RU2826218C2 - Dispersible compositions - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: present invention relates to a dispersible composition containing rilpivirine or a pharmaceutically acceptable acid addition salt thereof as an active substance.

EFFECT: such compositions are useful for treating HIV infection, and their inherent dispersibility properties make them applicable, in particular, for a pediatric or geriatric population.

11 cl, 10 tbl

Description

The present invention relates to a pharmaceutical composition comprising a certain anti-HIV (human immunodeficiency virus) agent, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular a hydrochloric acid salt, as an active substance. More particularly, the present invention relates to a dispersible or disintegrating tablet, a process for its preparation, and its use in the treatment of HIV infection. Such new compositions are particularly suitable for the pediatric population. They may also be suitable for the elderly population.

The active substance is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (rilpivirine) or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, represented by the following formula:

The product EDURANT ^TM containing this active substance is already approved for sale in, for example, the United States and the EU.

The utility of the present invention is due to the active substance, the action of which is directed against HIV infection, including drug-resistant and multidrug-resistant HIV strains, in particular drug-resistant and multidrug-resistant HIV-1 strains, more specifically, the active substance has an action against HIV strains, especially HIV-1 strains that have acquired resistance to one or more non-nucleoside reverse transcriptase inhibitors known in the art. Non-nucleoside reverse transcriptase inhibitors known in the art are such non-nucleoside reverse transcriptase inhibitors that are not the active substance of the present invention, and in particular, commercially available non-nucleoside reverse transcriptase inhibitors.

The ability of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile to inhibit HIV replication is described in WO 03/16306, which is incorporated herein by reference in its entirety. WO2006/024668, which is incorporated herein by reference in its entirety, discloses medicinal compositions containing hydrochloric acid E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.

The present invention discloses the development of a pediatric or geriatric dosage form of E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular its hydrochloric acid salt. For patients from the pediatric or geriatric population, it may be difficult to swallow solid compositions such as tablets, so a dispersible composition, in particular a dispersible tablet, may be preferable, but the creation of such a formulation may be associated with additional difficulties. This is especially important from the point of view of the prospect of developing such tablets, which are characterized by a sufficiently short dispersion time.

The present invention provides a dispersible composition (e.g., tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular a hydrochloric acid salt thereof, as an active substance. This may be referred to herein as the "(dispersible) tablet of the present invention".

By "dispersible" the inventors of the present invention mean a composition (e.g. a tablet) which disintegrates in a suitable medium, e.g. in an aqueous medium (e.g. water) or in other suitable medium or vehicles for administration (e.g. milk, juice (e.g. orange juice) or even a semi-solid carrier such as yoghurt, applesauce). More particularly, the composition, e.g. a tablet, disintegrates in a short period of time, in particular within a couple of minutes, in particular 1.5 minutes or less, or 1 minute or less, or less than one minute, such as within 55 seconds, or 50 seconds, or 45 seconds, or 40 seconds, or 35 seconds, or 30 seconds or less, in a small volume of medium (e.g. 50 ml or less of a dispersion medium, e.g. water) so that it disperses (in particular uniformly and/or rapidly) with brief stirring. Preferably, disintegration in a suitable disintegration medium yields a potable liquid, such as a potable suspension or a potable/edible semi-solid mass.

In one embodiment, such a dispersion may pass through a sieve mesh having a nominal sieve mesh size of 710 microns.

If the dispersion takes place in a small volume of liquid, for example, if 100 mg of the composition is dispersed in a small amount of water, for example, only 1 ml - 5 ml, then the resulting mixture can be described as a dispersion, but also as a soft mass. In the case of such a soft mass, it cannot pass through the above-mentioned sieve (given the small volume of water with which it is mixed), but it can still be suitable for administration, i.e. this soft mass can be conveniently administered with a spoon.

By "dispersed" it is meant that the composition (e.g., a tablet composition) rapidly disintegrates in a dispersion medium, e.g., water, into smaller physical particles which are distributed (or dispersed) throughout the volume of the medium, e.g., water. If the composition is uniformly dispersed, this results in any equal parts of the medium, e.g., water, containing approximately equal amounts of particles (by weight) of the composition (e.g., a tablet composition), by which we mean within a tolerance (% w/v) of ±25%, preferably ±15%, and in particular ±10% (or less, e.g., within ±5%). Therefore, if 100 mg of a tablet composition is dispersed in 50 ml of water, each portion comprising 25 ml of water (if divided) should contain approximately 50 mg by weight of the tablet composition, but with a possible deviation of ±25% (i.e. ±12.5 mg), preferably ±15% (i.e. ±7.5 mg), and in particular ±10% (i.e. ±5 mg), the deviation will most preferably be ±5% (i.e. ±2.5 mg). The tablet composition is therefore physically uniformly or homogeneously dispersed or distributed throughout the dispersion medium, e.g. water, into which it is placed (after a period of time necessary for dispersion; see above). It is clear that in order to obtain uniform dispersion of a dispersible composition, for example, a dispersible tablet, in a dispersion medium, for example, water, it should be slightly stirred or gently shaken.

Where it is stated that a dispersible composition (e.g. a tablet composition) can pass through a 710 µm sieve, this indicates that the dispersible composition (e.g. tablet) meets certain quality parameters/requirements, such as those given in the current (or future) editions of the British Pharmacopoeia and the European Pharmacopoeia. While these properties are important for a given dispersion in an aqueous medium, it will be understood that a dispersion (e.g. in water) need not be prepared and the dispersible tablet may be administered by alternative routes. For example, the dispersible tablet may be mixed with certain foodstuffs (either as such or by forming a soft mass by mixing the tablet composition with a small amount/volume of water, as described above).

