NL1040498C2

NL1040498C2 - Powders for reconstitution.

Info

Publication number: NL1040498C2
Application number: NL1040498A
Authority: NL
Inventors: Lieven Elvire Colette Baert; Remi Emiel Maria Broeck
Original assignee: Jalima Pharma Bvba
Priority date: 2013-11-14
Filing date: 2013-11-14
Publication date: 2015-05-19

Description

Powders for Reconstitution

Field of the Invention

This invention relates to powders for reconstitution comprising carbamazepine dispersed in certain water-soluble polymers, for use in the treatment of subjects in need of carbamazepine treatment.

Background of the Invention

Carbamazepine or 5//-dibenzo[6/)azepine-5-carboxamide is indicated as an anticonvulsant in the treatment of seizure disorders. It is used primarily in the treatment of epilepsy with the following seizure types: partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal) and mixed seizure patterns, which include the above, or other partial or generalized seizures. Carbamazepine also finds use in the treatment of simple partial (focal or Jacksonian) seizures. It is not used in the treatment of absence seizures (petit mal). Carbamazepine is also useful in the treatment of bipolar disorder and neuropathic pain. It is further indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. It may also be applied in the treatment of a variety of indications, including attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, congenital myotonia, and post-traumatic stress disorder.

The dose of carbamazepine varies along the condition that is being treated and along the patient group. For treatment of epilepsy in adults, the initial dose is 200 mg orally twice daily (immediate and extended release) or 100 mg orally 4 times a day (suspension). Subsequently the dose is increased at weekly intervals in 200 mg/day increments using a twice daily regimen of extended release or a three times a day or four times a day regimen of the other formulations. The maintenance dose is 800 to 1200 mg/day and generally does not exceed 1200 mg/day although doses up to 1600 mg/day have been used in rare instances.

For treatment of trigeminal neuralgia in adults, the initial dose is 100 mg orally twice daily (immediate or extended release) or 50 mg orally four times a day (suspension). The dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours (immediate or extended release), or 50 mg four times a day (suspension), only as needed to achieve freedom from pain. A treshold of 1200 mg/ day is observed while the maintenance dose is 400 to 800 mg/day. Some patients may be maintained on as little as 200 mg/day while others may require as much as 1200 mg/day.

For treatment of bipolar disorder in adults, the initial dose is 200 mg orally in tablet or capsule form every 12 hours or 100 mg of oral solution 4 times a day. Following autoinduction, higher doses will be necessary to maintain drug levels within the therapeutic range of 6 to 12 pg/mL. Using tablets and solution the daily dose usually is increased in 100 to 200 mg increments at 1 to 2 week intervals. The maintenance dose is up to 1200 mg daily in 3 or 4 divided doses may be necessary to maintain plasma levels in the therapeutic range. Using extended release capsules, the dose usually is adjusted in 200 mg daily increments (increase by 100 mg twice daily) to achieve optimal clinical response.

Treatment of diabetic neuropathy in adults requires an initial dose of 100 mg orally in tablet form every 12 hours or 50 mg of oral solution 4 times a day. The daily dose is increased in 100 mg increments at 1 to 2 week intervals. The maintenance dose is 600 to 1200 mg daily in 3 or 4 divided doses to maintain plasma levels in the therapeutic range.

For pediatric applications, carbamazepine is administered in the form of tablets or as a suspension at doses varying with age. For children up to 6 years the initial dose usually is 10 to 20 mg/kg/day orally in 2 to 3 divided doses (tablets) or 4 divided doses (suspension). The dose is then increased to achieve optimal clinical response to a maximum dose of 35 mg/kg/day. For children from 6 to 12 years the initial dose usually is 100 mg orally twice a day (immediate or extended release tablets) or 50 mg orally 4 times a day (suspension). The dose is then increased in 100 mg/day increments using a twice daily regimen of extended release or a three times a day or four times a day regimen of the other formulations. The maintenance dose is 400 to 800 mg/day. For children over 12 years the initial dose usually is 200 mg orally twice a day (immediate and extended release) or 100 mg orally 4 times a day (suspension). The dose is then increased in 200 mg/day increments using a twice a day regimen of extended release or a three times daily to four times daily regimen of the other formulations. The maintenance dose is 800 to 1200 mg/day.

