Powders for reconstitution

(54) Title: POSTS FOR RECONSTITUTION (57) Summary:

(30) Unionist Priority: 03/14/2007 ep 07104082.8 (73) Holder (s): Tibotec Pharmaceuticals LTD.

(72) Inventor (s): Elke Van Gyseghem, Guy René Jaak Van Den Mooter, Lieven Elvire Colette Baert, Peter Jozef Maria Van Remoortere (74) Attorney (s): Dannemann, Siemsen, Bigler & Ipanema Moreira (86) International Request : pct ep2008053056 of 14/03/2008 (87) International Publication: wo 2oos / uo6i9de 18/09/2008

DESCRIPTION REPORT OF THE INVENTION PATENT FOR POST FOR

RECONSTITUTION.

Field of the Invention

The present invention relates to reconstitution powders comprising NNRTI TMC278 dispersed in certain water-soluble polymers, useful in the treatment of HIV infection.

Background of the Invention

The treatment of Human Immunodeficiency Virus (HIV) infection, known as the cause of acquired immunodeficiency syndrome (AIDS), remains an important medical challenge. HIV is able to evade immune pressure, to adapt to a variety of cell types and growth conditions, and to develop resistance against currently available drug therapies. The latter include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV protease inhibitors (Pis) and the latest fusion inhibitors .

Although effective in suppressing HIV, each of these drugs, when used alone, is faced with the emergence of resistant mutants. This led to the introduction of combination therapy with various anti-HIV agents, usually having a different activity profile. In particular, the introduction of HAART (Highly Active Antiretroviral Therapy) has resulted in a remarkable improvement in anti-HIV therapy, leading to a major reduction in HIV-associated morbidity and mortality. Current guidelines for antiretroviral therapy recommend such a triple combination therapy regimen, even for initial treatment. However, none of the currently available drug therapies is capable of completely eradicating HIV. Even HAART can face the emergence of resistance, often due to non-adherence to and non-persistence with antiretroviral therapy. In such cases, HAART can become effective again by replacing one of its components with one of another class. If applied correctly, treatment with HAART combinations can suppress the virus for many years, even decades, at a level where the outbreak or progress of AIDS is halted.

One class of HIV drugs frequently used in HAART is that of NNRTIs, numerous of which are currently on the market and several others are in various stages of development. A NNRTI currently in development is the compound 4 - [[4 - [[4 - (2 - cyano - ethylenyl) - 2,6 - dimethyl - phenyl] - amino] - 2 - pyrimidinyl] - amino] - benzonitrile, to which also referred to as TMC278. This compound not only shows pronounced activity against wild-type HIV, but also against many of its mutated variants. The compound TMC278, its pharmacological activity, as well as numerous procedures for its preparation have been described in document number WO 03/16306. Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified there.

Babies and children are a growing group of HIV-infected patients. Pediatric anti-HIV medication poses particular challenges because the dose regimens vary to a great extent, due to variations in age and body weight (infants - children). Especially in the first year after birth, a baby undergoes rapid changes and body weight increases dramatically. Due to these rapid changes at a young age, the dosage 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 dosage flexibility required in pediatric applications. In addition, these dosage forms are not suitable 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 a dry form and is converted to a liquid form by adding water.

Reconstitution powders are attractive for liquid oral dosage forms because of their compact nature, making them more convenient for storage and transportation. The incorporation of TMC278 in a powder for reconstitution poses particular challenges due to the fact that it is poorly soluble in water. When adding water, only a limited amount is dissolved, not resulting in effective absorption of the active ingredient. Conversion of the free base form to an acid addition salt can increase the solubility of this active agent, but only salt forms with strong acids, such as hydrochloric acid, exhibit processable solubility profiles. For pediatric applications, these salts are not attractive because of their low pH. Therefore, the challenge is to provide a reconstitution powder using the base form of TMC278 that, when adding water, results in a dosage form that has effective therapeutic concentrations of the active.

It has now been found that NNRTI TMC278 can be converted into a powder for reconstitution that allows a flexible application of the active ingredient and, in addition, that is suitable for pediatric applications. The reconstitution powders of this invention can also be applied to groups of adult patients who have difficulty or find inconvenience in swallowing, for example, in old age. The reconstitution powders of this invention may contain various active ingredients, whereby the administration of drug cocktails is permitted in one administration. This results in a reduced number of administrations, thereby being beneficial in terms of pill burden and compliance with the patient's drug.

Description of the Invention

In one aspect, the present invention relates to the application of a powder comprising TMC278, dispersed in a water-soluble polymer selected from polyvinylpyrrolidone, a vinylpyrrolidone copolymer and vinyl acetate, a hydroxy-alkyl-alkyl-cellulose, and a poloxamer, to be mixed with water, for the preparation of a drug for the treatment of an HIV-infected subject. In one embodiment, the powder is obtained by spray drying.

In another aspect, a method of treating an HIV-infected patient is provided, the method comprising administering to the patient a powder comprising TMC278, dispersed in a water-soluble polymer selected from polyvinylpyrrolidone, a vinylpyrrolidone and acetate copolymer of vinyl, a hydroxy-alkyl-alkyl-cellulose, and a poloxamer, and, before administration, the powder is mixed with water. The amount of TMC278 in the powder is preferably an antiviral effective amount.

In another aspect, a supersaturated solution of TMC278 and a water-soluble polymer selected from polyvinylpyrrolidone, a vinylpyrrolidone and vinyl acetate copolymer, a hydroxy-alkyl-alkyl-cellulose, and a poloxamer are provided in an aqueous medium. . The supersaturated solution can be obtained by adding water to a powder comprising an antiviralally effective amount of TMC278 dispersed in a water-soluble polymer, selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, a hydroxy-alkyl-alkyl- cellulose, and a poloxamer. In an alternative aspect, a supersaturated solution of TMC278 and a water-soluble polymer selected from polyvinylpyrrolidone, a vinylpyrrolidone and vinyl acetate copolymer, a hydroxy-alkyl-alkyl-cellulose, and a poloxamer, obtainable or obtained by adding water to a powder comprising an antiviralally effective amount of TMC278 dispersed in a water-soluble polymer, selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, a hydroxy-alkyl-alkyl-cellulose, and a poloxamer.

