Patent Description:
Nanoparticles or nanosuspensions are known in the prior art, having been described, for example, in <CIT>.

<CIT> describes powders for reconstitution comprising TMC278 dispersed in certain water-soluble polymers, useful in the treatment of HIV infection.

<CIT> describes a pharmaceutical composition comprising a basic drug compound, a surfactant and a physiologically tolerable water-soluble acid characterized in that the acid:drug compound ratio is at least <NUM>:<NUM> by weight or comprising an acidic drug compound, a surfactant and a physiologically tolerable water-soluble base characterized in that the base: drug compound ratio is at least <NUM>:<NUM> by weight.

<CIT> concerns pharmaceutical compositions for administration via intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the compound TMC278, suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment and prophylaxis of HIV infection.

The drug nanosuspension formulation which is the precursor formulation for the freeze-dried drug nanosuspension formulation of the present specification is a liquid formulation wherein the drug is suspended in the form of nanoparticles. The liquid or dispersion medium is preferably an aqueous medium, such as water.

The drug nanosuspension precursor formulation typically comprises a steric stabilizer, preferably a surfactant (e.g. a polymeric surfactant) or a polymer. The steric stabilizer is adsorbed or attached onto the surface of the drug nanoparticles and provides a large and dense steric barrier which overcomes attractive van der Waals forces and hence the steric stabilizer reduces aggregation, agglomeration or even particle fusion. This technique allows remarkable high dose loadings of the nanosuspension (e.g. up to <NUM> of drug/mL). The steric stabilizers are preferably excipients which are pharmaceutically acceptable.

The drug nanoparticles have typically a mean particle size below <NUM> and a d<NUM>-value of less than <NUM>. More in particular, the d<NUM>-value is <NUM>. (d99 is X or d95 is X means that <NUM>% or <NUM>% of the particles by weight (or by other suitable measurement techniques such as by volume or number) are below that size X).

In particular, the average particle size of the nanoparticles of the nanosuspensions to be freeze dried or the nanosuspension resulting from reconstitution of the freeze-dried drug nanosuspension may be below about <NUM>, or below about <NUM>, or below about <NUM>, or below about <NUM>, or below about <NUM>. Preferably, the average particle size is about <NUM> or about <NUM> or about <NUM>, more preferably about <NUM>.

A possible approach to produce a drug-nanosuspension is comminution of the drug substance in a stirred media mill by wet bead milling.

Drug nanosuspensions can improve solubility, dissolution rate, bioavailability. Drug nanosuspensions can also be used as sustained or delayed release (depot) formulation. Such formulations can be used for long term treatment or long term prevention, for instance when administered parenterally, e.g. intramuscularly or subcutaneously. This means that the formulation is able to provide effective plasma levels -plasma levels above a minimal therapeutical concentration- for a certain period, such as for at least <NUM> week, or at least two weeks, or at least <NUM> month or at least two months or at least three months. The formulation is also able to provide plasma level which are below a side-effect producing threshold value. The threshold value is the mean plasma level during a considerable period of time, e.g. for more than <NUM> minutes depending on the actual drug, above which patients may experience undesirable side effects, or conversely, the value of the plasma level under which the systemic tolerance of the formulation in question is still acceptable. The threshold value does not hold for transient, high plasma levels during a short period of time, e.g. for less than <NUM> minutes depending on the actual drug, which are due, for example to unexpected burst-release of the active ingredient.

Both of the foregoing features - plasma levels above a minimal therapeutical concentration but below a side-effect producing threshold value - are considered to be basic requirements that a contemporary depot formulation should fulfil in order to be acceptable for the intended patients. Limiting the number of drug administrations and the occurrence of undesirable side effects after each administration will undoubtedly improve the patients' compliance with the therapy. However, beyond these basic requirements, a number of further desiderata can be identified which would further improve patients' compliance, the two most notable being good local tolerance and ease of administration.

For injectables, good local tolerance means minimal irritation and inflammation at the site of injection; ease of administration refers to the size of needle and length of time required to administer a dose of a particular drug formulation.

A significant drawback of a liquid drug-nanosuspension is its limited long term stability. Settling and Ostwald-ripening effects are frequently recognized instability issues.

Therefore, freeze-dried drug nanosuspensions may be an appealing alternative. In this way, the shelf life of the formulation with the drug in nanoparticle range may be increased. Preferably, the freeze-dried drug nanosuspension itself has an acceptable long term stability, especially in relation with the average particle size or the particle size distribution. After storage and upon reconstitution of the freeze-dried drug nanosuspension, the average particle size, the particle size distribution, the d<NUM>, d<NUM>, d<NUM> or d<NUM> is preserved or is still acceptable.

These freeze-dried drug nanosuspensions may be reconstituted ex tempore to a liquid nanosuspension which can then be administered. Administration of said reconstituted nanosuspension includes oral administration or parenteral administration, such as for example intravenous, intramuscular or subcutaneous administration. Administration is preferably parenteral administration such as for example intramuscular or subcutaneous administration. Care has to be taken that the reconstituted suspension stays evenly dispersed or that it is easily dispersable upon shaking enabling homogenous administration.

The claimed invention is set out in the appended set of claims.

Described is a freeze-dried drug nanosuspension, meaning a freeze-dried nanosuspension comprising a drug or an aqueous nanosuspension comprising a drug and being freeze-dried to a solid composition.

Suitable drugs or active pharmaceutical ingredients that can be used in the freeze-dried nanosuspensions of the present specification include, without limitation:.

including their stereochemically isomeric forms;
the N-oxides thereof, the pharmaceutically acceptable acid or base addition salts thereof or the solvates thereof.

Pharmaceutically acceptable acid addition salts comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the active ingredient with appropriate organic and anorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, <NUM>-hydroxypropanoic, <NUM>-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, <NUM>-hydroxy-<NUM>,<NUM>,<NUM>-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, <NUM>-methylbenzenesulfonic, cyclohexanesulfamic, <NUM>-hydroxybenzoic, <NUM>-amino-<NUM>-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

Active ingredients containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, <NUM>-amino-<NUM>-(hydroxymethyl)-<NUM>,<NUM>-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term solvates comprises the hydrates and solvent addition forms which the active ingredients or the pharmaceutically acceptable salts thereof, are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the active ingredients comprise those active ingredients wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.

The term "stereochemically isomeric forms" defines all the possible stereoisomeric forms which the active ingredients may possess. More in particular, stereogenic centers may have the R- or S-configuration, and active ingredients containing one or more double bonds may have the E- or Z-configuration.

Described is that the drug or active pharmaceutical ingredient is an antifungal, such as for example itraconazole, or an antiviral, in particular an anti-HIV agent, more in particular a non nucleoside reverse transcriptase inhibitor (NNRTI), such as for example dapivirine, etravirine or rilpivirine.

The concentration of the drug in the nanosuspension to be freeze dried may range between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or is about <NUM>/ml or is about <NUM>/ml.

A high nanoparticle concentration improves the mechanical stability of the freeze-dried cake.

The freeze-dried drug nanosuspension may be reconstituted to a liquid drug nanosuspesnion with the same drug concentration as in the nanosuspension which was freeze-dried or with a different drug concentration (more or less concentrated).

Described is a freeze-dried drug nanosuspension wherein the drug is slightly soluble, very slightly soluble or practically insoluble according to USP <NUM>, general notes, <NUM>. Monograph components. In particular, the slightly soluble, very slightly soluble or practically insoluble drug is selected from the slightly soluble, very slightly soluble or practically insoluble drugs listed in the above list. Preferred drugs are selected from itraconazole, etravirine, dapivirine, rilpivirine. The drug is preferably a small chemical molecule active pharmaceutical ingredient (different from a large molecule such as for example a peptide or protein or DNA/RNA sequence).