Pediatric medication poses particular challenges in that the dose regimens vary to a large extent due to variations in age and body weight (babies - children).

Especially in the first year after birth, an infant undergoes rapid changes and body weight increases spectacularly. Because of these rapid changes at young age, dosing of a drug needs to be adjusted frequently and dosage forms need to offer flexibility in dosing. Traditional dosage forms such as pills and capsules lack the dosing flexibility required in pediatric applications. Moreover, these dosage forms are not fit for administration to young children and especially to infants in which case drinkable formulations are the preferred route of administration. These comprise liquid formulations such as syrups as well as dry formulations such as powders for reconstitution in which the drug is distributed in dry form and is converted in liquid form by adding water.

Powders for reconstitution are attractive over liquid oral dosage forms because of their compactness making them more convenient to store and transport. Incorporating carbamazepine in a powder for reconstitution however poses particular challenges in that it is poorly soluble in water. Upon addition of water, only a limited amount is dissolved not resulting in effective uptake of the active ingredient.

Summary of the Invention

An object of the present invention is to provide formulations, in particular for pediatric use, of carbamazepine that are convenient to use, that are compact and are flexible in use while showing effective bioavailability.

It has been found that carbamazepine can be converted into a powder for reconstitution, which allows flexible application of the active ingredient and moreover can be used in pediatric applications. The powders for reconstitution of the invention allow the prescribing physician to precisely adapt the dosing to the patient’s needs, for example in selecting the initial dose, the dose increments and the final dose. The dose can be easily adapted to the length and weight of the patient to be treated or to the condition to be treated.

The powders for reconstitution of the invention may also be applied in adult patient groups that have difficulty or find inconvenience in swallowing solid dosage forms, for example the elderly. The inventive powders for reconstitution, upon addition of water, result in dosage forms that upon intake result in effective therapeutic plasma concentrations and bioavailability of the active ingredient.

In one aspect the present invention relates to a powder for reconstitution comprising a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose, to be mixed with water, for use in the treatment of a subject suffering from a condition that can be treated with carbamazepine. In another aspect there is provided a powder for reconstitution as specified herein for the manufacture of a medicament for the treatment of a subject suffering from a condition that can be treated with carbamazepine.

In one embodiment said powder is obtained by spray-drying.

In a further aspect there is provided a method of treating a subject suffering from a disorder that can be treated with carbamazepine in need of such treatment, said method comprising the administration to said subject of a powder for reconstitution comprising a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose, wherein prior to administration the powder is mixed with water.

In one embodiment the disorder that can be treated with carbamazepine is a seizure disorder, in particular the disorder is epilepsy. In a further embodiment, the disorder is bipolar disorder or neuropathic pain.

The amount of carbamazepine in the powders for reconstitution in accordance with the invention in particular is an amount effective to treat the concerned disorder.

In a further aspect there is provided a supersaturated solution of carbamazepine and a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose, in an aqueous medium. Said supersaturated solution can be obtained by adding an aqueous medium, in particular by adding water, to a powder for reconstitution comprising a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose. In an still a further aspect there is provided a supersaturated solution of carbamazepine and a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose, obtainable or obtained by adding water to a powder for reconstitution comprising a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose.

In another aspect, there is provided a method of treating a subject suffering from a condition that can be treated with carbamazepine, said method comprising the administration of a supersaturated solution of carbamazepine in an effective amount and a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinyl-pyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose, in an aqueous medium. The invention in addition provides a supersaturated solution of carbamazepine as specified herein for use in the treatment of a subject suffering from a condition that can be treated with carbamazepine, or, for the manufacture of a medicament for use in the treatment of a subject suffering from a condition that can be treated with carbamazepine.

The present invention also provides a method or process of preparing a supersaturated solution of carbamazepine and a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose, in an aqueous medium, said method or process comprising adding water to a powder for reconstitution comprising a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and a hydroxyalkyl alkylcellulose.