In another aspect, a method is provided for the treatment of an HIV-infected subject, the method comprising the administration of a supersaturated solution of TMC278 and a water-soluble polymer, selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate , a hydroxy-alkyl-alkyl-cellulose, and a poloxamer, in an aqueous medium.

The invention furthermore provides a method of, or, alternatively, a process for the preparation of a supersaturated solution of TMC278 and a water-soluble polymer selected from polyvinylpyrololidone, a copolymer of vinylpyrrotidone and vinyl acetate, a hydroxyalkylalkyl -alkylcellulose, and a poloxamer, in an aqueous medium, the method or process comprising adding water to TMC278, dispersed in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, a hydroxy-alkyl-alkylcellulose, and a poloxamer. In one embodiment, the supersaturated solution is prepared by adding water to a TMC278 powder, dispersed in a water-soluble polymer selected from polyvinylpyrrolidone, a vinylpyrrolidone copolymer and vinyl acetate, a hydroxy-alkyl-alkyl-cellulose, and a poloxamer.

The compound used in the invention is 4 - [[4 - [[4 - (2 - cyano - ethylene)

- 2,6 - dimethyl - phenyl] amino] - 2 - pyrimidinyl] amino] benzonitrile, having the generic name rilpivirine, also known as TMC278 (or referred to as R278474). TMC278 is in clinical development as an HIV inhibitor of the NNRTI class.

TMC278 occurs in stereoisomeric forms, more particularly, as E- and Z-isomeric forms. Both isomers can be used in the present invention. Whenever reference is made here to TMC278, form E or form Z, as well as any mixture of both forms, it is understood that they are included. A preferred form of TMC278, for application in the invention, is the E isomer, i.e. (E) - 4 - [[4 - [[4 - (2 - cyano - ethylene)

- 2,6 - dimethyl - phenyl] - amino] - 2 - pyrimidinyl] - amino] - benzonitrile, which can be referred to as E-TMC278. The Z isomer of TMC278, that is, (Z) - 4 - [[4 - [[4

- (2 - cyano - ethenyl) - 2,6 - dimethyl - phenyl] - amino] - 2 - pyrimidinyl] - amino] - benzonitrile, which can be referred to as Z-TMC278, can also be used.

Whenever reference is made here to the E form of TMC278 (ie E-TMC278), the pure E isomer or any isomeric mixture of the E and Z forms, in which the E form is predominantly present, is understood to be comprised, that is, an isomeric mixture containing more than 50% or, in particular, more than 80% of the E form, or even more than 90% of the E form. Of particular interest is the substantially free form E form Z. Substantially free, in this context, refers to EZ mixtures with or without the Z form, for example, isomeric mixtures containing as much as 90%, in particular, 95% or even 98% or 99%, of the E form. Likewise, whenever reference is made here to the Z form of TMC278 (ie Z-TMC278), the pure Z isomer or any isomeric mixture of the Z and E forms, in which the Z form is predominantly present, is understood to be comprised, that is, an isomeric mixture containing more than 50% or, in particular, more than 80% of the Z form, or even more than 90%, of the Z form. Of particular interest is the Z form substantially free from form E. Substantially free, in this context, refers to EZ mixtures with or without the E form, for example, isomeric mixtures containing as much as 90%, in particular, 95% or even 98% or 99%, of the Z form.

Whenever used here, the term TMC278 also refers to stereoisomeric forms of TMC278, as well as to any mixtures of the stereoisomeric forms. In particular, the term TMC278 refers to the E isomer of TMC278.

Reconstitution powders for application in the present invention comprise the active ingredient TMC278 dispersed in particular water-soluble polymers, which may refer to as a solid dispersion of the active ingredient TMC278 in the particular water-soluble polymers. The latter include polyvinylpyrrolidone (PVP) and copolymers of vinylpyrrolidone and vinyl acetate (PVPCoVA, which is sometimes referred to as PVP-VA); hydroxy-alkyl-alkyl-celluloses, in particular, hydroxy-C₁_4-alkyl-Cv4-alkylcelluloses, such as hydroxy-propyl-methylcellulose (HPMC) and poloxamers, in particular poloxamer P407.

The amount of water-soluble polymer, in the TMC278 solid dispersion, in the particular water-soluble polymers, can be in the range of about 50% to about 99%, in particular, about 70% to about 98%, or about 80% to about 95% or about 85% to about 95%, for example, about 90% by weight, relative to the total weight of the solid dispersion. The weight: weight ratio of water-soluble polymer to TMC278, in the solid dispersion of TMC278, in the particular water-soluble polymers, can be in the range of about 50: 1 to about 1: 1, or about 20: 1 to about 1: 1, or about 10: 1 to about 1: 1, or about 10:

at about 5; 1, for example, the weight: weight ratio is about 9: 1. The amount of TMC278, in the solid dispersion of TMC278, in the particular water-soluble polymers, can be in the range of about 1% to about 40% , in particular, about 1% to about 30%, or about 1% to about 20% or about 5% to about 15%, for example, about 10% by weight relative to weight total solid dispersion.

The reconstitution powders for application in the present invention may comprise the solid dispersion of the active ingredient TMC278, in the particular water-soluble polymers, in an amount that can be in the range of about 60% to about 100%, in particular about 70 % to about 100%, or about 80% to about 100% or about 90% to about 100%, by weight, relative to the total weight of the powder for reconstitution. Other ingredients may be present, such as the ingredients mentioned below, in an amount that constitutes the remainder of the powder for reconstitution, in particular, in an amount that can 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%, by weight, relative to the total weight of the powder for reconstitution.

As used herein, the term Ci-4-alkyl defines saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as methyl, ethyl, 1-propifa, 2-propyl, 1-butyl, 2-butyl, 2-methyl -2-propyl, 2-methyl-1propyl.

