 |
WO2010081815A1 (en) | 2010-07-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10532028B2 (en) | Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced | |
US10189957B2 (en) | Formulation process method to produce spray dried products | |
CN101193624B (en) | Production of solid solutions based on poorly-soluble active substances by a short-term heating and rapid drying | |
US6953593B2 (en) | Sustained-release microencapsulated delivery system | |
CA2311308C (en) | Method for producing solid dosing forms | |
US6368634B1 (en) | High release solid preparation, preparation and use thereof | |
KR101442069B1 (en) | Method for improving the aqueous solubility of poorly-soluble substances | |
US6669879B1 (en) | Method for producing solid dosing forms | |
CA2339913C (en) | Pharmaceutical formulations and method for making | |
US20110294864A1 (en) | Aqueous coacervate compositions suitable for making powders and water-soluble formulations of biologically-active agents | |
EP2376061A1 (en) | Aqueous coacervate composition comprising poorly water-soluble biologically-active agents | |
Shinde et al. | Recent advances in granulation techniques | |
EP2407156A2 (en) | Aqueous coacervate compositions suitable for making powders and water-soluble formulations of biologically-active agents | |
CA2253700A1 (en) | The production of solid dosage forms | |
CA2257547A1 (en) | Process for producing solid dosage forms | |
EP2034965A2 (en) | Process for preparing a solid dosage form | |
JP2005255619A (en) | Solid pharmaceutical preparation composition comprising sublimable active ingredient and porous cellulose particle | |
JPWO2006106799A1 (en) | Microcapsules using polyvinyl alcohol copolymer | |
JP2024091760A (en) | Composites containing amorphous solid dispersions | |
DE10010509A1 (en) | Oral pharmaceutical formulations with controllable release characteristics, e.g. rapid or delayed release, contain sucrose fatty acid ester as drug release controlling agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20110629 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20120426 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20120801 |