Description of the Figures

Figure 1: dissolution in water of a powder for reconstitution of carbamazepine /polymer (HPMC) 20/80 (w/w)

Figure 2: dissolution in 0.02M HC1; carbamazepine /polymer (HPMC) 20/80 (w/w) Description of the Invention

The powders for reconstitution for use in the present invention comprise the active ingredient carbamazepine dispersed in particular water-soluble polymers, which may be referred to as a solid dispersion of the active ingredient carbamazepine in the particular water-soluble polymers. The latter are selected from polyvinylpyrrolidone (PVP) and copolymers of vinylpyrrolidone and vinyl acetate (PVPCoVA, sometimes also referred to as PVP-VA); and hydroxyalkyl alkylcelluloses, in particular hydroxyCi^alkyl Ci^alkylcelluloses such as hydroxypropyl methylcellulose (HPMC).

The active ingredient carbamazepine may be dispersed more or less evenly throughout the water-soluble polymer or can be dispersed uniformly or homogenously throughout the polymer. In the former instance the active ingredient is dispersed less homogenous throughout the polymer. There may be domains or small regions wherein amorphous, microcrystalline or crystalline carbamazepine, or amorphous, microcrystalline or crystalline water-soluble polymer, or both, are dispersed more or less evenly in the water-soluble polymer.

The active ingredient carbamazepine may be dispersed as fine particles comprising or consisting of carbamazepine in the water-soluble polymer, of clusters of molecules of carbamazepine, or of individual carbamazepine molecules. In the latter instance, the solid dispersion can be referred to as a “solid solution”. Particular embodiments of this invention relate to solid solutions of carbamazepine in the particular water-soluble polymers mentioned herein, e.g. solid solutions of carbamazepine in hydroxypropyl methylcellulose. Whenever used herein, the term “solid dispersion” is meant to comprise any of the types of dispersions mentioned herein, including solid solutions. Of interest for use in the present invention are solid solutions.

The amount of water-soluble polymer in the solid dispersion of carbamazepine in the particular water-soluble polymers may be in the range from about 50% to about 99%, in particular about 60% to about 95%, or about 70% to about 90%, e.g. about 80%. The weight: weight ratio of water-soluble polymer to carbamazepine in the solid dispersion of carbamazepine in the particular water-soluble polymers may be in the range of about 20 : 1 to about 1 : 1, or about 10 : 1 to about 1: 1, or about 8 : 1 to about 2 : 1, for example said weight: weight ratio may be about 5 : 1. The amount of carbamazepine in the solid dispersions of carbamazepine of the invention may be in the range from about 1% to about 50%, in particular about 5% to about 40%, or about 10% to about 30%, e.g. about 20%. The solid dispersions of carbamazepine of the invention may contain further excipients that make up the remainder of the solid dispersions, i.e. an amount making up 100%. In particular said excipients may be present in an amount that may be in the range from about 0% to about 30%, in particular about 0% to about 20%, or about 0% to about 10%, or part of these ranges to make up 100%. In one embodiment no further excipients are present. All percentages herein are by weight relative to the total weight of the solid dispersion.

The powders for reconstitution for use in the present invention may comprise the solid dispersion of the active ingredient carbamazepine in the particular water-soluble polymers in an amount that may be in the range from about 60% to about 100%, in particular about 70% to about 100%, or about 80% to about 100% or about 90% to about 100%, all percentages by weight relative to the total weight of the powder for reconstitution. Other excipients may be present, such as the excipients suitable for addition to the powders for reconstitution mentioned hereinafter, in an amount that makes up the remainder of the powder for reconstitution, i.e. an amount making up 100%. In particular said excipients may be present in an amount that may be in the range from about 0% to about 40%, in particular about 0% to about 30%, or about 0% to about 20% or about 0% to about 10%, or part of these ranges to make up 100%. All percentages herein are by weight relative to the total weight of the powder for reconstitution.

As used herein the term “alkyl” refers to straight or branched saturated hydrocarbon radicals. In one embodiment alkyl is Ci^alkyl, which defines straight or branched saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl. In one embodiment, the water-soluble polymer has a molecular weight in the range 500 D to 2 MD. The water-soluble polymer may have an apparent viscosity of 1 to 15,000 mPa.s, or of 1 to 5000 mPa.s, or of 1 to 700 mPa.s, or of 1 to 100 mPa.s when in a 2% (w/v) aqueous solution at 20°C.

Particular hydroxyalkyl alkylcelluloses include hydroxyethyl methylcellulose and hydroxypropyl methylcellulose (or HPMC, e.g. HPMC 2910 15 mPa.s; HPMC 2910 5 mPa.s).