In one embodiment, the water-soluble polymer has a molecular weight in the range of 500 D to 2 MD. The water-soluble polymer can have an apparent viscosity of 1 to 15,000 mPa.s, or 1 to 5,000 mPa.s, or 1 to 700 mPa.s, or 1 to 100 mPa.s, when in aqueous solution at 2% (w / v) at 20 ° C.

Particular hydroxy-alkyl-alkyl-celluloses include hydroxy-ethylmethyl-cellulose and hydroxy-propyl-methyl-cellulose (or HPMC, for example, HPMC 2910, 15 mPa.s; HPMC 2910, 5 mPa.s). Particular vinylpyrrolidones included in PVP K29-32, PVP K90.

Said HPMC contains sufficient hydroxy-propyl and methoxy groups to make it soluble in water. HPMC having a degree of methoxy substitution of from about 0.8 to about 2.5 and a molar substitution with hydroxy-propyl of about 0.05 to about 3.0 are, in general, soluble in water. The degree of substitution with methoxy refers to the average number of methyl ether groups present per unit of anhydroglycosis of the cellulose molecule. Molar substitution with hydroxy-propyl refers to the average number of moieties of propylene oxide that reacted with each anhydroglycosis 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. Hydroxy-propyl-methyl-cellulose is the Adopted Name in the United States for hypromellosis (see Martindale, The Extra Pharmacopoeia, 29^The 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 represent the approximate percentage composition in hydroxy-propyl groups; 15 mPa.s or 5 mPa.s is a value indicative of the apparent viscosity of a 2% aqueous solution, at 20 ° C.

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

Polyvinylpyrrolidone polymers, which can be used, are known as povidone (PVP) and are commercially available. They can have a molecular weight that is in the range of about 30 KD to about 360 KD. Examples are PVP K25 (BASF, PM = 29,000), PVP K30 (BASF,

PM = 40,000) and PVP K90 (BASF, PM = 360,000), available under the trade name Kolidon®.

Poloxamers are copolymers of three nonionic blocks composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide) flanked by two hydrophilic chains of polyoxyethylene (polyethylene oxide), with varying lengths of polymer blocks. By the generic term poloxamer, these copolymers are commonly named with the letter P (for poloxamer) followed by three digits, the first digits x 100 give the approximate molecular mass of the polyoxypropylene core, and the last digit x 10 gives the percentage polyoxyethylene content (for example, P407 = Poloxamer with a polyoxypropylene molecular mass of 4,000 g / mol and a 70% polyoxyethylene content). Poloxamers are commercially available under the trade name Pluronic®. By the Pluronic trade name, the codification of these copolymers begins with a letter to define their physical form at room temperature (L = liquid, P = paste, F = flakes (solid)) followed by two or three digits, the first (s) (s) digit (s) refers to the molecular mass of the polyoxypropylene core and the last digit x 10 gives the percentage polyoxyethylene content (for example, F127 = Pluronic® with a polyoxypropylene molecular mass of 4,000 g / mol and a 70% polyoxyethylene content). Pluronic® F127 corresponds to poloxamer P407 (P407).

The active ingredient TMC278 can be dispersed more or less uniformly throughout the entire water-soluble polymer or it can be dispersed uniformly or evenly throughout the entire polymer. In the first case, the active ingredient is dispersed less homogeneously throughout the polymer. There may be domains or small regions, in which the compound of formula (I) is amorphous, microcrystalline or crystalline, or amorphous, microcrystalline or crystalline water-soluble polymer, or both, are more or less uniformly dispersed in the water-soluble polymer.

There are several techniques for preparing solid dispersions, including melt extrusion, spray drying and solution evaporation.

The solution evaporation process comprises the following steps:

a) dissolving TMC278 and the water-soluble polymer in an appropriate solvent, optionally at elevated temperature;

b) allow 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 can also be poured over a large surface, to form a thin film, and the solvent evaporated from it.

The melt extrusion process usually comprises the following steps:

a) mixture of TMC278 and the water-soluble polymer,

b) optionally, mixing additives with the mixture thus obtained,

c) heating and composting the mixture thus obtained, until a homogeneous melting mass is obtained,

d) forcing the melt thus obtained through one or more nozzles; and

e) cooling the melting mass until it solidifies.

The terms melting and melting mass should be interpreted widely. These terms not only mean the change from a solid state to a liquid state, but they can also refer to a transition to a glassy state or a rubbery state, and in which it is possible for a component of the mixture to become embedded more or less. less homogeneously in the other. In particular cases, one component will melt and the other component (s) will dissolve in the melt, thus forming a solution that, upon cooling, can form a solid solution having advantageous dissolving properties .

After preparing the solid dispersions as described above, the products obtained are ground and, optionally, sieved. The solid dispersion product can be ground or crushed to form particles having a particle size less than 600 pm, or less than 400 pm, or less than 125 pm, or to the particle sizes mentioned below.

A preferred process for preparing powders for reconstitutions for use in the present invention is by the spray drying technique. In the spray drying technique, TMC278 and the water-soluble polymer are dissolved in an appropriate solvent and the resulting solution is then atomized through the nozzle of an spray dryer, whereby the solvent from the resulting droplets is evaporated, usually at high temperatures, for example, by introducing hot air.

The amount of water-soluble polymer in the spray dried product can be in the range of about 50% to about 99%, in particular, about 70% to about 98%, or about 80% to about 95% or about 85% to about 95% by weight, based on the total weight of the spray dried product, comprising TMC278, water-soluble polymers and optional excipients. The amount of water-soluble polymer in the feed mixture can be calculated based on these percentages and the amount of solvent used.

The weight: weight ratio of water-soluble polymer to TMC278 is in the range of about 50: 1 to about 1: 1, or about 20: 1 to about 1: 1, or about 10: 1 to about 1: 1, or about 10: 1 to about 5: 1, for example, the weight: weight ratio is about 9: 1.