Described is a freeze-dried nanosuspension comprising a drug, in particular a slightly soluble, very slightly soluble or practically insoluble drug, and further comprising a steric stabilizer. In one embodiment, the steric stabilizer is a solid at room temperature. In one embodiment, the steric stabilizer is a crystalline solid at room temperature, in particular the steric stabilizer is a crystalline solid at room temperature and has a melting point equal to or above <NUM><NUM>C or a melting point equal to or above <NUM> <NUM>C or a melting point equal to or above <NUM> <NUM>C or a melting point equal to or above <NUM> <NUM>C.

In one embodiment, the steric stabilizer is an amorphous solid at room temperature, in particular the steric stabilizer is an amorphous solid at room temperature and has a glass transition temperature (Tg) equal to or above <NUM> <NUM>C or a Tg equal to or above <NUM> <NUM>C or a Tg equal to are above <NUM> <NUM>C or a Tg equal to or above <NUM> <NUM>C.

The steric stabilizer provides an acceptable stability of the particle size distribution during storage, including long term storage, of the freeze-dried drug nanosuspension. It was found that the freezing rate is not a critical factor to preserve the original particle size distribution of the nanoparticles in the freeze-dried drug nanosuspension.

Determination of particle size distribution stability of the freeze-dried drug nanosuspension can be done by calculating the re-dispersibility index (RDI) or by determining the d<NUM> or d<NUM> or d<NUM> values directly after freeze drying (T0) and after the storage period, for example after <NUM> or <NUM> or <NUM> months of storage (T1, T2,T3). The RDI is defined as D<NUM>/D where D<NUM> is the volume weighed mean particle size after freeze-drying at T<NUM> and D is the corresponding value after the storage period for instance after <NUM> months of storage. A RDI of <NUM>% would therefore mean that the stored freeze-dried drug-nanosuspension can be completely transformed to the original particle size at T<NUM> after rehydration. A freeze dried drug nanosuspension has an acceptable particle size storage stability if the RDI after <NUM> months at <NUM> <NUM>C is at least <NUM> %, in particular at least <NUM> % or <NUM>% or <NUM> % or <NUM>%. In particular a freeze dried drug nanosuspension has an acceptable particle size storage stability if the RDI after <NUM> months at <NUM> <NUM>C is at least <NUM> %, in particular at least <NUM> % or <NUM>% or <NUM> % or <NUM>%.

In one embodiment, the steric stabilizer is a solid, crystalline or amorphous, at room temperature and is a polymer or a surfactant (e.g. a polymeric surfactant). In a preferred embodiment, the steric stabilizer is poloxamer <NUM>, especially in freeze-dried nanosuspensions for parenteral formulations.

The concentration of the steric stabilizer in the nanosuspension to be freeze dried may range between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or is about <NUM>/ml or about <NUM>/ml.

In one embodiment, the present invention relates to a freeze-dried drug nanosuspension comprising a steric stabilizer as described in any of the above embodiments, and further comprising a cryoprotectant or a lyoprotectant. A cryoprotectant is a compound that stabilizes the components to be freeze-dried during the freezing step. A lyoprotectant is a compound that stabilizes the components to be feeze-dried during the dehydration step. Many excipients can serve as both cryoprotectants and lyoprotectants.

In the present invention the cryoprotectant or lyoprotectant is a mono- or disaccharide. such as for example sucrose, trehalose, mannitol.

In one embodiment the cryoprotectant or lyoprotectant is a mixture of a saccharide and a polymer, e.g. a mixture of PVP and trehalose.

The cryoprotectant or lyoprotectant may further improve the stability of the particle size distribution during storage, including long term storage, of the freeze-dried drug nanosuspension.

The concentration of the cryoprotectant or lyoprotectant in the nanosuspension to be freeze dried may range between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or between <NUM> and <NUM>/ml or is about <NUM>/ml or about <NUM>/ml or about <NUM>/ml or about <NUM>/ml.

In a preferred embodiment, the lyoprotectant or cryoprotectant concentration is as low as possible to prevent shrinkage or collapse of the freeze-dried cake but sufficiently high to assure stabilization of the nanoparticles and the concentration of the steric stabilizer is a minimum concentration which is typically higher than the minimum concentration to achieve initial nanoparticle stability right after milling to obtain the nanosuspension.

In one embodiment the freeze-dried drug nanosuspension as described in any of the above embodiments has a residual moisture content equal to or below <NUM>% w/w or equal to or below <NUM> % w/w or equal to or below <NUM> % w/w. This limited residual moisture content further improves the stability of the particle size distribution during storage, including long term storage, of the freeze-dried nanosuspension.

Described is a freeze-dried drug nanosuspension as described in any of the above embodiments for use in the preparation of a medicament, in particular a liquid drug nanosuspension, more in particular an aqueous drug nanosuspension for oral or parenteral administration, in particular parenteral administration, more in particular subcutaneous or intramuscular administration.

Described is an aqueous nanosuspension obtained by reconstituting a freeze-dried drug nanosuspension as described hereinabove or hereinafter with a liquid or dispersion medium, in particular an aqueous dispersion medium, for example water or water for injection.

The present invention also relates to a process for preparing an aqueous nanosuspension, characterized by reconstituting the freeze-dried drug nanosuspension as described hereinabove or hereinafter with an aqueous dispersion medium.

The freeze-dried drug nanosuspension of the present invention may also further comprise pharmaceutically acceptable ingredients. The latter comprise any ingredients for use in injectable formulations or in suspension formulations or in oral formulations. These ingredients may be selected from one or more of a suspending agent, a buffer, a pH adjusting agent, a preservative, an isotonizing agent, and the like ingredients. In one embodiment, said ingredients are selected from one or more of a suspending agent, a buffer, a pH adjusting agent, and optionally, a preservative and an isotonizing agent. Particular ingredients may function as two or more of these agents simultaneously, e.g. behave like a preservative and a buffer, or behave like a buffer and an isotonizing agent.

Examples of pharmaceutically acceptable ingredients are described further below.

Described is a freeze-dried nanosuspension as described in any of the above embodiments wherein the drug is an anti HIV drug, in particular a non nucleoside reverse transcriptase inhibitor (NNRTI) such as for example dapivirine, etravirine or rilpivirine, in particular rilpivirine. Said nanosuspension may be for use in the preparation of a medicament, in particular a liquid nanosuspension of the anti HIV agent, more in particular an aqueous nanosuspension of the anti HIV drug for parenteral administration, in particular subcutaneous or intramuscular administration, in particular for the long term prevention or long term treatment of HIV infection.

Because of their pharmacokinetic properties and the need to keep plasma levels above a minimum level, currently used anti-HIV drugs require frequent administration of relatively high doses. The number and/or volume of dosage forms that need to be administered are commonly referred to as "pill burden". A high pill burden is undesirable for many reasons, such as the frequency of intake, often combined with the inconvenience of having to swallow large dosage forms, as well as the need to store and transport a large number or volume of pills. A high pill burden increases the risk of patients not taking their entire dose, thereby failing to comply with the prescribed dosage regimen. As well as reducing the effectiveness of the treatment, this also leads to the emergence of viral resistance. The problems associated with a high pill burden are prominent in anti-HIV therapy where a patient must take a large number of different anti-HIV agents.

Therefore, it would be desirable to provide HIV inhibitory therapy that reduces pill burden in that it involves the administration of dosage forms of relatively small size and additionally does not require frequent dosing. It would be attractive to provide anti-HIV therapy involving the administration of dosage forms at long time intervals such as one week or longer, or even one month or longer.

Currently, HIV cannot completely be eradicated so that persons infected with HIV pose a continuous risk of infecting others. After initial infection it takes a long time before the outbreak of the first symptoms of AIDS. People may live for years with the infection without experiencing any effects of it thereby being unaware of the risk of further transferring the virus to others. Prevention of HIV transmission therefore is crucial. Prevention currently focuses on avoiding transmission by sexual contacts, in particular by the use of condoms in populations at risk of being infected, on careful monitoring of blood samples for the presence of HIV and on avoiding of contact with blood of potentially infected subjects.