Said HPMC contains sufficient hydroxypropyl and methoxy groups to render it water-soluble. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble. The term “methoxy degree of substitution” refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hvdroxvoronvl molar substitution refers to the averaee number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. A preferred HPMC is hypromellose 2910 15 mPa.s or hypromellose 2910 5 mPa.s, especially hypromellose 2910 15 mPa.s. Hydroxypropyl methylcellulose is the United States Adopted Name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). In the four digit number "2910", the first two digits represent the approximate percentage of methoxy groups and the third and fourth digits the approximate percentage composition of hydroxypropoxyl groups; 15 mPa.s or 5 mPa.s is a value indicative of the apparent viscosity of a 2 % aqueous solution at 20°C.

Solid dispersions of carbamazepine in HPMC, and in particular HPMC 2910 15 mPa.s, are particularly attractive for use in the present invention due to their superior properties such as, for example, stability of the solid dispersion and of the supersaturated solution obtained upon mixture with water, the high content of active ingredient in said supersaturated solution, dissolution characteristics, bioavailability, ease of manufacture and other properties.

Copolymers of vinylpyrrolidone and vinyl acetate that may be used include those copolymers wherein the molecular ratio of the monomers vinylpyrrolidone to vinyl acetate is about 1.2 or wherein the mass ratio of the monomers vinylpyrrolidone to vinyl acetate is about 3 : 2. Such copolymers are commercially available and are known as copovidone or copolyvidone, sold under trademarks Kolima™ or Kollidon VA 64™. The molecular weight of these polymers may be in the range of about 45 to about 70 kD. The K-value, obtained from viscosity measurements may be in the range of about 25 to about 35, in particular the K value may be about 28.

Polyvinylpyrrolidine polymers that may be used are known as povidone (PVP) and are commercially available. They may have a molecular weight that is in the range of about 30 kD to about 360 kD. Examples include PVP K25 (BASF, MW of about 29,000), PVP K29-32, PVP K30 (BASF, MW of about 40,000), and PVP K90 (BASF, MW of about 360,000), available under the tradename Kolidon™.

Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation.

The solution-evaporation process comprises the following steps: a) dissolving carbamazepine and the water-soluble polymer in an appropriate solvent, optionally at elevated temperature; b) allowing the solvent in the solution obtained in step a) to evaporate, optionally by heating, or optionally under vacuum, or both, until dry material is obtained. The solution may also be poured onto a large surface so as to form a thin film, and the solvent evaporated therefrom.

The melt-extrusion process usually comprises the following steps: a) mixing carbamazepine and the water-soluble polymer, b) optionally blending additives with the thus obtained mixture, c) heating and compounding the thus obtained blend until one obtains a homogeneous melt, d) forcing the thus obtained melt through one or more nozzles; and e) cooling the melt until it solidifies.

The terms "melt" and “melting” should be interpreted broadly. These terms not only mean the alteration from a solid state to a liquid state, but can also refer to a transition to a glassy state or a rubbery state, wherein it is possible for one component of the mixture to get embedded homogeneously or more or less homogeneously into the other. In particular cases, one component will melt and the other component(s) will dissolve in the melt thus forming a solution, which upon cooling may form a solid solution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, the obtained products are milled and optionally sieved. The solid dispersion product may be milled or ground to particles having a particle size of less than 600 pm, or less than 400 pm, or less than 125 pm, or any of the particle sizes mentioned hereinafter. A preferred process to prepare the powders for reconstitution for use in the present invention is by the spray-drying technique. In this technique carbamazepine and the water-soluble polymer are dissolved in an appropriate solvent and the resulting solution is then sprayed through the nozzle of a spray dryer whereby the solvent from the resulting droplets is evaporated, usually at elevated temperatures, e.g. by the introduction of hot air.

The amount of water-soluble polymer in the spray dried product may be as specified above more generally for the solid dispersions of the invention. The amount of water-soluble polymer in the feed mixture can be calculated based on these amounts and on the amount of solvent used.