For therapeutic use, the salts of rilpivirine are those whose counterion is pharmaceutically acceptable.

It is intended in the context of this document that pharmaceutically acceptable addition salts comprise the therapeutically active non-toxic acid addition salt forms that rilpivirine is able to form. The latter can be readily prepared by treating the base form with suitable acids such as inorganic acids, for example, hydrohalic acids, e.g., hydrochloric, hydrobromic, etc.; sulfuric acid; nitric acid; phosphoric acid, etc.; or organic acids such as acetic, propionic, hydroxyacetic, 2-hydroxypropionic, 2-oxopropionic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids, when chemically feasible. Conversely, the salt form can be converted into the free base form by treatment with alkali. A preferred salt is rilpivirine hydrochloride.

The dispersible composition (e.g. tablet) according to the present invention will now be described in more detail. It is characterized by properties that provide dispersibility (or disintegration) properties.

Therefore, in an aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (rilpivirine) or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules additionally comprise a pharmaceutically acceptable excipient (granular fraction).

Thus, the dispersible composition of the present invention contains a granular fraction (granules) containing E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance and additionally contains a pharmaceutically acceptable excipient and an extragranular fraction (a fraction of the composition next to the granular fraction (granules) or in addition to it).

By including the active substance of the present composition in the form of granules, the processability of the composition during production is improved. In one aspect, the ability to compress and/or flowability of the final mixture of the composition is improved in that the resulting mixture is less sticky compared to a mixture containing the active substance as such, and not in the form of granules. Granules contain the active substance and a pharmaceutically acceptable excipient. Granules can be produced by dry or wet technology. Preferably, a wet granulation method is used. Preferably, a binder is used.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a binder as a pharmaceutically acceptable excipient.

Such a binder may be a polymer, such as an organic polymer.

The organic polymer used in the compositions (e.g. tablets) of the present invention may be any of the physiologically acceptable, preferably water-soluble, synthetic, semi-synthetic or non-synthetic organic polymers.

Thus, for example, the polymer may be a natural polymer such as a polysaccharide or a polypeptide or a derivative thereof, or a synthetic polymer such as a polyalkylene oxide (e.g. PEG), polyacrylate, polyvinylpyrrolidone, etc. Mixed polymers such as block copolymers and glycopeptides may of course also be used.

A suitable polymer has an apparent viscosity of 1 to 15,000 mPa.s when in a 2% aqueous solution at 20°C. For example, the water-soluble polymer may be selected from the group consisting of

- alkyl celluloses such as methyl cellulose,

- hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose,

- hydroxyalkyl alkyl celluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose,

- carboxyalkyl celluloses such as carboxymethyl cellulose,

- alkali metal salts of carboxyalkyl celluloses, such as sodium carboxymethyl cellulose,

- carboxyalkyl alkyl celluloses such as carboxymethyl ethyl cellulose,

- carboxyalkyl cellulose esters,

- types of starch,

- pectins such as sodium carboxymethyl amylopectin,

- chitin derivatives such as chitosan,

- heparin and heparinoids,

- polysaccharides such as alginic acid, its alkali metal salts and its ammonium salts, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum, xanthan gum,

- polyacrylic acids and their salts,

- polymethacrylic acids and their salts, methacrylate copolymers,

- polyvinyl alcohol,

- polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate,

- polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, for example poloxamers and poloxamines.

Polymers not included in this list, but which are pharmaceutically acceptable and have appropriate physicochemical properties for the composition in question, are equally suitable for preparing the compositions of the present invention.

Preferably, the organic polymer is starch, polyvinylpyrrolidone or a cellulose ether, such as PVP K29-32, PVP K90, methylcellulose, hydroxypropylcellulose, hydroxyethylpropylcellulose or hydroxypropylmethylcellulose (HPMC).

Said HPMC contains a sufficient amount of hydroxypropyl groups and methoxy groups to provide its solubility in water. HPMC characterized by a degree of methoxy substitution of about 0.8 to about 2.5 and a hydroxypropyl molar substitution of about 0.05 to about 3.0 are generally water soluble. Methoxy substitution refers to the average number of methyl ester groups present on the anhydroglucose moiety of the cellulose molecule. Hydroxypropyl molar substitution refers to the average number of moles of propylene oxide that have reacted with each anhydroglucose moiety of the cellulose molecule. A preferred HPMC is hypromellose 2910 15 mPa.s or hypromellose 2910 5 mPa.s, in particular hypromellose 2910 15 mPa.s. Hydroxypropyl methylcellulose is the U.S. accepted name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). In the four-digit number "2910", the first two digits represent the approximate percentage of methoxy groups and the third and fourth digits represent the approximate percentage of hydroxypropyl groups; 15 mPa.s or 5 mPa.s is the value characteristic of the apparent viscosity of a 2% aqueous solution at 20°C.

The preferred polymer used in the composition of the present invention is PVP K30 (povidone K30).

In one aspect of the present invention, the granules of the dispersible composition contain a wetting agent as a pharmaceutically acceptable excipient.

A wetting agent may increase the bioavailability of the active substance.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a binder and a wetting agent as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a disintegrant as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules of the dispersible composition contain a wetting agent and a disintegrating agent as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a binder and a disintegrant as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a binder, a wetting agent and a disintegrant as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a diluent as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a binder and a diluent as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a wetting agent and a diluent as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules (granular fraction) of the dispersible composition contain a disintegrant and a diluent as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules of the dispersible composition contain a wetting agent, a disintegrant and a diluent as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules of the dispersible composition contain a wetting agent, a disintegrant and a binder as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules of the dispersible composition contain a wetting agent, a diluent and a binder as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules of the dispersible composition contain a diluent, a disintegrant and a binder as a pharmaceutically acceptable excipient.