The solvent used in the process of the present invention can be any solvent that is inert to TMC278 and that is capable of dissolving TMC278 and the water-soluble polymer. Suitable solvents include acetone, tetrahydrofuran (THF), dichloromethane, ethanol (anhydrous or aqueous), methanol, and combinations. Of interest, are mixtures of methanol and methylene chloride, in particular mixtures of the last two solvents, in which the v / v methanol / methylene chloride ratio is in the range of about 50: 50 to about 90: 10; or in the range of about 50: 50 to about 80: 20, for example, in a 50: 50 ratio, or in a 90: 10 ratio.

In one embodiment, the solvent is a mixture of dichloromethane and methanol, the latter, in particular, being anhydrous methanol. In another embodiment, the solvent is dichloromethane.

The amount of solvent present in the feed mixture will be such that TMC278 and the water-soluble polymer are dissolved and that the feed mixture has sufficiently low viscosity for it to be atomized. In one embodiment, the amount of solid materials in the feed mixture is less than 20%, in particular, less than 10%, more particularly less than 5%, the percentages expressing the weighted amount of solid materials for the total volume of the feed mixture.

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

The drying gas can 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 from about 25 ° C to about 300 ° C, or from about 60 ° C to about 300 ° C, or about 60 ° C to about 150 ° C.

Spray drying is carried out in conventional spray drying equipment, comprising a spray drying chamber, spraying means for introducing the feed mixture into the spray drying chamber in the form of droplets, a source of heated drying gas. , which 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 driving force operating from a source and high pressure compressed air, for example, a 0.6 MPa (6 bar) compressed air source, which supplies dust to a atomization wheel to atomize the feed mixture. The atomization wheel can be finned (vaned). Preferably, the rotary atomizer is located at the top of the spray drying chamber, for example, on the roof of the chamber, so that the droplets produced dry and fall to the bottom of the chamber. Typically, rotary atomizers produce droplets that have a size in the range of about 20 to about 225 pm, in particular, about 40 to about 120, the size of the droplet depending on the peripheral speed of the wheel.

Suitable pneumatic nozzles (including two fluid nozzles) comprise those which are located on the top of the spray drying chamber, for example, on the chamber roof, and which operate in the so-called co-current mode. Atomization occurs using compressed air, such that the air-to-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 atomization gas are passed separately to the nozzle head, where atomization takes place. The size of the droplets produced by pneumatic nozzles depends on the operational parameters and can be in the range of from about 5 to 125 pm, in particular, from about 20 to 50 pm.

Two-fluid nozzles, operating in the so-called countercurrent mode, can also be used. These nozzles operate in a similar way to two-fluid nozzles in co-current modes, except that they are located at the bottom of the drying chamber and atomize the droplets upwards. Typically, countercurrent two fluid nozzles generate droplets, which, when dried, produce particles having a size in the range of from about 15 to about 80 pm.

A preferred type of atomizer for use in the invention is the high pressure nozzle, in which liquid feed is pumped into the nozzle under pressure. The pressure energy is converted into kinetic energy, and the feed emerges from the nozzle orifice as a high-speed film, which readily disintegrates into an atomization, since the film is unstable. The feed is forced to rotate inside the nozzle using a whirling insert or whirling chamber, resulting in cone-shaped atomization patterns emerging from the nozzle orifice. The swirling insert, swirling chamber and orifice dimensions, together with pressure variation, give control over the feed rate and atomization characteristics. The size of the droplets produced by high pressure nozzles depends on the operational parameters and can be in the range of about 5 to 125 pm, in particular, about 20 to 50 pm.

Suitable atomization media can be selected depending on the desired droplet size, which depends on numerous factors, such as the viscosity and temperature of the feed mixture, the desired flow rate and the maximum acceptable pressure for pumping the feed mixture, have about the droplet size. After selecting the atomisation means, so that the desired average droplet size is obtained for a feed mixture having a particular viscosity, the mixture is admitted to an atomisation drying chamber at a particular flow rate.

The solid dispersion produced by the spray drying process, or produced by the other processes described above (such as solution evaporation and melt extrusion), followed by grinding and optional sieving, typically comprises particles having an average effective particle size in the 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 one skilled in the art, and can be measured by any particle size measurement techniques known in the art, such as, for example, fractionation by flow in sedimentation field, photon correlation spectroscopy, laser diffraction or disk centrifugation. The average effective particle sizes mentioned here can be related to the particle weight distributions. In that case, by an average effective particle size of about 150 pm it is understood that at least 50% by weight of the particles consist of particles having a particle size less than the average size of 50 pm, and the same applies to the other effective particle sizes mentioned. In a similar way, the average effective particle sizes can be related to the volume distributions of the particles, but usually this will result in the same or almost the same value for the average effective particle size.

Optionally, additional excipients can be included in the feed mixture, for example, to improve the properties of the feed mixture or the resulting solid pharmaceutical composition, such as handling and processing properties. Regardless of whether or not excipients are added to the feed mixture, which obviously results in the fact that they are incorporated into the solid dispersion, excipients can also be mixed with the resulting solid pharmaceutical composition during formulation in the desired dosage form.

Excipients suitable for inclusion in pharmaceutical dosage forms include surfactants, solubilizers, disintegrants, pigments, flavorings, fillers, lubricants, preservatives, thickening agents, buffering agents and pH modifiers. In particular, surfactants can be added to further improve the solubility of the active agent, and can also function as wetting agents. Typical surfactants include sodium lauryl sulfate, polyethoxylated castor oil, for example, Cremophor EL®, Cremophor RH 40®, Vitamin E TPGS, and polysorbates, such as Tween 20® and Tween 80®, polyglycolated glycerides, such as Gelucire® 44/14 and Gelucire® 50/13 (available from Gattefossé, France).

Typical pH modifiers that can be added include acids, such as citric acid, succinic acid, tartaric acid, bases, or buffers.