The solvent used in the spray drying procedure may be any solvent that is inert towards carbamazepine and that is able to dissolve carbamazepine and the water-soluble polymer. Suitable solvents include acetone, tetrahydrofuran (THF), dichloromethane, ethanol (anhydrous or aqueous), methanol, and combinations thereof. Of interest are mixtures of methylene chloride and methanol, the latter in particular being anhydrous methanol, in particular mixtures of these two solvents wherein the v/v ratio methanol / methylene chloride is in the range of about 90 : 10 to about 10 : 90; or in the range of about 20 :.80 to about 80 : 20, or in the range of about 30 : 70 to about 70 : 30; e.g. in a 50 : 50 ratio. In one embodiment, the solvent is dichloromethane.

The amount of solvent present in the feed mixture will be such that carbamazepine and the water-soluble polymer are dissolved and that the feed mixture has sufficient low viscosity for it to be sprayed. In one embodiment the amount of solid materials in the feed mixture is less than 20%, in particular less than 10%, more in particular less than 5%, these percentages expressing the weight amount of solid materials to the total volume of the feed mixture.

The solvent is removed from the droplets of the feed mixture by the spraydrying step. Preferably the solvent is volatile, with a boiling point of 150°C or less, preferably 100°C or less.

The drying gas may be any gas. Preferably, the gas is air or an inert gas such as nitrogen, nitrogen-enriched air or argon. The temperature of the drying gas at the gas inlet of the spray-drying chamber can be in the range from about 25°C to about 300°C, or from about 60°C to about 300°C, or from about 60°C to about 150°C.

The spray-drying process may be conducted in a conventional spray-drying apparatus comprising a spray-drying chamber, atomizing means for introducing the feed mixture into the spray-drying chamber in the form of droplets, a source of heated drying gas that flows into the spray-drying chamber through an inlet, and an outlet for the heated drying gas. The spray-drying apparatus also comprises a means for collecting the solid pharmaceutical powder that is produced. The atomizing means can be a rotary atomizer, a pneumatic nozzle or, preferably, a high-pressure nozzle.

Suitable rotary atomizers include those having an air turbine drive operating from a high pressure compressed air source, for example a 6 bar compressed air source, which supplies power to an atomization wheel for atomizing the feed mixture.

The atomization wheel may be vaned. Preferably, the rotary atomizer is located in the upper part of the spray-drying chamber, for example in the chamber roof, so that the droplets produced dry and fall to the lower part of the chamber. Typically, rotary atomizers produce droplets that have a size in the range of from about 20 to about 225 pm, in particular from about 40 to about 120 pm, the droplet size depending upon the wheel peripheral velocity.

Suitable pneumatic nozzles (including two-fluid nozzles) comprise those that are located in the upper part of the spray-drying chamber, for example in the chamber roof, and operate in so-called "co-current mode". Atomization takes place using compressed air such that the air-liquid ratio is in the range of about 0.5-1.0 : 1 to about 5 : 1 , in particular from about 1 : 1 to about 3 : 1. The feed mixture and the atomizing gas are passed separately to the nozzle head, where the atomization takes place. The size of the droplets produced by pneumatic nozzles depends on the operating parameters and can be in the range from about 5 to 125pm, in particular from about 20 to 50 pm.

Two-fluid nozzles that operate in so-called "counter-current mode" may also be used. These nozzles operate in a similar way to two-fluid nozzles in co-current modes except that they are located in a lower part of the drying chamber and spray droplets upwards. Typically, counter-current two-fluid nozzles generate droplets, which, when dried, produce particles having a size in the ranging from about 15 to about 80 pm. A preferred atomizer type for use in the invention is the high-pressure nozzle where liquid feed is pumped to the nozzle under pressure. Pressure energy is converted to kinetic energy, and feed issues from the nozzle orifice as a high-speed film that readily disintegrates into a spray as the film is unstable. The feed is made to rotate within the nozzle using a swirl insert or swirl chamber resulting in cone-shaped spray patterns emerging from the nozzle orifice. Swirl insert, swirl chamber and orifice dimensions together with variation of pressure gives control over feed rate and spray characteristics. The size of the droplets produced by high-pressure nozzles depends on the operating parameters and can be in the range from about 5 to 125 pm, in particular from about 20 to 50 pm.

Suitable atomizing means may be selected depending on the desired droplet size, which depends on a number of factors, such as the viscosity and temperature of the feed mixture, the desired flow rate and the maximum acceptable pressure to pump the feed mixture, have on droplet size. After selecting the atomizing means so that the desired average droplet size is obtained for a feed mixture having a particular viscosity, the mixture is admitted to the spray-drying chamber at a particular flow rate.