In one aspect of the present invention, the granules of the dispersible composition contain a wetting agent, a disintegrant, a diluent and a binder as a pharmaceutically acceptable excipient.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction, further comprises a diluent, in particular an insoluble diluent.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction, further comprises a disintegrant.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction further comprises a diluent, in particular an insoluble diluent, and a disintegrant.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction, further comprises a wetting agent.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction further comprises a diluent, in particular an insoluble diluent, and a wetting agent.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction further comprises a wetting agent and a disintegrant.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction further comprises a diluent, in particular an insoluble diluent, a disintegrant and a wetting agent.

The wetting agent in the extra-granular fraction can ensure uniform wetting of the composition and can accelerate disintegration/dispersibility.

In one aspect of the invention, the diluent present in the extragranular fraction (and not present in the granules containing the active substance) is preferably an insoluble diluent. The presence of an insoluble diluent (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose) may be advantageous from the point of view of the disintegration/dispersibility properties of the composition of the present invention due to the fact that it promotes rapid absorption of water from the dispersion medium, i.e. it may enhance the wicking action, which is beneficial for improving the disintegration/dispersibility properties. The wicking action may lead to faster dispersion and at the same time the solubilization process may be avoided (e.g. liquid may be drawn in or "wicked" by capillary action and the rupture of bonds between particles, leading to disintegration of the tablet/composition), which may have a beneficial effect. Also, the insoluble diluent can be easily resuspended even after a long period of time (e.g. 6 hours), which may have the advantage that the compositions of the present invention do not require a suspending agent to re-disperse the granules/particles.

As for the wetting agent in the compositions of the present invention, it can be any of the physiologically tolerable wetting agents suitable for use in a pharmaceutical composition.

It is widely known from the prior art that a wetting agent is an amphiphilic compound; it contains polar, hydrophilic fragments, as well as non-polar, hydrophobic fragments.

The terms "hydrophilic" or "hydrophobic" are relative concepts.

The relative hydrophilicity or hydrophobicity of a wetting agent may be expressed by its hydrophilic-lipophilic balance ("HLB value"). Wetting agents with a lower HLB value are categorized as "hydrophobic" wetting agents, while wetting agents with a higher HLB value are categorized as "hydrophilic" wetting agents. As a general rule, wetting agents with an HLB value greater than about 10 are generally considered to be hydrophilic wetting agents; wetting agents with an HLB value below about 10 are generally considered to be hydrophobic wetting agents.

The compositions of the present invention preferably comprise a hydrophilic wetting agent.

It is understood that the HLB value of a wetting agent is only a rough criterion for indicating the hydrophilicity/hydrophobicity of the wetting agent. The HLB value of a particular wetting agent may vary depending on the method used to determine the HLB value; it may vary depending on its supplier; and it may vary from lot to lot. A person skilled in the art can readily determine hydrophilic wetting agents suitable for use in the pharmaceutical compositions of the present invention.

The wetting agent according to the present invention may be an anionic, cationic, zwitterionic or nonionic wetting agent, the latter being preferred. The wetting agent according to the present invention may also be a mixture of two or more wetting agents.

Suitable wetting agents for use in the compositions of the present invention are listed below. It should be emphasized that the list of wetting agents is merely illustrative, indicative, and not exhaustive. Thus, the present invention is not limited to the wetting agents listed below. Mixtures of wetting agents can also be used in the compositions of the present invention.

Suitable wetting agents that can be used in the present invention include:

a) fatty acid monoesters of polyethyleneglycol, including esters of lauric acid, oleic acid, stearic acid, ricinoleic acid, etc. with PEG 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 32, 40, 45, 50, 55, 100, 200, 300, 400, 600, etc., for example, PEG-6 laurate or stearate, PEG-7 oleate or laurate, PEG-8 laurate or oleate or stearate, PEG-9 oleate or stearate, PEG-10 laurate or oleate or stearate, or PEG-12 ricinoleate, PEG-15 stearate or oleate, PEG-20 laurate or oleate or stearate, PEG-25 stearate, PEG-32 laurate or oleate or stearate, PEG-30 stearate, PEG-40 laurate or oleate or stearate, PEG-45 stearate, PEG-50 stearate, PEG-55 stearate, PEG-100 oleate or stearate, PEG-200 oleate, PEG-400 oleate, PEG-600 oleate (wetting agents belonging to this group are known, for example, as Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emulgante, Nikkol, Myrj, Crodet, Albunol, Lactomul);

b) diesters of fatty acids and polyethyleneglycol, containing diesters of lauric acid, stearic acid, palmitic acid, oleic acid, etc. with PEG-8, 10, 12, 20, 32, 400, etc., for example PEG-8 dilaurate or distearate, PEG-10 dipalmitate, PEG-12 dilaurate or distearate or dioleate, PEG-20 dilaurate or distearate or dioleate, PEG-32 dilaurate or distearate or dioleate, PEG-400 dioleate or distearate (wetting agents belonging to this group are known, for example, as Mapeg, Polyalso, Kessco, Cithrol);

c) mixtures of mono- and diesters of fatty acids and polyethyleneglycol, such as, for example,