Despite these measures there is always an imminent risk of individuals being in contact with HIV infected persons of becoming infected. This in particular is the case for those providing medical care to infected patients or patients at risk of being infected such as physicians, nurses or dentists.

Hence there is a need for further means that provide prevention against transmission of HIV. There is a particular need for effective prevention means that are easy to apply. Providing such prevention means is another object of the present invention.

The present invention is therefore a freeze-dried nanosuspension as described in any of the above embodiments of the anti HIV drug <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof.

Described is a freeze-dried nanosuspension, whenever possible, in any of the above embodiments, of the anti HIV drug <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, said freeze-dried nanosuspension further comprising a steric stabilizer, in particular poloxamer <NUM>, and further comprising a cryoprotectant. For the concentrations of the anti HIV drug, the steric stabilizer and the cryoprotectant in the nanosuspension to be freeze-dried in order to obtain this freeze-dried nanosuspension, refence is made to the relevant sections hereinabove.

Said freeze-dried nanosuspension can be reconstituted to an aqueous nanosuspension by dilution with an aqueous dispersions medium, in particular water or water for injection. Said reconstituted nanosuspension can be used as a depot formulation, in particular as an injectable depot formulation, which may find use in the treatment of HIV infection as well as in the prevention against transmission of HIV.

These reconstituted nanosuspensions can intermittently be administered at time intervals of one week or longer that result in plasma levels that may be sufficient to suppress the growth (replication) of HIV. This allows for a reduced number of administrations thereby being beneficial in terms of pill burden and drug compliance of the patient. The nanoparticle formulations of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, of the invention therefore may be useful in the long-term treatment of HIV infection.

The intermittent administration of the reconstituted nanosuspension of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; at time intervals of one week or longer furthermore results in plasma levels that may be sufficient to provide prevention against transmission of HIV. Also in this instance, a reduced number of administrations is required, which again is advantageous in terms of pill burden and drug compliance of the individual at risk of being infected. The nanoparticle formulations of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, of the invention therefore may be useful in the long-term prevention of HIV infection.

Described is a pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, in the form of a reconstituted nanosuspension of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; in a pharmaceutically acceptable aqueous carrier; wherein the nanosuspension is reconstituted from a freeze-dried nanosuspension comprising:.

In one embodiment, the steric stabilizer in the above reconstituted nanosuspesnion is a crystalline solid at room temperature, in particular the steric stabilizer is a crystalline solid at room temperature and has a melting point equal to or above <NUM><NUM>C or a melting point equal to or above <NUM> <NUM>C or a melting point equal to or above <NUM> <NUM>C or a melting point equal to or above <NUM> <NUM>C.

In one embodiment, the steric stabilizer in the above reconstituted nanosuspension is an amorphous solid at room temperature, in particular the steric stabilizer is an amorphous solid at room temperature and has a glass transition temperature (Tg) equal to or above <NUM> <NUM>C or a Tg equal to or above <NUM> <NUM>C or a Tg equal to are above <NUM> <NUM>C or a Tg equal to or above <NUM> <NUM>C.

In one embodiment, the steric stabilizer in the above reconstituted nanosuspesnion is poloxamer <NUM>.

In one embodiment the above reconstituted nanosuspension further comprises a cryoprotectant or lyoprotectant, such as for example a mixture of PVP and a saccharide, such as for example trehalose.

Described is a method of treating a subject infected with HIV, said method comprising the administration, in particular by intramuscular or subcutaneous injection, of a pharmaceutical composition as specified above or hereinafter. Or, alternatively, described is the use of a pharmaceutical composition as specified above or hereinafter, for the manufacture of a medicament for treating HIV infection. Or, alternatively, described is a pharmaceutical composition as specified above or hereinafter for use in the treatment of HIV infection.

Described is a method for the long term treatment of HIV infection, said method comprising the administration to a subject infected with HIV of an effective amount of a pharmaceutical composition as specified above or hereinafter, by intramuscular or subcutaneous injection; wherein the composition is administered or is to be administered intermittently at a time interval that is in the range of one week to one year, or one week to two years. Or, alternatively, described is the use of a pharmaceutical composition as specified above or hereinafter, for the manufacture of a medicament for the long term treatment of HIV infection and for administration by intramuscular or subcutaneous injection, wherein the medicament is administered or is to be administered intermittently at a time interval that is in the range of one week to one year, or one week to two years. Or alternatively, described is a pharmaceutical composition as specified above or hereinafter for use in the long term treatment of HIV infection, wherein the composition is for administration by intramuscular or subcutaneous injection, and wherein the composition is administered or is to be administered intermittently at a time interval that is in the range of one week to one year, or one week to two years.

Described is a method for the prevention of HIV infection in a subject at risk of being infected by HIV, said method comprising administering an effective amount, effective in preventing HIV infection, of a pharmaceutical composition as specified above or hereinafter, to said subject. Or alternatively, described is the use of a pharmaceutical composition as specified above or hereinafter for the manufacture of a medicament for the prevention of HIV infection in a subject at risk of being infected by HIV. Or, alternatively, described is a pharmaceutical composition as specified above or hereinafter for use in the prevention of HIV infection in a subject at risk of being infected by HIV.

Described is a method for the long term prevention of HIV infection in a subject at risk of being infected by HIV, said method comprising administering to said subject an effective amount, effective in preventing HIV infection, of a pharmaceutical composition as specified above or hereinafter, by intramuscular or subcutaneous injection; wherein the composition is administered or is to be administered intermittently at a time interval that is in the range of one week to one year, or one week to two years. Or alternatively, described is the use of a pharmaceutical composition as specified above or hereinafter, for the manufacture of a medicament for the long term prevention of HIV infection in a subject at risk of being infected by HIV, and for administration by intramuscular or subcutaneous injection, wherein the medicament is administered or is to be administered intermittently at a time interval that is in the range of one week to one year or one week to two years. Or alternatively, described is a pharmaceutical composition as specified above or hereinafter for use in the long term prevention of HIV infection in a subject at risk of being infected by HIV, wherein the composition is for administration by intramuscular or subcutaneous injection, and wherein the composition is administered or is to be administered intermittently at a time interval that is in the range of one week to one year, or one week to two years.

Described is a use or a method or a pharmaceutical composition for use as specified herein, wherein the pharmaceutical composition is administered or is to be administered at a time interval that is in the range of one week to one month, or in the range of one month to three months, or in the range of three months to six months, or in the range of six months to twelve months, or in the range of <NUM> months to <NUM> months.

Described is a use or a method or a pharmaceutical composition for use as specified herein, wherein the pharmaceutical composition is administered or is to be administered once every two weeks, or once every month, or once every three months.

<NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile can be used in base form or as a suitable pharmaceutically acceptable addition salt form, such as an acid addition salt form. The pharmaceutically acceptable addition salts are meant to comprise the therapeutically active non-toxic salt forms. The acid addition salt forms can be obtained by treating the base form with appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, <NUM>-hydroxypropanoic, <NUM>-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, <NUM>-hydroxy-<NUM>,<NUM>,<NUM>-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, <NUM>-methylbenzenesulfonic, cyclohexanesulfamic, <NUM>-hydroxybenzoic, <NUM>-amino-<NUM>-hydroxybenzoic and the like acids. A preferred form for use in the present invention is <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile active ingredient in its base form.

<NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile occurs in stereoisomeric forms, more in particular as E- and Z-isomeric forms. Both isomers may be used in the present invention. Whenever reference is made herein to <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, the E- or the Z-form as well as any mixture of both forms are meant to be included. A preferred form of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile for use in the present invention is the E-isomer, i.e. (E)-<NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]-amino]-<NUM>-pyrimidinyl]-amino]-benzonitrile, especially the E-isomer in base form, which may be referred to as rilpivirine. The Z-isomer of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, i.e. (Z)-<NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]-amino]-<NUM>-pyrimidinyl]-amino]-benzonitrile, can also be used.

Whenever reference is made herein to the E-form of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, the pure E-isomer or any isomeric mixture of the E- and the Z-forms wherein the E- form is predominantly present is meant to be comprised, i.e. an isomeric mixture containing more than <NUM>% or in particular more than <NUM>% of the E-form, or even more than <NUM>% of the E-form. Of particular interest is the E-form substantially free of the Z-form. Substantially free in this context refers to E-Z-mixtures with no or almost no Z-form, e.g. isomeric mixtures containing as much as <NUM>%, in particular <NUM>% or even <NUM>% or <NUM>% of the E-form. Equally, whenever reference is made herein to the Z-form of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, the pure Z-isomer or any isomeric mixture of the Z- and the E-forms wherein the Z-form is predominantly present is meant to be comprised, i.e. an isomeric mixture containing more than <NUM>% or in particular more than <NUM>% of the Z-form, or even more than <NUM>% of the Z-form. The Z-form substantially free of the E-form can also be used. Substantially free in this context refers to E-Z-mixtures with no or almost no E-form, e.g. isomeric mixtures containing as much as <NUM>%, in particular <NUM>% or even <NUM>% or <NUM>% of the Z-form. In one embodiment, <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile active ingredient is used in the E-form, in particular the E-form of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile base.

Also meant to be included for use in this invention are salts of the stereoisomeric forms of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile, in particular the salts mentioned above of the Z or E isomeric form of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile, such as for example the hydrochloric acid salt of E-<NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile.

Whenever used herein below, <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile also comprises a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, unless otherwise indicated.

It has been found that the physico-chemical properties of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile allow for the manufacture of nanosuspensions that have unique pharmacokinetic properties in that they can be used for the long-term treatment of HIV infection as well as for the long-term prevention of HIV infection and to this purpose only a limited number of drug administrations is required. This is beneficial in terms of pill-burden as well as patient compliance with the prescribed dose regimen.

As used herein the term "treatment of HIV infection" relates to the treatment of a subject being infected with HIV. The term "treatment of HIV infection" also relates to the treatment of diseases associated with HIV infection, for example AIDS, or other conditions associated with HIV infection including thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation, and further conditions where HIV infection has also been associated with, such as peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS-related complex (ARC).

The term "prevention of HIV infection" relates to the prevention or avoidance of a subject becoming infected with HIV. The source of infection can be various, a material containing HIV, in particular a body fluid that contains HIV such as blood or sperm, or another subject who is infected with HIV. Prevention of HIV infection relates to the prevention of the transmission of the virus from the material containing HIV or from the HIV infected individual to an uninfected person, or relates to the prevention of the virus from entering the body of an uninfected person. Transmission of the HIV virus can be by any known cause of HIV transfer such as by sexual transmission or by contact with blood of an infected subject, e.g. medical staff providing care to infected subjects. Transfer of HIV can also occur by contact with HIV infected blood, e.g. when handling blood samples or with blood transfusion. It can also be by contact with infected cells, e.g. when carrying out laboratory experiments with HIV infected cells.

The terms "treatment of HIV infection", "anti-HIV therapy", as well as similar terms, refer to a treatment by which the viral load of HIV (represented as the number of copies of viral RNA in a specified volume of serum) is reduced. The more effective the treatment, the lower the viral load. Preferably the viral load should be reduced to as low levels as possible, e.g. below about <NUM> copies/ml, in particular below about <NUM> copies/ml, more in particular below <NUM> copies/ml, if possible below the detection limit of the virus. Reductions of viral load of one, two or even three orders of magnitude (e.g. a reduction in the order of about <NUM> to about <NUM><NUM>, or more, such as about <NUM><NUM>) are an indication of the effectiveness of the treatment. Another parameter to measure effectiveness of anti-HIV treatment is the CD4 count, which in normal adults ranges from <NUM> to <NUM> cells per µl. Lowered CD4 counts are an indication of HIV infection and once below about <NUM> cells per µl, AIDS may develop. An increase of CD4 count, e.g. with about <NUM>, <NUM>, <NUM> or more cells per µl, is also an indication of the effectiveness of anti-HIV treatment. The CD4 count in particular should be increased to a level above about <NUM> cells per µl, or above about <NUM> cells per µl. Viral load or CD4 count, or both, can be used to diagnose the degree of HIV infection.

The terms "effective treatment of HIV" and similar terms refer to that treatment that lowers the viral load, or increases CD4 count, or both, as described above. The terms "effective prevention of HIV" and similar terms refer to that situation where there is a decrease in the relative number of newly infected subjects in a population in contact with a source of HIV infection such as a material containing HIV, or a HIV infected subject. Effective prevention can be measured, for example, by measuring in a mixed population of HIV infected and non-infected individuals, if there is a decrease of the relative number of newly infected individuals, when comparing non-infected individuals treated with a pharmaceutical composition of the invention, and non-treated non-infected individuals. This decrease can be measured by statistical analysis of the numbers of infected and non-infected individuals in a given population over time.

The terms "therapeutically effective amount", "an effective amount", "an amount, effective in preventing HIV infection", and similar terms, refer to amounts of the active ingredient <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile that result in efficacious blood plasma levels. With "efficacious blood plasma levels" is meant those blood plasma levels of the HIV inhibitor <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl] amino] -<NUM>-pyrimidinyl]amino]benzonitrile that provide effective treatment or effective prevention of HIV infection.

The term "subject" in particular relates to a human being.

The average particle size of the nanoparticles of the nanosuspensions to be freeze dried or the nanosuspension resulting from reconstitution of the freeze-dried nanosuspension may be below about <NUM>, or below about <NUM>, or below about <NUM>, or below about <NUM>, or below about <NUM>. Preferably, the average particle size is about <NUM> or about <NUM> or about <NUM>, more preferably about <NUM>.

As used herein, the term average particle size has its conventional meaning as known to the person skilled in the art and can be measured by art-known particle size measuring techniques such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation. The average particle sizes mentioned herein may be related to volume distributions of the particles. In that instance, by "an average particle size of less than about <NUM>" it is meant that at least <NUM>% of the volume of the particles has a particle size of less than about <NUM>, and the same applies to the other particle sizes mentioned. In a similar manner, the average particle sizes may be related to weight distributions of the particles. In that instance, by "an average particle size of less than about <NUM>" it is meant that at least <NUM>% of the weight of the particles has a particle size of less than about <NUM>, and the same applies to the other particle sizes mentioned. Usually volume and weight distribution result in the same or about the same value for the average particle size.

The pharmaceutical compositions described herein provide release of the active ingredient <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile over a prolonged period of time and therefore they can also be referred to as sustained or delayed release compositions. After administration, the compositions described herein stay in the body and steadily release <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, keeping such levels of this active ingredient in the patient's system for a prolonged period of time, thereby providing, during said period, anti-HIV therapy or prevention of HIV infection. Because of the fact that the pharmaceutical compositions described herein stay in the body and steadily release <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, they can be referred to as pharmaceutical compositions suitable as depot formulations.

As used herein with the term "prolonged period of time", there is meant a term (or time period) that may be in the range of one week up to one year or up to two years, or a term in the range of one to two weeks, or two to three weeks, or three to four weeks, or a term in the range of one to two months, or two to three months, or three to four months, or three to six months, or six months to <NUM> months, or <NUM> months to <NUM> months, or a term that is in the range of several days, e.g. <NUM>, <NUM> or <NUM> days, or several weeks, e.g. <NUM>, <NUM> or <NUM> weeks, or one month, or several months, e.g. <NUM>, <NUM>, <NUM>, <NUM> or six months or even longer, e.g. <NUM>, <NUM>, <NUM> or <NUM> months.