Before use, water or other aqueous media, such as those containing ingredients to make solutions more palatable, for example, sugars, such as glucose or flavorings, are added to the powders for reconstitution of the invention. The amount of water that is added is in the range of about 0.5 ml of water per mg of TMC278 to about 5 ml, or from about 0.5 ml of water per mg of TMC278 to about 2 ml, or from about 0.5 ml of water per mg of TMC278 to about 1 ml, for example, about 0.6 ml / mg of TMC278. The addition of water to a TMC278 powder, dispersed in a water-soluble polymer, as specified above, generates a supersaturated solution, from which the active ingredient TMC278 does not precipitate, which is unexpected.

The inventive reconstitution powders 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 depending on age and body weight. Another target group is adult patients who have difficulty swallowing solid dosage forms, such as tablets or capsules. Another advantage is that other anti-HIV agents can be combined with TMC278. The reconstitution powders of the invention show good assimilation of the active ingredient and result in good plasma levels, comparable to those obtained with a TMC278 tablet formulation.

Administration of TMC278, in accordance with the present invention, may be sufficient to treat HIV infection, although it may be advisable to co-administer other HIV inhibitors. The latter preferably include HIV inhibitors from other classes, in particular those selected from NRTIs, Pis and fusion inhibitors. In one embodiment, the other HIV inhibitor, which is co-administered, is a Pl. HIV inhibitors, which can be co-administered, are preferably those used in HAART combinations, comprising an NNRTI. For example, two additional NRTIs or one NRTI and one Pl can be co-administered.

In certain cases, the treatment of HIV infection may be limited only to the administration of a powder for reconstitution of TMC278, according to the methodology of this invention, that is, as monotherapy without co-administration of additional HIV inhibitors. This option can be recommended, for example, when the viral load is relatively low, for example, when the viral load (represented as the number of copies of

Viral RNA in a specified volume of serum) is below about 200 copies / ml, in particular, below about 100 copies / ml, more particularly below 50 copies / ml, specifically, below the virus detection limit. In one embodiment, this type of monotherapy is applied after initial treatment with a combination of anti-HIV drugs, in particular, with any combination of HAART for a certain period of time, until the viral load in the blood plasma reaches the level previously mentioned low viral.

Powders for reconstitution of TMC278 are preferably administered once daily.

As used here, the term treatment for HIV infection refers to a treatment situation for a subject being infected with HIV. The term subject, in particular, refers to a human being.

The dose of TMC278 administered, which is determined by the amount of TMC278 in the formulation for application in the invention and the amount of formulation administered, is selected such that the blood plasma concentration of TMC278 is maintained above a minimum blood plasma level. The term minimum blood plasma level, in this context, refers to the lowest effective level in the blood plasma, this being that level in the blood plasma that effectively inhibits HIV, so that the viral load is below the values ​​mentioned above. Plasma levels of TMC278 should be kept above the minimum blood plasma level to be avoided because, at lower levels, the virus is no longer suppressed, thereby increasing the risk of mutations. Levels in the blood plasma higher than what is strictly necessary as a minimum level may be preferred to build a safety margin. Maximum blood plasma levels, that is, those levels at which side effects are experienced, are relatively high, that is, about 500 ng / ml or even higher, such as 1,000 ng / ml.

In particular, the blood plasma level of TMC278 is maintained at a level between minimum and maximum blood plasma levels, for example, in the range of about 20 ng / ml_ to 1,000 ng / ml, or in the range of about from 50 ng / ml to about 500 ng / ml, or in the range of about 100 ng / ml to about 500 ng / ml, or in the range of about 200 ng / ml to about 500 ng / ml, or in the range of about 5 ng / ml to about 200 ng / ml, or in the range of 75 ng / ml to about 150 ng / ml, or in the range of about 90 ng / ml to about 100 mg / ml. An adequate daily dose of TMC278 can be in the range of about 0.1 mg to about 3 mg or in the range of about 0.2 mg to about 2.0 mg, or in the range of about 0.2 mg at about 1.0 mg, for example, about 0.36 mg; each of the previous values ​​expressed in mg being per kg of body weight. The attending physician will be able to determine the dose to be administered by multiplying the mentioned dosages by the patient's body weight.

TMC278 reconstitution powders in accordance with the present invention provide effective treatment for HIV infection in that the viral load is reduced as long as suppressed viral replication is maintained. Ease of administration can add to the patient's compliance with therapy.

As used here, the term about has its conventional meaning. When used in relation to a numerical value, it can be further interpreted to cover values ​​that vary within + 20%, or within ± 10%, or within ± 5%, or within ± 2%, or within ± 1 %, of the numerical value.

Examples

Example 1:

g of TMC278 and 36 g of PVP-VA 64 are dissolved in 800 ml of a 50:50 (v / v) methanol / methylene chloride mixture. This mixture is spray-dried at 80 ° C (inlet temperature) using a Mini Spray Dryer B-191 (Büchi, Switzerland). The flow control was adjusted to 800 NL / h of pressurized air, the aspirator to 100% and the pump to 50%. Thereafter, the resulting powders were post-dried in a vacuum dryer (Christ Alpha, Medizinischer Apparatebau, Osterode / Harz, Germany) for 44 hours.

Example 2:

g of TMC278 base, 34 g of PVP-VA 64 and 2 g of Cremophor EL are dissolved in 800 ml of a 50:50 (v / v) methanol / methylene chloride mixture. This mixture is spray-dried at 80 ° C (inlet temperature) using a Mini Spray Dryer B-191 (Büchi, Switzerland). The flow control was adjusted to 800 NL / h of pressurized air, the aspirator to 100% and the pump to 50%. After that, the resulting powders were post-dried in a vacuum dryer (Christ Alpha, as above) for 44 hours.