PEG 4-150 mono- and dilaurate, PEG 4-150 mono- and dioleate, PEG 4-150 mono- and distearate, etc. (wetting agents belonging to this group are known, for example, as Kessco);

d) mixed esters of polyethyleneglycol with glycerol and fatty acids, such as, for example, glyceryl laurate or glyceryl stearate or glyceryl oleate PEG-20, glyceryl laurate or glyceryl oleate PEG-30, glyceryl laurate PEG-15, glyceryl laurate PEG-40, etc. (wetting agents belonging to this group are known, for example, as Tagat, Glycerox L, Capmul);

e) alcohol-oil transesterification products containing esters of alcohols or polyhydric alcohols such as glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol, etc., with natural and/or hydrogenated oils or oil-soluble vitamins such as castor oil, hydrogenated castor oil, vitamin A, vitamin D, vitamin E, vitamin K, edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, almond oil, etc., such as PEG-20 and castor oil, or hydrogenated castor oil, or corn glycerides, or almond glycerides, PEG-23 and castor oil, PEG-25 and hydrogenated castor oil or PEG-25 trioleate, PEG-35 and castor oil, PEG-30 and castor oil or hydrogenated castor oil, PEG-38 and castor oil, PEG-40 and castor oil or hydrogenated castor oil or palm kernel oil, PEG-45 and hydrogenated castor oil, PEG-50 and castor oil or hydrogenated castor oil, PEG-56 and castor oil, PEG-60 and castor oil or hydrogenated castor oil or corn glycerides or almond glycerides, PEG-80 and hydrogenated castor oil, PEG-100 and castor oil or hydrogenated castor oil, PEG-200 and castor oil, PEG-8 and caprylic/capric glycerides, PEG-6 and caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogolglyceride, tocopheryl PEG-1000 succinate (TPGS) (wetting agents belonging to this group are known, for example, as Emalex, Cremophor, Emulgante, Eumulgin, Nikkol, Thornley, Simulsol, Cerex, Crovol, Labrasol, Softigen, Gelucire, vitamin E TPGS);

f) polyglycerized fatty acids containing polyglycerol esters of fatty acids, such as, for example, polyglyceryl-10-laurate or oleate or stearate, polyglyceryl-10-mono- and dioleate, polyglyceryl polyricinoleate, etc. (wetting agents belonging to this group are known, for example, as Nikkol Decaglyn, Caprol or Polymuls);

g) sterol derivatives containing polyethyleneglycol and sterol derivatives, such as

PEG-24-cholesterol ester, PEG-30-cholestanol, PEG-25-phytosterol, PEG-30-soy sterol, etc. (wetting agents belonging to this group are known, for example, as Solulan™ or Nikkol BPSH);

h) mixed polyethyleneglycol sorbitol fatty acid esters such as, for example, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, or sorbitan tristearate, or sorbitan monooleate, or sorbitan trioleate, or sorbitan monoisostearate, or sorbitan monopalmitate, or sorbitan monostearate, PEG-4 sorbitan monolaurate, PEG-5 sorbitan monooleate, PEG-6 sorbitan monooleate, or sorbitan monolaurate, or sorbitan monostearate, PEG-8 sorbitan monostearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan oleate or sorbitan tetraoleate, PEG-60 sorbitan tetrastearate, PEG-80-sorbitan monolaurate, PEG-sorbitol hexaoleate (Atlas G-1086), etc. (wetting agents belonging to this group are known, for example, as Liposorb, Tween, Dacol MSS, Nikkol, Emalex, Atlas);

i) polyethyleneglycol alkyl ethers, such as, for example, PEG-10 oleyl ether, or cetyl ether, or stearyl ether, PEG-20 oleyl ether, or cetyl ether, or stearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether (laureth-23), PEG-100 stearyl ether, etc. (wetting agents belonging to this group are known, for example, as Volpo, Brij);

j) sugar esters such as, for example, sucrose distearate/monostearate, sucrose monostearate or monopalmitate or monolaurate, etc. (wetting agents belonging to this group are known, for example, as Sucro ester, Crodesta, Saccharose monolaurate);

k) polyethyleneglycol alkyl phenols, such as, for example, PEG-10-100 nonylphenol (Triton X series), PEG-15-100 octylphenol ether (Triton N series), etc.;

l) block copolymers of polyoxyethylene and polyoxypropylene (poloxamers), such as, for example, poloxamer 108, poloxamer 188, poloxamer 237, poloxamer 288, etc. (wetting agents belonging to this group are known, for example, as Synperonic PE, Pluronic, Emkalyx, Lutrol™, Supronic, Monolan, Pluracare, Plurodac);

m) ionic wetting agents, including cationic, anionic and zwitterionic surfactants, such as fatty acid salts, for example sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, dioctyl sodium sulfosuccinate, sodium myristate, sodium palmitate, sodium ricinoleate, etc.; such as bile salts, for example sodium cholate, sodium taurocholate, sodium glycocholate, etc.; such as phospholipids, for example egg/soy lecithin, hydroxylated lecithin, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, etc.; such as phosphoric acid esters, for example diethanolammonium polyoxyethylene-10-oleyl ether of phosphoric acid, esterification products of fatty alcohols or fatty alcohol ethoxylates with phosphoric acid or phosphoric anhydride; such as carboxylates, for example succinylated monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono/diacetylated tartaric acid esters which are mono- and diglycerides, citric acid esters which are mono- and diglycerides, mixed esters of glycerol, lactic acid and fatty acids, mixed esters of lactic acid and fatty acids, calcium/sodium stearoyl-2-lactylate, calcium/sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ether carboxylates, etc.; such as sulfates and sulfonates, for example, ethoxylated alkyl sulfates, alkyl benzene sulfates, alpha-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, disodium octyl sulfosuccinate, disodium undecylenamido-MEA sulfosuccinate, etc.; such as cationic wetting agents, for example, hexadecyl triammonium bromide, decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyl dimethyl ammonium salts, diisobutyl phenoxy ethoxy dimethyl benzyl ammonium salts, alkyl pyridinium salts, betaines (lauryl betaine), ethoxylated amines (polyoxyethylene 15 coconut amine), etc.