The pharmaceutical compositions of this invention may be applied in the long-term treatment or the long-term prevention of HIV infection, or with other words they may be used in the treatment of HIV infection, or in the prevention of HIV infection, during a prolonged period of time. The compositions described herein are effective in anti-HIV therapy or in the prevention of HIV infection for a prolonged period of time, for example for at least about one week or longer, or for about <NUM> month or longer. By the expression "effective for at least about one week or longer", one means that the plasma level of the active ingredient, <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, should be above a threshold value. In case of therapeutic application said threshold value is the lowest plasma level at which <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile provides effective treatment of HIV infection. In case of application in the prevention of HIV infection said threshold value is the lowest plasma level at which <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is effective in preventing transmission of HIV infection.

With "long term" for example as used in relation to "long term prevention of HIV infection" or "long term treatment of HIV infection", or similar terminology, there are meant terms that may be in the range of one week up to one year or up to two years, or longer, such as five or <NUM> years. In particular in the case of treatment of HIV infection, such terms will be long, in the order of one to several years. Such terms may also be relatively short, in particular in the case of prevention. Shorter terms are those of several days, e.g. <NUM>, <NUM> or <NUM> days, or several weeks, e.g. <NUM>, <NUM> or <NUM> weeks, or one month, or several months, e.g. <NUM>, <NUM>, <NUM>, <NUM> or six months or even longer, e.g. <NUM>, <NUM>, <NUM> or <NUM> months. The methods and uses described herein are for the prevention of HIV infection during one month, or several months, e.g. <NUM>, <NUM>, <NUM>, <NUM> or six months or even longer, e.g. <NUM>, <NUM>, <NUM> or <NUM> months. The methods and uses described herein are for the treatment of HIV infection during one month, or several months, e.g. <NUM>, <NUM>, <NUM>, <NUM> or six months or even longer, e.g. <NUM>, <NUM>, <NUM> or <NUM> months.

The pharmaceutical compositions described herein can be administered at various time intervals. When used in the prevention of HIV infection, the pharmaceutical compositions described herein can be administered only once or a limited number of times such as twice, three, four, five or six times, or more. This may be recommendable where prevention is required during a limited period of time, such as the period during which there is a risk of infection.

The pharmaceutical compositions described herein can be administered at the time intervals mentioned above, such as at a time interval that is in the range of one week to one month, or in the range of one month to three months, or in the range of three months to six months, or in the range of six months to twelve months. In one embodiment, the pharmaceutical composition can be administered once every two weeks, or once every month, or once every three months. In another embodiment the time interval is in the range of one to two weeks, or two to three weeks, or three to four weeks, or the time interval is in the range of one to two months, or two to three months, or three to four months, or three to six months, or six months to <NUM> months, or <NUM> months to <NUM> months. The time interval may be at least one week, but may also be several weeks, e.g. <NUM>, <NUM>, <NUM>, <NUM> or <NUM> weeks, or at time intervals of one month, or of several months, e.g. <NUM>, <NUM>, <NUM>, <NUM> or <NUM> months or even longer, e.g. <NUM>, <NUM>, <NUM> or <NUM> months. In one embodiment, the pharmaceutical compositions described herein are administered at a time interval of one, two or three months. These longer periods between each administration of the pharmaceutical compositions described herein provide further improvements in terms of pill burden and compliance. To further improve compliance, patients can be instructed to take their medication at a certain day of the week, where the composition is administered on a weekly schedule, or at a certain day of the month in case of a monthly schedule.

The length of the time intervals between each administration of a composition described herein may vary. For example said time intervals may be selected in function of the blood plasma levels. The intervals may be shorter where the blood plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile are deemed too low, e.g. when these approach the minimum blood plasma level specified hereinafter. The intervals may be longer where the blood plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile are deemed too high. In one embodiment, the compositions described herein are administered at equal time intervals. The compositions may be administered without any interjacent additional administrations, or with other words, the compositions may be administered at particular points in time separated from one another by a time period of varying or equal length, e.g. a time period of at least one week, or any other time period specified herein, during which no further <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is administered. Having time intervals of the same length has the advantage that the administration schedule is simple, e.g. administration takes place at the same day in the week, or the same day in the month. Such administration schedule therefore involves limited "pill burden" thereby contributing beneficially to the patient's compliance to the prescribed dosing regimen.

The concentration (or "C") of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile in the blood plasma of a subject treated therewith is generally expressed as mass per unit volume, typically nanograms per milliliter (ng/ml). For convenience, this concentration may be referred to herein as "blood plasma drug concentration" or "blood plasma concentration".

The dose (or amount) of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile administered, depends on the amount of the drug in the pharmaceutical compositions of the invention, or on the amount of a given composition that is administered. Where higher blood plasma levels are desired, either or both of a composition of higher <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile concentration, or more of a given composition, may be administered. This applies vice versa if lower plasma levels are desired. Also a combination of varying time intervals and varying dosing may be selected to attain certain desired blood plasma levels.

The dose (or amount) of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile administered also depends on the frequency of the administrations (i.e. the time interval between each administration). Usually, the dose will be higher where administrations are less frequent. All these parameters can be used to direct the blood plasma levels to desired values.

The dosing regimen also depends on whether prevention or treatment of HIV infection is envisaged. In case of therapy, the dose of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile administered or the frequency of dosing, or both, are selected so that the blood plasma concentration of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is kept above a minimum blood plasma level. The term "minimum blood plasma level" (or Cmin) in this context refers to the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile that provides effective treatment of HIV. In particular, the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is kept at a level above a minimum blood plasma level of about <NUM> ng/ml, or above about <NUM> ng/ml, or above about <NUM> ng/ml, or above about <NUM> ng/ml, or above about <NUM> ng/ml, or above about <NUM> ng/ml, or above about <NUM> ng/ml, or above about <NUM> ng/ml In one embodiment, the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is kept above a level of about <NUM> ng/ml. Or the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile may be kept within certain ranges, in particular ranges starting from a minimum blood plasma level selected from those mentioned above and ending at a higher blood plasma levels selected from those mentioned above and selected from <NUM> ng/ml and <NUM> ng/ml (e.g. from <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, etc., or from <NUM> to <NUM>, or <NUM> to <NUM>, or <NUM> to <NUM>, etc., or <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>, etc., or <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> -<NUM>, etc., each time from about the indicated value in ng/ml to about the indicated value in ng/ml). In one embodiment said range is from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, each time from about the indicated value in ng/ml to about the indicated value in ng/ml.

The plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile should be kept above the above-mentioned minimum blood plasma levels because at lower levels the virus may no longer be sufficiently suppressed so that it can multiply with the additional risk of the emergence of mutations.

In the instance of HIV prevention, the term "minimum blood plasma level" (or Cmin) refers to the lowest blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile that provides effective prevention of HIV infection. In the case of transmission of HIV from a material containing HIV or from a subject infected by HIV to a subject not infected by HIV, this is the lowest blood plasma level that is effective in inhibiting said transmission.

In particular, in the instance of HIV prevention, the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile can be kept at a level above a minimum blood plasma level mentioned above in relation to therapy. However in prevention the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile can be kept at a lower level, for example at a level above about <NUM> ng/ml, or about <NUM> ng/ml, or about <NUM> ng/ml.