Dissolution:

The powders for reconstitution of Examples 1 and 2 were tested for dissolution. During the dissolution test, the powders for reconstitution of TMC278 were suspended in 50 ml of water and the resulting suspension was added in 500 ml of 0.01 M HCI aqueous solution serving as a dissolution medium, resulting in a volume of suspension end of 550 mL. At each time point, 5.0 ml of the final suspension was removed and the volume was made up by adding 5.0 ml of fresh dissolution medium. Thus, to calculate the% of the substance in each period of time, the quantity that was removed up to that period of time was subtracted from the labeled quantity and the remaining quantity was considered as a 100% concentration for that period of time. TMC278 reached a steady state plateau in 5 minutes in both cases. Animal Study:

Six male Beagle dogs, approximately 1 to 3 years old and weighing between 8 and 14 kg at the beginning of the experimental phase, were used in the present study. Dogs were given free and continuous access to water. Each dosing day, the dogs were deprived of food for approximately 18 hours before dosing, and were fed immediately after dosing with free access to food for up to 6 hours, starting after dosing. The oral dosage in the first phase of the study was made with an oral probe of 40 mL of the freshly prepared aqueous suspensions of TMC278. The two suspensions were administered to 3 dogs, each. After a 14-day elimination period, all 6 dogs were dosed by administering a TMC278.HCI tablet providing a dose equivalent to 50 mg per animal. The dosage schedule is shown in Table 1.

Per dog, two vials, each containing 25 mg of TMC278, formulated as powder for reconstitution TMC278 / PVP-VA 64 10/90% (weight / weight or w / w) (dogs 1, 2, 3), or two vials , each containing 25 mg of TMC278, formulated as powder for reconstitution TMC278 / PVP-VA 64 / Cremophor EL 10/85/5% (w / w / m) (dogs 4, 5, 6) were used. For each dog, a tablet for clinical application containing 50 mg equivalent of TMC278 hydrochloride (HCI salt of TMC278) was provided.

Blood samples (1 mL in EDTA) were taken from a jugular vein from dogs at 0 ° (= pre-dose), 0.5 (30 minutes), 1, 2, 4, 8, 24, 32 and 48 h after dose administration. After sampling, blood samples were protected from light immediately. The samples were centrifuged within two hours of blood sampling at approximately 1,900 xg for approximately 10 minutes, at room temperature, to allow separation of the plasma. Immediately thereafter, the plasma was separated, transferred to a second tube and stored in the freezer within two hours after the start of centrifugation. At all times, blood and plasma samples were protected from light. Plasma samples were stored in a freezer below -18 ° C, until analysis. Plasma samples were analyzed using LC-MS / MS.

Individual plasma concentration versus time profiles was subjected to non-compartmental pharmacokinetic analysis using a validated WinNonlin v4.0.1a computer program. Peak concentrations (Cmax), corresponding to peak times (T_mx), half-lives (t-1/2) and stroke values ​​(area under the curve) were determined for TMC278. Concentrations of TMC278 in the mean plasma (n = 3 or 6, where n is the number of dogs, ± SD) or median were calculated by formulation and by instant of sampling. Average pharmacokinetic parameters (n = 3 or 6, ± SD) per formulation were also calculated. In addition, the relative bioavailability (Frei) of TMC278, dosed with powders for reconstitution versus the clinical tablet, was estimated individually.

Individual and mean plasma concentrations (n ​​= 3 or 6, ± SD) or medians in fasting male Beagle dogs and some basic pharmacokinetic parameters of TMC278 after single oral dosing of a suspension of powders for reconstitution or a TMC278 tablet are reported in Table 2 to Table 4. Individual bioavailability is shown in Table 5. The average plasma concentration versus time profiles of TMC278 is depicted in Figure 1.

After oral administration of a powder suspension for reconstitution TMC278 / PVP-VA 64 10/90% (w / w) (Treatment A) in 50 mg of TMC278 (actual dose range: 4.31 - 5.75 mg / Kg), high plasma concentrations were already observed in 1/2 h after dosing, with maximum levels (C_mThe_X) in 1/2 h to 4 hours after dosing, importing, on average, 544 ng / ml_. After that, plasma levels declined very slowly, with an average half-life between 32 and 48 h (tj / 2, 32 - 48 h) of

34.5 h. Since the half-lives were long, AVCo-inf values ​​could not be calculated properly. Therefore, exposure to TMC278 was expressed by AVCo-48 h> values ​​that imported, on average, at 11,900 ng.h / mL.

After oral dosing of a powder suspension for reconstitution TMC278 / PVP-VA 64 / Cremophor EL® 10/85/5% (w / w / m) (Treatment B) at 50 mg of TMC278 (actual dose range: 3.83 - 6.06 mg / Kg), plasma levels were already elevated in 0.5 h after the dose and peak plasma concentrations (C_mThe_X) were reached within 0.5 h 8 h after dose. C values_mThe_X they imported, on average, at 443 ng / mL, after which plasma levels declined very slowly, with a half-life between 32 and 48 h (ti / 2, 32 - 48 h) of 46.8 h on average. Since the half-lives were long, AVCo-inf values ​​could not be calculated properly. Therefore, exposure to TMC278 was expressed by AVCo-48 h values. The average exposure amounted to 11,200 ng.h / mL.

After oral administration of the clinical pill of TMC278.HCI (Treatment C) equivalent to 50 mg of TMC278 (actual dose range: 3.88 - 6.25 mg / kg), absorption was slower than with suspension . Peak plasma levels (C_mThe_X) were reached between 2 h and 24 h after the dose and im5 carried, on average, 501 ng / mL. After that, the decline in plasma concentrations was very slow, with a half-life between 32 and 48 h (ti / 2, 32 48 h) of 45.7 h. Since the half-lives were long, AVCo-inf values ​​could not be calculated properly. Therefore, exposure to TMC278 was expressed by AVCo-48 h values, which imported, on average, in

12,300 ng.h / mL.

Relative bioavailability (F_rei, based on individual AVCo-48 h values) of the formulation containing TMC278 / PVP-VA 64 10/90% vs. the clinical pill varied between 69 and 89%. Relative bioavailability (F_rei, based on individual ASCo-48 h values) of the formulation containing

TMC278 / PVP-VA 64 / Cremophor EL 10/85/5% vs. the clinical pill, was estimated at 85 to 157%.