The solid dispersion produced by the spray drying process or by the other processes described above (such as solution evaporation and melt extrusion), followed by milling and optional sieving, may result in particles having an average effective particle size in the range of from about 10 pm to about 150 pm, or about 15 pm to about 100 pm, particularly about 20 pm to about 80 pm, or 30 pm to about 50 pm, preferably about 40 pm. As used herein, the term "average effective particle size" has its conventional meaning as known to the person skilled in the art and can be measured by art-known techniques such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation. The average effective particle sizes mentioned_herein may be related to weight distributions of the particles. In that instance, by the term "an average effective particle size of about 150 pm" is meant that at least 50% of the weight of the particles consists of particles having a particle size of less than the effective average of 50 pm, and the same applies to the other effective particle sizes mentioned. In a similar manner, the average effective particle sizes may be related to volume distributions of the particles but usually this will result in the same or about the same value for the average effective particle size.

Optionally, further excipients may be included in the feed mixture, for example to improve properties of the feed mixture or the resulting solid pharmaceutical composition, such as handling or processing properties. Further excipients may also be mixed with the resulting solid dispersion.

Excipients that can be included in the solid dispersions, or mixed with the solid dispersion in the powders for reconstitution prepared therefrom, or both, comprise disintegrants, surfactants, pigments, flavors, fillers, lubricants, preservatives, thickening agents, buffering agents, and pH modifiers. Typical pH modifiers that can be added include acids, such as citric acid, succinic acid, tartaric acid; bases; or buffers.

Prior to use, water or other aqueous media such as those containing ingredients to make the solutions more palatable e.g. sugars, such as glucose or flavors, is added to the powders for reconstitution. The quantity of water that is added is in the range of about 0.5 ml to about 5 ml water per mg carbamazepine, or of about 0.5 ml to about 2 ml water per mg carbamazepine, or of about 0.5 ml to about 1 ml water per mg carbamazepine, e.g. about 0.6 ml water per mg carbamazepine. Addition of water to a powder for reconstitution comprising a solid dispersion in a water-soluble polymer as specified herein, generates a supersaturated solution from which the carbamazepine active ingredient does not precipitate, which is unexpected.

The powders for reconstitution of the invention can be packed in suitable containers from which the desired amount of powder is dispensed. The containers may be equipped with a tool that allows dispensing variable amounts of powder. The powders may also be packed in units suchs as packs or capsules each containing a predetermined quantity of the drug. The amount of drug to be administered can also be adapted by administering specific volumes of reconstituted liquid.

The powders for reconstitution of the invention will find use mainly in pediatric applications, not only because of the ease of administration to infants and children but also because of the convenience of dosing in function of age and body weight. A further target group is adult patients that have difficulty in swallowing solid dosage forms such as tablets or capsules. The powders for reconstitution of the invention show good uptake of the active ingredient and result in effective plasma levels.

The powders for reconstitution of carbamazepine are preferably administered once or several times daily, in particular twice daily. They may also be administerd three or four times daily.

The powders for reconstitution of the present invention can be used in veterinary applications as well as for the treatment of human conditions. As used herein the term “subject” in particular relates to a human being. The terms “subject” and “patient” are used herein interchangeably.

The dose of carbamazepine administered, which is determined by the amount of carbamazepine in the formulation for use in the invention and the quantity of formulation administered, in adults is in the range of about 400 to about 1600 mg per day, or of about 800 to about 1200 mg per day. For children, the dose can be determined by the child’s body surface area, which is calculated using the child’s height and weight. A dose corresponding to that cited above is recommended.

The powders for reconstitution of the invention allow the treating physician to determine the dose to be administered by multiplying the mentioned dosages by a factor determined by the body weight of the patient.

The powders for reconstitution of the present invention can be applied for any medical condition or disease for which carbamazepine can be used, in particular the medical conditions mentioned herein above. The powders for reconstitution of the present invention can be used in the treatment of simple partial seizures, in particular Rolandic seizures (benign Rolandic epilepsy). Other conditions that can be treated include trigeminal neuralgia (tic douloureux) such as treatment of pain associated with true trigeminal neuralgia, bipolar disorders, and glossopharyngeal neuralgia. Other uses include treatment of neurogenic diabetes insipidus; certain psychiatric disorders, including schizoaffective illness, depression, agitation, behavioral disturbances related to dementia, resistant schizophrenia, and dyscontrol syndrome associated with limbic system dysfunction; alcohol withdrawal; fibromyalgia; neuropathy; status epilipticus; and refractory seizure disorders.