In the case where in the above list of suitable wetting agents different variants are listed, such as, for example, PEG-20-oleyl ether, or cetyl ether, or stearyl ether, this means that PEG-20-oleyl ether and PEG-20-cetyl ether and PEG-20-stearyl ether are meant. Thus, for example, PEG-20 and castor oil, or hydrogenated castor oil, or corn glycerides, or almond glycerides should be read as PEG-20 and castor oil, and PEG-20 and hydrogenated castor oil, and PEG-20 and corn glycerides, and PEG-20 and almond glycerides.

Preferred wetting agents in the present compositions are sodium lauryl sulfate, sodium dioctyl sulfosuccinate or those wetting agents which belong to the group of mixed polyethylene glycol and sorbitan esters with fatty acids, such as the wetting agents known as ^Tween® , for example ^Tween® 20, 60, 80. Preferably, the wetting agent in the granules containing the active substance is ^Tween® , for example ^Tween® 20. A preferred wetting agent in the extragranular fraction is sodium lauryl sulfate.

The preferred amount of wetting agent (or surfactant) is described herein, but it is understood that when used in these compositions it may depend, for example, on the amount of active substance present in the composition. A higher amount may require more wetting agent.

It is disclosed herein that the compositions (e.g., tablet compositions) of the present invention may comprise a disintegrant. Possible disintegrants include pharmaceutically acceptable disintegrants containing starch, ion exchange resins such as Amberlite, cross-linked polyvinylpyrrolidone, modified celluloses such as croscarmellose sodium (e.g., Ac-di- ^Sol® ), sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginate, powdered cellulose, crospovidone (such as Polyplasdone XL). Other disintegrants that may be included include L-HPC, xanthan gum, gellan gum, soya polysaccharides, etc. The most preferred disintegrant for granules containing the active substance is sodium croscarmellose (e.g. Ac-di-Sol ^® ).

The most preferred disintegrant for the extragranular phase is sodium croscarmellose (e.g. Ac-di-Sol ^® ).

It is disclosed herein that the compositions (e.g., tablet compositions) of the present invention may comprise a diluent. Unless such a diluent is already disclosed, such a diluent may be starch, powdered cellulose, microcrystalline cellulose (such as silicified microcrystalline cellulose), calcium phosphates (e.g., dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate), calcium carbonate, calcium sulfate, or the like (or combinations thereof, i.e., co-processed insoluble excipients; other contemplated substances include waxy hydrogenated oils, etc.). It is understood from the context herein and above that the most preferred diluent for the extragranular fraction is an insoluble diluent such as microcrystalline cellulose (e.g., silicified microcrystalline cellulose), since this provides compositions with advantageous properties. A preferred microcrystalline cellulose is microcrystalline cellulose PH112 ( ^avicel® PH 112). The extragranular fraction may further comprise a second diluent which may be more soluble. Sugars and polyhydric alcohols are suitable for this role, for example the following diluents may be considered: dextrates, dextrin, dextrose filler, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, sodium chloride, sucrose, compressed sugar, confectioners' sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), marketed under the name ^Microcelac® , a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2), marketed under the name ^Prosolv® . Preferably, the extragranular fraction contains a second diluent. Preferably, the second diluent is mannitol, in particular mannitol SD 200. This improves the taste sensation of the composition.

Preferably, the granules contain a diluent. Preferably, said diluent is a sugar. Preferably, said sugar is lactose, i.e., lactose monohydrate.

In one aspect of the present invention there is provided a dispersible composition (e.g. a tablet) comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a pharmaceutically acceptable acid addition salt thereof, in particular E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in the form of a hydrochloric acid salt, as an active substance, and wherein said active substance is present in the dispersible composition in the form of granules, wherein said granules further comprise a pharmaceutically acceptable excipient, and said composition adjacent to the granules, in the extragranular fraction further comprises a first diluent, in particular an insoluble diluent, and a second diluent, in particular a sugar or a polyhydric alcohol. In one aspect, the first diluent is microcrystalline cellulose. In one aspect, the second diluent is a sugar. In one aspect, the first diluent is microcrystalline cellulose and the second diluent is mannitol. In one aspect, the weight ratio of the first diluent and the second diluent is 1:1. In one aspect, the weight ratio of microcrystalline cellulose and mannitol is 1:1. It has been found that a combination of the first and second diluents in the extragranular fraction, in particular an insoluble diluent, and a second, more soluble diluent, in particular microcrystalline cellulose and sugar, in particular microcrystalline cellulose and mannitol, especially in a weight ratio of 1:1, improves the uniformity of the composition. Uniformity of composition is a test prescribed for dosage forms in the pharmacopoeia, in particular for tablets, where the dose and the ratio of active substances is < 25 mg or < 25%.

This document indicates that the compositions (e.g., tablet compositions) of the present invention may contain a lubricant. Such a lubricant may be pharmaceutically acceptable lubricants such as magnesium stearate, calcium stearate, stearic acid, talc, polyethyleneglycol, sodium lauryl sulfate, sodium stearyl fumarate, magnesium lauryl sulfate. Most preferably, the lubricant is sodium stearyl fumarate.

It is indicated herein that the compositions (e.g., tablet compositions) of the present invention may contain a glidant. Possible glidants include pharmaceutically acceptable glidants containing talc, colloidal silicon dioxide, starch, magnesium stearate. In one aspect, the compositions of the present invention do not contain glidants.

The compositions described herein may further comprise one or more pharmaceutically acceptable excipients (excipients), such as, for example, plasticizers, flavors, colorants, preservatives, etc. In an aspect of the invention, the compositions of the invention do not comprise a plasticizer or other such optional excipient mentioned herein.