Tables

Table 1: Dosage day, dose, formulation, group and animal feeding condition of male Beagíe dogs used in the present study.

<td>Dosing day</td><td>Total dose (mg (eq.))</td><td>Treatment</td><td>Group</td><td>Condition</td>

<td></td><td></td><td></td><td> 1</td><td>fasting, fed immediately</td>

<td>Day 0</td><td> 50</td><td>A '&gt;</td><td></td><td>after dosing</td>

<td></td><td></td><td>B²&gt;</td><td> 2</td><td>fasting, fed immediately</td>

<td>(July 24, 2006)</td><td> 50</td><td></td><td></td><td>after dosing</td>

<td></td><td></td><td></td><td> 1</td><td>fasting, fed immediately</td>

<td>Day 14</td><td> 50</td><td>_Ç3)</td><td></td><td>after dosing</td>

<td></td><td></td><td>_Ç3)</td><td> 2</td><td>fasting, fed immediately</td>

<td>(August 7, 2006)</td><td> 50</td><td></td><td></td><td>after dosing</td>

¹⁾ Treatment A: 2x TMC278 / PVP-VA 64 powder 10/90% (m / m).

²⁾ Treatment B: 2x TMC278 / PVP-VA 64 / Cremophor EL 10/85/5% (m / m / m) powder.

³⁾ Treatment C: one tablet equivalent to 50 mg of TMC278.

Table 2: Individual and mean plasma concentrations (n ​​= 3, ± SD) and some basic pharmacokinetic parameters of TMC278 after a single oral administration in 50 mg of TMC278 of a formulation containing TMC278 / PVP-VA 64 10/90% in dogs Beagle males fasting.

<td rowspan="3">Treatment Day Actual dose (mg eq./Kg) Time (h) Subject</td><td colspan="5">A (powder of (TMC278 / PVP-VA 64 10/90% (m / m))</td>

<td colspan="4"> 0</td><td rowspan="2">DP</td>

<td> 4,83 1</td><td> 4,31 2</td><td> 5,75 3</td><td>Average</td>

<td> 0</td><td> &lt;1,00</td><td> &lt;1,00</td><td> &lt;1,00</td><td> &lt;1,00</td><td> -</td>

<td> 0,5</td><td> 297</td><td> 140</td><td> 778</td><td> 405</td><td> 332</td>

<td> 1</td><td> 428</td><td> 323</td><td> 615</td><td> 455</td><td> 148</td>

<td> 2</td><td> 407</td><td> 373</td><td> 464</td><td> 415</td><td> 46</td>

<td> 4</td><td> 370</td><td> 427</td><td> 409</td><td> 402</td><td> 29</td>

<td> 8</td><td> 299</td><td> 371</td><td> 301</td><td> 324</td><td> 41</td>

<td> 24</td><td> 212</td><td> 259</td><td> 342</td><td> 271</td><td> 66</td>

<td> 32</td><td> 128</td><td> 186</td><td> 222</td><td> 179</td><td> 47</td>

<td> 48</td><td> 92,2</td><td> 145</td><td> 143</td><td> 127</td><td> 30</td>

<td>Cmax (ng / mL)</td><td> 428</td><td> 427</td><td> 778</td><td> 544</td><td> 202</td>

<td>Tmax (h)</td><td> 1</td><td> 4</td><td> 0,5</td><td> 2</td><td> 2</td>

<td>f 1/2, 32-48h (h)</td><td> 33,8</td><td> 44,5</td><td> 25,2</td><td> 34,5</td><td> 9,7</td>

<td>AVCo-48 h (ng.h / mL)</td><td> 9910</td><td> 12300</td><td> 13600</td><td> 11900</td><td> 1870</td>

<td>AVCo-inf (ng.h / mL)</td><td> 14400 ¹⁾</td><td> 21600 ¹⁾</td><td> 18800¹⁾</td><td> 18300¹⁾</td><td> 3620</td>

<td>Extrapolated stroke (%)</td><td> 31,2</td><td> 43,1</td><td> 27,7</td><td> 34,0</td><td> 8,1</td>

1) calculated with> 25% extrapolation

Table 3: Individual and mean plasma concentrations (n ​​= 3, ± SD) and some basic pharmacokinetic parameters of TMC278 after a single oral administration in 50 mg of TMC278 of a formulation containing TMC278 / PVP-VA 64 / Cremophor EL 10/85 / 5% in male fasting Beagle dogs.

<td colspan="2" rowspan="2">Treatment Day Actual dose (mg eq./Kg)</td><td colspan="3">B (powder of (TMC278 / PVP-VA 64 / Cremophor</td><td rowspan="3">EL 10/85/5% Average</td><td rowspan="3">(m / m / m)) DP</td>

<td rowspan="2"> 0 3,83 4</td><td rowspan="2"> 6,06 5</td><td rowspan="2"> 5,26 6</td>

<td>Time (h)</td><td>Subject</td>

<td> 0</td><td></td><td> &lt;1,00</td><td> &lt;1,00</td><td> &lt;1,00</td><td> &lt;1,00</td><td> -</td>

<td> 0,5</td><td></td><td> 284</td><td> 174</td><td> 466</td><td> 308</td><td> 147</td>

<td> 1</td><td></td><td> 289</td><td> 205</td><td> 427</td><td> 307</td><td> 112</td>

<td> 2</td><td></td><td> 379</td><td> 260</td><td> 400</td><td> 346</td><td> 76</td>

<td> 4</td><td></td><td> 485</td><td> 317</td><td> 352</td><td> 385</td><td> 89</td>

<td> 8</td><td></td><td> 339</td><td> 379</td><td> 253</td><td> 324</td><td> 64</td>

<td> 24</td><td></td><td> 292</td><td> 310</td><td> 176</td><td> 259</td><td> 73</td>

<td> 32</td><td></td><td> 177</td><td> 193</td><td> 99,4</td><td> 156</td><td> 50</td>

<td> 48</td><td></td><td> 153</td><td> 136</td><td> 70,7</td><td> 120</td><td> 43</td>