The blood plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile should preferably be kept above these minimum blood plasma levels because at lower levels the drug may no longer be effective thereby increasing the risk of transmission of HIV infection. Plasma levels of TMC278 may be kept at somewhat higher levels to have a safety margin. Such higher levels start from about <NUM> ng/ml or more; or from about <NUM> ng/ml or more. The blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile can be kept at a level that is in the ranges mentioned above in relation to therapy, but where the lower limits include the blood plasma levels of about <NUM> ng/ml, or about <NUM> ng/ml, or about <NUM> ng/ml.

An advantage of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is that it can be used up to relatively high blood plasma levels without any significant side effects. The plasma concentrations of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile may reach relatively high levels, but as with any drug should not exceed a maximum plasma level (or Cmax), which is the blood plasma level where <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile causes significant side effects. As used herein, the term "significant side effects" means that the side effects are present in a relevant patient population to an extend that the side effects affect the patients' normal functioning. The Cmax for <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile can be determined from the extrapolation of test data in cellular assays or from the evaluation of clinical testing and preferably should not exceed a value of about <NUM> ng/ml or <NUM> ng/ml. In an embodiment, the amount and the frequency of administrations of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile to be administered are selected such that the blood plasma concentrations are kept during a long term at a level comprised between a maximum plasma level (or Cmax as specified above) and a minimum blood plasma level (or Cmin as specified above).

In certain instances it may be desirable to keep the plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile at relatively low levels, e.g. as close as possible to the minimum blood plasma levels specified herein. This will allow reducing the frequency of the administrations and/or the quantity of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile administered with each administration. It will also allow avoiding undesirable side effects, which will contribute to the acceptance of the dosage forms in most of the targeted population groups who are healthy people at risk of being infected and therefore are less inclined to tolerate side effects. The plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile may be kept at relatively low levels in the instance of prevention. One embodiment concerns uses or methods for prevention of HIV infection, as specified above or hereinafter, wherein the minimum blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is as specified herein and the maximum blood plasma level is about equal to the lowest blood plasma level that causes the RT inhibitor to act therapeutically, also as specified herein.

In other embodiments, the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is kept at a level below a lower maximum blood plasma level of about <NUM> ng/ml, more in particular about <NUM> ng/ml, further in particular about <NUM> ng/ml, still more in particular about <NUM> ng/ml. In a particular embodiment, the blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is kept below a level of about <NUM> ng/ml. In one embodiment, the plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile is kept in an interval of the lower maximum blood level specified above, and the minimum blood plasma levels mentioned in relation to prevention. For example the blood plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino] -<NUM>-pyrimidinyl] amino]benzonitrile are kept below about <NUM> ng/ml and above a minimum level of about <NUM> ng/ml.

In other instances it may be desirable to keep the plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile at relatively higher levels, for example where there is a high risk of infection and more frequent and/or higher doses are not an issue. In these instances the minimum blood plasma level may be equal to the lowest blood plasma level of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile that provides effective treatment of HIV, such as the specific levels mentioned herein.

In the instance of prevention, the dose of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, in particular rilpivirine, to be administered should be calculated on a basis of about <NUM>/day to about <NUM>/day, or <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, e.g. about <NUM>/day or about <NUM>/day or about <NUM>/day. This corresponds to a weekly dose of about <NUM> to about <NUM>, in particular of about <NUM> to about <NUM>, in particular of about <NUM> to about <NUM>, or of about <NUM> to about <NUM>, or of about <NUM> to about <NUM>, or of about <NUM> mf to about <NUM>, or of about <NUM> to about <NUM>, e.g. about <NUM> or about <NUM> or about <NUM>, or to a monthly dose of from <NUM> to about <NUM>, in particular about <NUM> to about <NUM>,<NUM>, more in particular of about <NUM> to about <NUM>, or about <NUM> to about <NUM>, or of about <NUM> to about <NUM>, or of about <NUM> to about <NUM>, or of about <NUM> to about <NUM>, e.g. about <NUM> or about <NUM> or about <NUM>. Doses for other dosing regimens can readily be calculated by multiplying the daily dose with the number of days between each administration.

In the instance of therapy, the dose of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, in particular rilpivirine, to be administered should be somewhat higher and should be calculated on a basis of about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, or about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day, or of about <NUM>/day to about <NUM>/day,, e.g. about <NUM>/day or about <NUM>/day or about <NUM>/day. The corresponding weekly or monthly doses can be calculated as set forth above. For applications in prevention, the doses may be lower although the same dosing as for therapeutic applications may be used.

In one embodiment, the monthly dose of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, in particular rilpivirine, is <NUM>. In one embodiment, the concentration of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, in particular rilpivirine, in the aqueous reconstituted nanosuspension is <NUM>/ml or <NUM>/ml.

It has been found that, once administered, the blood plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile are more or less stable, i.e. they fluctuate within limited margins. The blood plasma levels have been found to approach more or less a steady state mode or to approximate more or less a zero order release rate during a prolonged period of time. By "steady state" is meant the condition in which the amount of drug present in the blood plasma of a subject stays at more or less the same level over a prolonged period of time. The plasma levels of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile generally do not show any drops below the minimum plasma level at which the drug is effective. The term "stays at more or less the same level" does not exclude that there can be small fluctuations of the plasma concentrations within an acceptable range, e.g. fluctuations within a range of about +/- <NUM> %, or about +/- <NUM> %, or about +/- <NUM> %, or about +/- <NUM> %.

In some instances there may be an initial plasma concentration peak after administration, after which the plasma levels achieve a "steady-state", as mentioned hereinbefore.

The compositions described herein show good local tolerance and ease of administration. Good local tolerance relates to minimal irritation and inflammation at the site of injection; ease of administration refers to the size of needle and length of time required to administer a dose of a particular drug formulation.

In one embodiment, the nanoparticles in the compositions described herein mainly comprise crystalline <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile; and a steric stabilizer, the combined amount of which may at least comprise by weight about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>%, or at least about <NUM>% of the nano particles.

The reconstituted pharmaceutical compositions described herein contain a carrier, in particular an aqueous carrier that preferably is pharmaceutically acceptable. Said aqueous carrier comprises sterile water optionally in admixture with other pharmaceutically acceptable ingredients. The latter comprise any ingredients for use in injectable formulations or I suspension formulations or in oral formulations. These ingredients may be selected from one or more of a suspending agent, a buffer, a pH adjusting agent, a preservative, an isotonizing agent, and the like ingredients. In one embodiment, said ingredients are selected from one or more of a suspending agent, a buffer, a pH adjusting agent, and optionally, a preservative and an isotonizing agent. Particular ingredients may function as two or more of these agents simultaneously, e.g. behave like a preservative and a buffer, or behave like a buffer and an isotonizing agent. As stated above, the other pharmaceutically acceptable ingredients may also be present in the freeze-dried drug nanosuspension itself. Or the other pharmaceutically acceptable ingredients may be present in both the freeze-dried drug nanosuspension itself as well as in the carrier, in particular the aqueous carrier. Preferably, the other pharmaceutically acceptable ingredients are present in the freeze-dried drug nanosuspension as such.

Suitable buffering agents and pH adjusting agents should be used in amount sufficient to render the dispersion neutral to very slightly basic (up to pH <NUM>), preferably in the pH range of <NUM> to <NUM>. Particular buffers are the salts of week acids. Buffering and pH adjusting agents that can be added may be selected from tartaric acid, maleic acid, glycine, sodium lactate/lactic acid, ascorbic acid, citric acid, sodium citrates/citric acid, sodium acetate/acetic acid, sodium bicarbonate/carbonic acid, sodium succinate/succinic acid, sodium benzoate/benzoic acid, sodium phosphates, tris(hydroxymethyl)aminomethane, sodium bicarbonate/sodium carbonate, ammonium hydroxide, benzene sulfonic acid, benzoate sodium/acid, diethanolamine, glucono delta lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic, glyceric, gluratic, glutamic, ethylene diamine tetraacetic (EDTA), triethanolamine, including mixtures thereof.