The compositions of the present invention are characterized by good taste sensation and good disintegration.

In one aspect of the present invention, there is provided a dispersible composition (e.g., a tablet composition) containing, based on the total weight of the composition, a mass fraction of from 1% to 50%, from 1 to 30%, from 1 to 20%, from 1 to 15%, from 1 to 10%, from 1 to 5%, from 2 to 5%, from 2 to 3% of the active substance.

In one aspect of the present invention, there is provided a dispersible composition (e.g. a tablet composition) comprising 2.5 mg of the base equivalent of E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, which corresponds to 2.75 mg of E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile HCl.

In one aspect of the present invention, there is provided a dispersible composition (e.g. a tablet composition) comprising 5 mg of the base equivalent of E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, which corresponds to 5.5 mg of E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile HCl.

In one aspect of the present invention, there is provided a dispersible composition (e.g., a tablet composition) comprising (e.g., consisting of) the following weight fractions, based on the total weight of the composition:

1-50% (eg 1-10% or 2-5%) active substance

35%-95% (e.g. 70-95%) diluent

0.1%-10% (e.g. 2-5%) baking powder

0-5% (eg 0-3.5%) glide agent

0.01-5% (e.g. 0.01-1.5%) wetting agent

0-10% (e.g. 0.1-2%) binder

0-5% (eg 1-3%) lubricant.

In one aspect of the present invention, there is provided a dispersible composition (e.g., a tablet composition) comprising, based on the total weight of the composition, a weight fraction of from 35% to 70% (e.g., 35-50%) of an insoluble diluent, for example, microcrystalline cellulose, such as silicified microcrystalline cellulose.

In one aspect of the present invention, there is provided a dispersible composition (e.g., a tablet composition) comprising, based on the total weight of the composition, a mass fraction of from 35% to 70% (e.g., 35-50%) of a diluent - a sugar, for example, mannitol.

In one aspect of the present invention, there is provided a dispersible composition (e.g., a tablet composition) comprising, based on the total weight of the composition, a mass fraction of from 1% to 10% (e.g., 2-50%) of a disintegrant, e.g., sodium croscarmellose.

In another aspect, a composition (e.g., a tablet composition) is provided, wherein the various parts of the composition, in particular the granular and extra-granular fractions, contain the following mass fractions of ingredients based on the total weight of the composition:

Granular fraction

1-50% (eg 2-5%) active substance

1%-8% (eg 5-8%) thinner

0.01-2.5% (e.g. 0.01-1.5%) wetting agent

0-10% (e.g. 0.1-2%) binder

0.1%-5% (e.g. 0.1-2%) baking powder

Extragranular fraction

35%-87% (e.g. 70-87%) diluent

1%-5% (eg 2-5%) baking powder

0.01-2.5% (e.g. 0.1-1.5%) wetting agent

0-5% (eg 1-3%) lubricant

In the context of the compositions (e.g., tablet compositions) described herein, the features of the composition may be described as comprising a granular fraction and an extragranular fraction. Such fractions of the composition are ultimately intermingled with one another. However, it will be understood (e.g., with reference to a method for preparing such a composition) that the distinctiveness of these fractions results in distinctive properties of the resulting compositions.

The mass fraction of the granular fraction may be up to 50% of the total weight of the composition (e.g. tablet) and preferably is from 5 to 20% (e.g. from 5 to 10%) of the composition (or tablet). The mass fraction of the extragranular fraction may be up to 95% of the total weight of the composition (e.g. tablet) and preferably is from 50 to 95% (e.g. from 70 to 95%) of the composition (or tablet).

The compositions of the invention described herein may be a mixture or dry mixture of granular and extragranular fractions and may, after being subjected to a suitable compression technique, be presented in the form of a (unit) dosage form such as a tablet.

In the aspects of the invention described herein, especially the dispersible compositions described above, the total weight of the composition, for example the total weight of the tablet, can be about 100 mg. The weight of the active substance present therein can vary from 1 to 25 mg, for example from 1 mg to 5 mg, for example about 2.5 mg of the base equivalent (2.75 mg of the corresponding HCl salt) or, for example, about 5 mg of the base equivalent (5.5 mg of the corresponding HCl salt). In this way, it is possible to obtain a composition for children (or the elderly), suitable for dispersing, in which the dose can be varied depending on the population for which it is intended, for example for the pediatric population, for example for children aged 0 to 12 years.

The present invention also relates to methods for producing compositions according to the present invention (e.g. tablet compositions) and therefore provides:

- a method (e.g. described herein) for producing a composition (e.g. tablet) of the present invention

- a product (e.g. a composition of the present invention, e.g. a dispersible tablet described herein) obtainable by a process of the present invention (e.g. described herein).

As indicated above, the compositions according to the present invention preferably comprise different fractions - a granular fraction and an extragranular fraction.

Therefore, a method for producing the composition of the present invention is proposed, which includes:

(a) obtaining a granular fraction using the granular fraction constituents mentioned herein, preferably using a binder solution (e.g. in water) containing a binder as mentioned herein;

(b) obtaining an extragranular fraction using the extragranular fraction constituents mentioned herein;

and the use of these fractions to obtain the composition of the present invention.

More specifically, the granular fraction (defined herein) can be obtained by mixing or kneading the respective constituents (dry granulation, roller compaction) or, preferably, by wet granulation using a suitable binder mentioned herein. Dry and wet granulation techniques are well known to those skilled in the art.

The resulting granules can be dried and/or separated by size (or sieved).

The granules are then mixed or co-screened and mixed with the constituents of the extra-granular fraction (defined herein). Such mixing also inherently involves lubrication if the extra-granular layer also includes a lubricant.