<td>Ç_max (ng / ml)</td><td></td><td> 485</td><td> 379</td><td> 466</td><td> 443</td><td> 57</td>

<td>Tmax (h)</td><td></td><td> 4</td><td> 8</td><td> 0,5</td><td> 4</td><td> 4</td>

<td>tJ / 2, 32-48h (h)</td><td></td><td> 76,1</td><td> 31,7</td><td> 32,6</td><td> 46,8</td><td> 25,4</td>

<td>Stroke₀-48h (ng.h / mL)</td><td></td><td> 12600</td><td> 12400</td><td> 8520</td><td> 11200</td><td> 2290</td>

<td>Stroke₀_inf (ng.h / mL)</td><td></td><td> 29400 ¹⁾</td><td> 18600¹⁾</td><td> 11800¹⁾</td><td> 19900¹⁾</td><td> 8830</td>

<td>AVCE_xt_frogP_O|_B.Cj_The (%)</td><td></td><td> 57,2</td><td> 33,4</td><td> 28,0</td><td> 39,5</td><td> 15,5</td>

1) calculated with> 25% extrapolation

Table 4: Individual and mean (n = 6, ± SD) or median plasma concentrations and some basic pharmacokinetic parameters of TMC278 after a single oral administration of a clinical tablet of TMC278.HCI equivalent to 50 mg in fasted male Beagle dogs .

<td>Treatment Day Actual dose (mg eq./Kg) Time (h) Subject</td><td>C (50 mg equivalent tablet of TMC27Í 14 4.90 4.55 5.95 3.88 6.25 5.15 1 2 3 4 5 6</td><td>5) Mean SD</td>

<td> 0 0,5</td><td> &lt;1,00 &lt;1,00 &lt;1,00 2,43 &lt;1,00 &lt;1,00 &lt;1,00 7,63 69,1 150 13,5 55,7</td><td> &lt;1,00¹⁾ 34,6¹⁾</td>

<td rowspan="2">Treatment Day Actual dose (mg eq./Kg) Time (h) Subject</td><td colspan="2">C (compressed</td><td colspan="3">equivalent to 50 mg of</td><td colspan="2">TMC278)</td><td rowspan="2">DP</td>

<td> 14 4,90 1</td><td> 4,55 2</td><td> 5,95 3</td><td> 3,88 4</td><td> 6,25 5</td><td> 5,15 6</td><td>Average</td>

<td> 1</td><td> &lt;1,00</td><td> 124</td><td> 86,3</td><td> 348</td><td> 99,0</td><td> 160</td><td> 112 ¹⁾</td><td> -</td>

<td> 2</td><td> 1,27</td><td> 367</td><td> 252</td><td> 536</td><td> 263</td><td> 351</td><td> 295</td><td> 176</td>

<td> 4</td><td> 19,1</td><td> 647</td><td> 346</td><td> 369</td><td> 518</td><td> 225</td><td> 354</td><td> 220</td>

<td> 8</td><td> 237</td><td> 558</td><td> 581</td><td> 249</td><td> 500</td><td> 161</td><td> 381</td><td> 185</td>

<td> 24</td><td> 370</td><td> 407</td><td> 362</td><td> 203</td><td> 344</td><td> 121</td><td> 301</td><td> 113</td>

<td> 32</td><td> 251</td><td> 275</td><td> 213</td><td> 125</td><td> 212</td><td> 63,3</td><td> 190</td><td> 80</td>

<td> 48</td><td> 158</td><td> 204</td><td> 147</td><td> 115</td><td> 130</td><td> 42,4</td><td> 133</td><td> 54</td>

<td>Ç_max (ng / ml)</td><td> 370</td><td> 647</td><td> 581</td><td> 536</td><td> 518</td><td> 351</td><td> 501</td><td> 117</td>

<td>Tmax (h)</td><td> 24</td><td> 4</td><td> 8</td><td> 2</td><td> 4</td><td> 2</td><td> 7</td><td> 9</td>

<td>tl / 2, 32-48h (h)</td><td> 24,0</td><td> 37,1</td><td> 29,9</td><td> 133,0</td><td> 22,7</td><td> 27,7</td><td> 45,7</td><td> 43,1</td>

<td>Stroke₀_48h (ng.h / ml_)</td><td> 11100</td><td> 17900</td><td> 15200</td><td> 9530</td><td> 14600</td><td> 5440</td><td> 12300</td><td> 4480</td>

<td>Stroke₀._inf (ng.h / mL)</td><td> 16500²⁾</td><td> 28800 ²⁾</td><td> 21500²⁾</td><td> 31600²’</td><td> 18800</td><td> 7140</td><td> 20700</td><td> 8830</td>

<td>AVCE_xt_raDoi_Thed_The (%)</td><td> 33,1</td><td> 38,0</td><td> 29,5</td><td> 69,8</td><td> 22,6</td><td> 23,7</td><td> 36,1</td><td> 17,5</td>

1) median value

2) calculated with> 25% extrapolation

Table 5: Individual relative bioavailability of TMC278 in male fasting Beagle dogs after a single oral administration equivalent to 50 mg

<td rowspan="2">Subject Treatment</td><td colspan="6">Stroke₀-48h (ng.h / mL)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td>

<td>C (50 mg equivalent tablet) TMC278)</td><td> 11100</td><td> 17900</td><td> 15200</td><td> 9530</td><td> 14600</td><td> 5440</td>

<td>A (TMC278 / PVP-VA 64 powder 10/90% (m / m))</td><td> 9910</td><td> 12300</td><td> 13600</td><td> -</td><td></td><td></td>

<td>B (TMC278 / PVP-VA 64 / Cremophor powder EL 10/85/5% (m / m / m))</td><td> -</td><td></td><td> -</td><td> 12600</td><td> 12400</td><td> 8520</td>

<td>Frei (%&gt;</td><td> 89%</td><td> 69%</td><td> 89%</td><td> 132%</td><td> 85%</td><td> 157%</td>