Preservatives comprise antimicrobials and anti-oxidants which can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-piccolinium chloride, phenylmercuric acetate and thimerosal. Radical scavengers include BHA, BHT, Vitamin E and ascorbyl palmitate, and mixtures thereof. Oxygen scavengers include sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, acetone sodium bisulfite, isoacorbic acid, hydroxypropyl cyclodextrin. Chelating agents include sodium citrate, sodium EDTA and malic acid. Citric acid can be used as anti-oxidant, buffer and isotonizing agent.

An isotonizing agent or isotonifier may be present to ensure isotonicity of the pharmaceutical compositions described herein, and includes sugars such as glucose, dextrose, sucrose, fructose, trehalose, lactose; polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol. Alternatively, sodium chloride, sodium sulfate, or other appropriate inorganic salts may be used to render the solutions isotonic. These isotonifiers can be used alone or in combination. The suspensions conveniently comprise from <NUM> to <NUM>% (w/v), in particular <NUM> to <NUM>% of isotonizing agent. Of interest are nonionic isotonifiers, e.g. glucose or trehalose, as electrolytes may affect colloidal stability.

A desirable feature for a pharmaceutical composition described herein relates to the ease of administration. The viscosity of the pharmaceutical compositions described herein should preferably be sufficiently low to allow administration by injection. In particular they should be designed so that they can be taken up easily in a syringe (e.g. from a vial), injected through a fine needle (e.g. a <NUM> 1½, <NUM> 1½, <NUM> <NUM> or <NUM> 1¼ needle) in not too long a time span. In one embodiment the viscosity of the compositions of the invention is below about <NUM> mPa·s, or below <NUM> mPa·s. Aqueous suspensions of such viscosity or lower usually meet the above-mentioned criteria.

Ideally, the reconstituted aqueous suspensions described herein will comprise as much <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile as can be tolerated so as to keep the injected volume to a minimum, in particular from <NUM> to <NUM>% (w/v), or from <NUM> to <NUM>% (w/v), or from <NUM> to <NUM>% (w/v), or from <NUM> to <NUM>% (w/v), or from <NUM> to <NUM>% (w/v), or from <NUM> to <NUM>% (w/v), of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile. In one embodiment the reconstituted aqueous suspensions described herein contain about <NUM>% (w/v) of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile, or about <NUM>% (w/v) of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, or about <NUM>% (w/v) of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]-amino]benzonitrile.

In one embodiment, the reconstituted aqueous nanosuspensions may comprise by weight, based on the total volume of the composition:.

To the suspensions may optionally be added an amount of acid or base to bring the pH to a value of about pH <NUM>. Suitable acids or bases are any of those that are physiologically acceptable, e.g. HCl, HBr, sulfuric acid, alkali metal hydroxides such as NaOH.

The administration of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile as in the present invention may suffice to treat HIV infection although in a number of cases it may be recommendable to co-administer other HIV inhibitors. The latter preferably include HIV inhibitors of other classes, in particular those selected from NRTIs, PIs and fusion inhibitors. In one embodiment, the other HIV inhibitor that is co-administered is a PI inhibitor. HIV inhibitors that may be co-administered by preference are those used in HAART combinations comprising an NNRTI. For example two further NRTIs or an NRTI and a PI may be co-administered. Such co-administration may be by oral administration or parenterally, including parenteral administration for long term treatment of HIV infection or long term prevention of HIV infection.

In certain instances, the treatment of HIV infection may be limited to only the administration of a composition of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile in accordance with this invention, i.e. as monotherapy without co-administration of further HIV inhibitors. This option may be recommended, for example, where the viral load is relatively low, for example where the viral load (represented as the number of copies of viral RNA in a specified volume of serum) is below about <NUM> copies/ml, in particular below about <NUM> copies/ml, more in particular below <NUM> copies/ml, specifically below the detection limit of the virus. In one embodiment, this type of monotherapy is applied after initial treatment with a combination of HIV drugs, in particular with any of the HAART combinations during a certain period of time until the viral load in blood plasma reaches the afore mentioned low viral level.

Described is the use of a reconstituted pharmaceutical composition comprising an antivirally effective amount of <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile, in accordance with the present invention, for the manufacture of a medicament for maintenance therapy of a subject being infected with HIV, wherein the composition is administered or is to be administered intermittently at a time interval that is in the range of one week to one year, or one week to two years.

Thus described is a method for the long term treatment of a patient being infected with HIV, said method comprising.

As used herein, the word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention. The term "about" in connection with a numerical value is meant to have its usual meaning in the context of the numerical value. Where necessary the word "about" may be replaced by the numerical value ±<NUM>%, or ±<NUM>%, or ±<NUM>%, or ±<NUM>%.

The following examples including reference examples are intended to illustrate the present invention and should not be construed as limiting the invention thereto.

Two poorly water-soluble crystalline API's :Itraconazole and Rilpivirine. <NUM> yttrium stabilized zirconia beads. Lutrol F108 Prill (Poloxamer <NUM>) and Cremophor EL (BASF, Ludwigshafen, Germany). PVP K15, trehalose and sucrose of analytical grade (Sigma Chemical Company, Munich, Germany) used as received. Water for injection purchased from Braun (Braun-Melsungen AG, Melsungen, Germany) for the production of the nanosuspensions. Demineralised water was filtered through Sartobran PH<NUM>O membrane filters (Sartorius stedim biotech, Germany) and used for laser diffraction analysis.

15R Vials from Lutz GmbH (Wertheim, Germany) and <NUM> West Flurotec® lyophilization stoppers from West Pharmaceutical Services, Inc. (Lionville, PA, USA) were used as received. All vials were placed onto the shelf using a bottomless-tray.

<NUM>/mL Itraconazole was mixed with either <NUM>/mL of Poloxamer <NUM> or <NUM>/mL of Cremophor EL and prepared by wet bead milling in a high shear-media mill (Netzsch MiniCer®). For milling, <NUM> yttrium stabilized zirconia beads were used. For data comparison purpose, <NUM>/mL Rilpivirine was stabilized with <NUM>/mL Poloxamer <NUM> and milled using the same procedure as mentioned above. The rilpivirne concentration was then further increased to <NUM>/mL and stabilized again with <NUM>/mL Poloxamer <NUM>. The resulting stock-nanosuspensions were mixed with <NUM>/mL PVP K15, trehalose or sucrose.

A Malvern MasterSizer® was used to allow a determination of the particle size distribution over a range in which even agglomerates can be found. Dependent on the steric stabilizer present in the formulation, an aqueous solution of <NUM>/mL Poloxamer <NUM> or Cremophor EL was used as a medium since particle stability was not sufficient in pure water during a measurement. Basis for particle size calculation was the Mie theory with a product refractive index of <NUM> and product absorption of <NUM>. The obtained fitting curve achieved by the MasterSizer <NUM> Software indicated validity of the optical model. Background and measurement integration time were kept at <NUM> seconds, measurements were conducted in triplicate (n=<NUM>) per unit sample.

<NUM> of each formulation was filled in 15R vials. Lyophilization was then performed on a laboratory scale freeze-dryer (VirTis Advantage Plus, SP Scientific, USA). Freezing was conducted at -<NUM> (shelf inlet temperature) for <NUM> minutes including equilibrating steps at +<NUM> and -<NUM> for <NUM> minutes each. To facilitate crystallization of the Poloxamer <NUM> in the formulation, an annealing step at -<NUM> (shelf inlet temperature) for <NUM> minutes was implemented. The shelf temperature ramp rates from the freezing set-point to the primary drying shelf temperature setting were <NUM>/min throughout the study. The shelf inlet temperature set-point during primary and secondary drying was <NUM>. The holding time (soak period) of this step was either <NUM> minutes or <NUM> minutes to allow a modulation in water content in the samples. The chamber pressure during primary and secondary drying was controlled at <NUM> mTorr throughout the experiments. Note that the freeze-drying cycles were performed in duplicate (n=<NUM>) per formulation.