If the composition according to the invention has been obtained, for example, in the manner provided above, including mixing the granular and extragranular fractions, such a composition may optionally, but preferably, be converted into tablet forms. In a preferred aspect of the process according to the invention, the compositions thus obtained are preferably compressed into the form of a tablet, thereby providing a dispersible tablet according to the invention. Such a tablet may be any suitable dosage, but each of them may contain from 1 to 25 mg of the active substance (base equivalent, not including the acid moiety). One tablet preferably contains from 2 to 5 mg of rilpivirine base equivalent, preferably 2.5 mg of rilpivirine base equivalent, i.e. 2.75 mg of rilpirivine HCl, or 5 mg of rilpivirine base equivalent, i.e. 5.5 mg of rilpirivine HCl.

The manufacturing process for the tablets as such is otherwise standard and easily accomplished, in which the tablet is formed from the required dry mixture or blend of ingredients and shaped accordingly using a conventional tablet press. The hardness of the tablet corresponds to that of a dispersible tablet.

The tablets according to the present invention can be additionally coated with a film to improve the taste, to ensure easy swallowing and/or an attractive appearance. A large number of suitable polymeric materials for creating the coatings are known from the prior art. A preferred material for creating the coatings is hydroxypropyl methylcellulose HPMC, in particular HPMC 2910 5 mPa.s. Other suitable polymers for creating the coatings can also be used herein, including hydroxypropyl cellulose and copolymers of acrylic and methacrylic acids. In addition, the polymer for creating the coating, the film coating can additionally contain a plasticizer (for example, propylene glycol) and optionally a pigment (for example, titanium dioxide). The suspension for creating the coating can also contain talc as an anti-adhesive agent. In the immediate-release tablets according to the invention, the film coating is small and, in terms of weight, accounts for less than about 3% (w/w) of the total weight of the tablet. In one embodiment of the present invention (e.g., a preferred embodiment), the tablets of the present invention are not coated.

As stated above, the usefulness of the invention is due to the active substance and its salt, which is known for its action against HIV.

Therefore, in one aspect of the present invention there are provided compositions (eg tablets) according to the present invention that are useful for treating HIV infection, or compositions (eg tablets) according to the present invention for use in treating HIV infection, or compositions (eg tablets) according to the present invention for treating HIV infection.

In addition, the present invention also relates to the use of a composition (eg, a tablet) of the present invention, as described hereinafter, for the manufacture of a medicament for the treatment of HIV infection.

Accordingly, in another aspect, the present invention provides a method of treating a patient suffering from or at risk of HIV infection, in particular suffering from HIV infection, which comprises administering to the patient a therapeutically effective amount of a dispersible composition (eg, a tablet) according to the present invention.

This composition can be used alone or in combination with other pharmaceuticals, such as antivirals, antibiotics, immunomodulators or vaccines, to treat viral, such as HIV, infections. They can be used alone or in combination with other prophylactic agents to prevent viral, such as HIV, infections.

In addition, a combination of an antiretroviral compound and a composition of the present invention can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of the present invention and (b) one or more other antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in the treatment of HIV infection. Various drugs can be combined in the compositions of the present invention as a single preparation together with pharmaceutically acceptable carriers. Thus, the present invention also relates to a dispersible composition as described herein and further comprising one or more other antiretroviral agents.

The other antiretroviral compounds mentioned may be known antiretroviral compounds such as suramin, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet sodium (trisodium phosphonoformate); nucleoside reverse transcriptase inhibitors such as zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine

(2',3'-dideoxyinosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine

(2'-3'-dideoxy-3'-thiacytidine, 3TC), stavudine (2',3'-didehydro-3'-deoxythymidine, d4T), abacavir, abacavir sulfate, emtricitabine ((-) FTC), racemic FTC, etc.; non-nucleoside reverse transcriptase inhibitors such as nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6 H -dipyrido-[3,2-b : 2',3'-e][1,4]diazepin-6-one), efavirenz, delavirdine, TMC-120, TMC-125, etc.; TIBO type (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1 H )-one and thione) compounds, such as (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1 H )-thione; α-APA (α-anilino phenylacetamide) type compounds, such as α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, etc.; transactivating protein inhibitors such as TAT inhibitors, such as RO-5-3335 or REV inhibitors, etc.; protease inhibitors, such as indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir, amprenavir, TMC-114, BMS-232632,

VX-175, etc.; fusion inhibitors, such as T-20, T-1249, etc.; CXCR4 receptor antagonists, such as AMD-3100, etc.; viral integrase inhibitors, such as, for example, dolutegravir or cabotegravir; nucleotide-like reverse transcriptase inhibitors, such as tenofovir, tenofovir diphosphate, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (semi)fumarate (TAF), etc.; ribonucleotide reductase inhibitors, such as hydroxyurea, etc.; CCR5 antagonists, such as ancriviroc, aplaviroc hydrochloride, vicriviroc.

By administering rilpivirine with other antiviral agents that target different events in the viral life cycle, the therapeutic effect of these compounds may be enhanced. Combination therapies, as described above, may have a synergistic effect in suppressing HIV replication because each component of the combination acts on a different site of HIV replication. The use of such combinations may reduce the dosage of the selected conventional antiretroviral agent that would be required for the desired therapeutic or prophylactic effect, compared with administration of that agent as monotherapy. These combinations may reduce or avoid the side effects of conventional antiretroviral monotherapy without interfering with the antiviral activity of those agents. These combinations reduce potential resistance to single-agent treatment while minimizing any associated toxicity. These combinations may also enhance the efficacy of the conventional agent without increasing associated toxicity.