As used herein, the term “about” has its conventional meaning. When used in relation to a numerical value, it may additionally interpreted to cover values that vary within + 20%, or within ± 10%, or within ± 5%, or within ± 2%, or within ± 1 % of the numerical value. In some embodiments, the term “about” in relation to a numerical value may be left out. The term “w/w” means weight by weight.

Any references cited herein are incorporated by reference in their entirity.

The following examples are meant to illustrate the present invnetion and should not be construed as a limitation thereof.

Example 1: preparation of solid dispersions 4 g carbamazepine and 16 g hydroxypropyl methylcellulose (HPMC 2910 15 mPa.s) were dissolved in 800 ml of a mixture of methanol/methylene chloride 50:50 (v/v). This mixture was spray dried at 80°C (inlet temperature) using a Mini Spray Dryer B-191 (Biichi, Switzerland). The flow control was set at 800 N 1/h pressurized air, the aspirator at 100% and the pump at 50%. Afterwards, the resulting powders were post-dried in a vacuum dryer for 44 hours, resulting in a dry powder for reconstitution of20/80 carbamazepine/ hydroxypropyl methylcellulose (w/w).

Example 2: Dissolution

The powders for reconstitution of example 1 were tested on dissolution. During the dissolution test, a quantity of the powder for reconstitution representing 100 mg of carbamazepine was suspended into 500 ml of simulated gastric fluid (SGF) 1. A USP II apparatus was used and set at a paddle speed of 100 rpm. At each time point, 5.0 ml of the final suspension was removed and the volume was compensated by adding 5.0 ml of fresh dissolution medium. So, to calculate the % of the substance at each time period, the amount which was removed until that time period was subtracted from labeled amount and the remaining amount was considered as 100 % concentration for that time period.

The results are depicted in figures 1-2.

Claims

A powder for reconstitution containing a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and hydroxyalkyl alkylcellulose, for mixing with water, for use in the treatment of an individual suffering from a disorder which can be treated with carbamazepine.

The powder of claim 1, wherein the water-soluble polymer is a copolymer of vinyl pyrrolidone and vinyl acetate.

The powder of claim 1, wherein the water-soluble polymer is hydroxypropyl methylcellulose.

A powder according to any one of claims 1 to 3, wherein the weight / weight ratio of water-soluble polymer to carbamazepine is from 10: 1 to 2: 1.

The powder of claim 1, wherein the weight / weight ratio of water-soluble polymer to carbamazepine is 5: 1.

A powder according to any one of claims 1-5, wherein the solid dispersion is a solid solution.

A powder according to any one of claims 1 to 6, wherein the solid dispersion is obtained by spray drying.

A powder according to any one of claims 1 to 7, wherein the condition that can be treated with carbamazepine is epilepsy, trigeminal neuralgia, bipolar disorder or diabetic neuropathy.

A powder according to any one of claims 1 to 8 for the treatment of pediatric patients.

A super-saturated solution of carbamazepine and a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate and a hydroxyalkyl alkyl cellulose in an aqueous medium.

A super-saturated solution according to claim 10, obtained by adding water to a powder for reconstitution containing a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinyl pyrrolidone, a copolymer of vinyl pyrrolidone and vinyl acetate and hydroxyalkyl alkylcellulose.

The super-saturated solution of claim 10 or claim 11, wherein the water-soluble polymer is selected from polyvinyl pyrrolidone, a copolymer of vinyl pyrrolidone and vinyl acetate and a hydroxyalkyl alkyl cellulose.

The super-saturated solution of claim 12, wherein the hydroxyalkyl alkyl cellulose is hydroxypropyl methyl cellulose.

A process for preparing a super-saturated solution according to claim 9, wherein said process comprises adding water to a powder for reconstitution containing a solid dispersion of carbamazepine in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, and hydroxyalkyl alkyl cellulose.

The method of claim 14, wherein the water-soluble polymer is hydroxypropyl methylcellulose.