Product temperatures during freeze-drying were measured using calibrated <NUM> gauge T-type copper/constantan thermocouples from Omega (Omega Engineering, Stamford, CT). Each thermocouple was introduced through a stopper and positioned bottomcenter of the vial to obtain both a representative temperature monitoring in the product and an accurate endpoint detection of the ice sublimation phase.

Determination of thermal transitions in all formulation mixtures was performed using a MettlerDSC822e (Mettler Toledo, Greifensee, Switzerland). Data acquisition was performed in the temperature range between <NUM> and <NUM>. The applied heating rate was <NUM>/min.

Residual moisture of the lyophilized samples was measured using a Metrohm Karl Fischer <NUM> KF Coulometer combined with a Metrohm Thermoprep <NUM> unit. About <NUM> of product was weighed into a custom glass vial and then inserted into the oven unit after purging the sample vial with dry nitrogen. The product was heated to <NUM> for a defined time period and the moisture was accumulated in the titration solvent. Dependent on the sample weight, residual moisture content was reported in percent (%).

Directly after freeze-drying the products (n=<NUM>) were sealed and stored at <NUM> and <NUM>/75RH, respectively. After <NUM>, <NUM> and <NUM> months samples were analyzed in terms of mean particle size and particle size distribution. DSC and Karl-Fischer measurements were performed after freeze-drying as well as after <NUM> months of storage.

<NUM> of Poloxamer <NUM> was dissolved in water for injection. <NUM> of rilpivirine was added and suspended. Water for injection was added until the desired end weight (<NUM> rilpivirine and <NUM> Poloxamer/ml). The resulting suspension was milled in a Netzsch Pharma Labstar (<NUM> milling chamber) with <NUM>% bead load of <NUM> yttrium stabilized zirconia beads. Milling was performed at agitator speed of <NUM> rpm until the appropriate particle size was reached (measured on Malvern).

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added. Water for injection was added until <NUM> (or <NUM>) and the mixture was stirred until homogeneous.

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added and the mixture was stirred until homogeneous. Water for injection was added until <NUM> (or <NUM>) and the mixture was stirred until homogeneous.

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K12 stock solution was added. Water for injection was added until <NUM> (or <NUM>) and the mixture was stirred until homogeneous.

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml trehalose stock solution was added. Water for injection was added until <NUM> (or <NUM>) and the mixture was stirred until homogeneous.

For drug nanosuspension 5a, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added. <NUM> of a <NUM>/ml trehalose stock solution was added. Water for injection was added until <NUM> (or <NUM>) and the mixture was stirred until homogeneous.

<NUM> of Poloxamer <NUM> was dissolved in water for injection. <NUM> of rilpivirine was added and suspended. Water for injection was added until the desired end weight. The resulting suspension was milled in a Netzsch Pharma Labstar (<NUM> milling chamber) with <NUM>% bead load of <NUM> yttrium stabilized zirconia beads. Milling was performed at agitator speed of <NUM> rpm until the appropriate particle size was reached (measured on Malvern). <NUM> of PVP K17 powder was added and stirred until dissolved.

<NUM> of Poloxamer <NUM> was dissolved in water for injection. <NUM> of rilpivirine was added and suspended. Water for injection was added until the desired end weight. The resulting suspension was milled in a Netzsch Pharma Labstar (<NUM> milling chamber) with <NUM>% bead load of <NUM> yttrium stabilized zirconia beads. Milling was performed at agitator speed of <NUM> rpm until the appropriate particle size was reached (measured on Malvern). To <NUM> of said suspension, <NUM> of PVP K17 powder was added and stirred until dissolved.

<NUM> of each formulation (for drug nanosuspension <NUM> and 7a, <NUM> of fill volume was used) was filled in <NUM> lyo vials. Lyophilization was then performed on a HOF pilot plant freeze-dryer. Freeze drying cycle was conducted as follows : loading at <NUM> ; freezing for <NUM> at <NUM>, <NUM> at -<NUM>, 2h40min at -<NUM>, 2h10min at -<NUM>, <NUM> at -<NUM>; under vacuum (<NUM> mbar), after <NUM> period at -<NUM>, drying for 110h21min at <NUM> and <NUM> further drying at <NUM>.

The d<NUM>, d<NUM>, <NUM><NUM> and d<NUM> (µm) determined before freeze drying (FD) and determined directly after freeze drying (T0) and after <NUM> weeks, <NUM> month, <NUM> months and <NUM> month storage at <NUM> are reported in Table <NUM>. Reconstitution was done in water (up to and including <NUM> month stability) or <NUM> % glucose water (<NUM> and <NUM> month stability).

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added and the mixture was stirred until homogeneous. Water for injection was added until end volume (<NUM>) or end weight (<NUM>).

Drug nanosuspensions <NUM> to <NUM> were freeze dried as follows :
<NUM> of each formulation was filled in <NUM> lyo vials. Lyophilization was then performed on a HOF pilot plant freeze-dryer. Freeze drying cycle was conducted as follows : loading at <NUM> ; freezing for <NUM> at <NUM>, <NUM> at -<NUM>, 2h40min at - <NUM>, 2h10min at -<NUM>, <NUM> at -<NUM>; under vacuum (<NUM> mbar), after <NUM> period at -<NUM>, drying for 42h21min at <NUM> and <NUM> further drying at <NUM>.

The d<NUM>, d<NUM>, d<NUM> and d<NUM> (µm) determined before freeze drying (FD) and determined directly after freeze drying (T0) and after <NUM> and <NUM> months storage at <NUM> are reported in Table <NUM>.

The nanosuspensions were reconstituted in <NUM>% glucose water to a corresponding concentration of <NUM> rilpivirine/ml.

Preparation of concentrated nanosuspension :.

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added and the mixture was stirred until homogeneous. <NUM> of a <NUM>/ml glucose stock solution (<NUM>/ml of glucose monohydrate) was added and the mixture was stirred until homogeneous. Water for injection was added until end volume (<NUM>) or end weight (<NUM>).

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added and the mixture was stirred until homogeneous. <NUM> of a <NUM>/ml glucose stock solution (<NUM>/ml of glucose monohydrate) was added and the mixture was stirred until homogeneous. <NUM> of a <NUM>/ml citric acid stock solution pH <NUM> was added and the mixture was stirred until homogeneous. NaOH solution was added until pH <NUM>. Water for injection was added until end volume (<NUM>) or end weight (<NUM>).

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added and the mixture was stirred until homogeneous. <NUM> of a <NUM>/ml citric acid stock solution pH <NUM> was added and the mixture was stirred until homogeneous. NaOH solution was added until pH <NUM>. Water for injection was added until end volume (<NUM>) or end weight (<NUM>).

For drug nanosuspension <NUM>, <NUM> (or <NUM>) of the concentrated nanosuspension was taken and <NUM> of a <NUM>/ml PVP K17 stock solution was added and the mixture was stirred until homogeneous. <NUM> of a <NUM>/ml NaCl stock solution was added and the mixture was stirred until homogeneous. Water for injection was added until end volume (<NUM>) or end weight (<NUM>).

The nanosuspensions were reconstituted in water to a corresponding concentration of <NUM> rilpivirine/ml. (hypertonic).

Claim 1:
A freeze-dried nanosuspension comprising <NUM>-[[<NUM>-[[<NUM>-(<NUM>-cyanoethenyl)-<NUM>,<NUM>-dimethylphenyl]amino]-<NUM>-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof and a steric stabilizer which is a solid at room temperature, wherein the stabilizer is a poloxamer, and further comprising a cryoprotectant, wherein the cryoprotectant is a mono- or disaccharide.