The compositions of the present invention can also be administered in combination with immunomodulatory agents such as levamisole, bropirimine, anti-human alpha interferon antibody, interferon-alpha, interleukin 2, methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor, naltrexone, etc.; antibiotics such as pentamidine isethionate, etc.; cholinergic agents such as tacrine, rivastigmine, doneresil, galantamine, etc.; NMDA channel blockers such as memantine for the prevention or control of infection and diseases or symptoms associated with HIV infection such as AIDS and AIDS-associated complex, such as dementia.

The term “about” when applied to a numerical quantity is intended to have its ordinary meaning in the context of the numerical quantity. Where necessary, the word “about” may be replaced by the numerical quantity ±10%, or ±5%, or ±2%, or ±1%.

All documents cited in this document are incorporated by reference in their entirety.

For the avoidance of doubt, it should be understood that each general or specific preference, embodiment, aspect, and example given herein may be combined, if possible, with any other general or specific preference, embodiment, aspect, and example defined herein, and that all such embodiments are encompassed by the present application.

The following examples are intended to illustrate the present invention.

Experimental part

The active substance - rilpivirine and its pharmaceutically acceptable salt - can be prepared, for example, in accordance with the procedures described in international patent applications WO 03/16306, WO2004/016581 and WO2006/024668.

1) Obtaining a dispersible composition of the present invention

Rilpivirine HCl 2.75 mg

Lactose monohydrate

Croscarmellose sodium

Polyvinylpyrrolidone (eg Povidon K30)

Polysorbate 20

Water, purified (removed during processing)

Total: 8.73 mg

Mannitol

Microcrystalline cellulose

Sodium Lauryl Sulfate

Croscarmellose sodium

Sodium stearyl fumarate

Total: 100 mg

Rilpivirine HCl granules were prepared by wet granulation. The first 1/2 portion of lactose monohydrate 200 mesh was loaded into a suitable container. Rilpivirine HCl was loaded into a suitable container. Croscarmellose sodium was loaded into a suitable container. The second 1/2 portion of lactose monohydrate 200 mesh was loaded into a suitable container. The mixture was mixed. The binder solution was prepared by loading purified water and povidone into a suitable container. Polysorbate 20 was added. The mixture was mixed. Granulation was performed in a fluid bed granulator (Glatt WSG 200). The powder mixture was loaded into the granulator under vacuum. The binder solution was sprayed onto the mixture. The dried material was discharged from the granulator, milled, and loaded into a suitable container (step 1). The granules contain 31.48% rilpivirine HCl.

The rilpivirine containing granules were sieved together with mannitol, microcrystalline cellulose, sodium croscarmellose and sodium lauryl sulfate using a suitable sieve and the co-sieved mixture was mixed using a suitable mixer (step 2). Sodium stearyl fumarate was sieved, added to the mixture obtained in step 2 and the mixture was lubricated using a suitable mixer (step 3).

The mixture obtained in step 3 was compressed into tablets using a suitable tablet press. The obtained tablets were packed in suitable containers (e.g. high-density polyethylene (HDPE) bottles, e.g. with a child-resistant polypropylene cap and a desiccant (e.g. silica gel, 2 g in a HDPE sachet).

2) Identification and quantitative determination of the active substance

To determine the content (% w/w) of the active substance, the composition described in 1) was stored under different conditions using the following conditions:

Conditions for performing HPLC:

Column: Zorbax Extend C18, 100 mm long x 4.6 mm i.d., particle size 3.5 µm

Column temperature: 45ºC

Flow rate: 1 ml/min

Injection volume: 10 µl

Detection: UV at 280 nm

Mobile phase: A: 10 mM ammonium acetate buffer in water

B: acetonitrile

Elution mode: gradient:

Time (minutes) A (% vol.) B (% vol.) 0 95 5 30 40 60 31 40 60 32 95 5 37 95 5

Analysis duration: 37 minutes

Relative retention time (minutes) 1.0 for rilpivirine HCl.

Results of content (% w/w) and total degradation products (% w/w) (study ID 151187: 65 tablets in 40 cm3 ^LDPE bottle with 2 g desiccant; child-resistant PP cap)

Storage conditions Duration of the test Content Total content of decomposition products (%) Original 101.7 0.3 Light according to ICH ^a , without protection ^b 8 hours 103.7 0.7 Light according to ICH ^a , with protection ^c 8 hours 100.4 0.3 5ºC 1 month
3 months 101.8
105.3 0.4
0.3 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 100.5
102.4
102.2
101.3
101.3 0.3
0.3
0.3
0.3
0.3 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 100.3
102.1
100.3
99.9
103.6 0.3
0.3
0.3
0.3
0.3 40ºC/75%RH 1 month
2 months
3 months
6 months 99.3
102.6
102.5
98.6 0.3
0.3
0.3
0.3 50ºC 1 month 101.8 0.4

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

Results of content (% w/w) and total degradation products (% w/w) (study ID 151188: 65 tablets in 75 cm3 ^LDPE bottle with 2 g desiccant; child-resistant PP cap)

Storage conditions Duration of the test Content Total content of decomposition products (%) Start 103.4 0.3 Light according to ICH ^a , without protection ^b 8 hours 101.3 0.6 Light according to ICH ^a , with protection ^c 8 hours 100.3 0.3 5ºC 1 month
3 months 101.9
102.6 0.4
0.3 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 102.0
102.0
102.0
100.2
102.0 0.4
0.3
0.3
0.3
0.3 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 100.6
102.1
101.5
99.6
105.5 0.3
0.3
0.3
0.3
0.3 40ºC/75%RH 1 month
2 months
3 months
6 months 101.2
100.9
103.5
100.4 0.3
0.3
0.3
0.3 50ºC 1 month 100.7 0.3

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

3) Dissolution test

In testing the dissolution properties of the composition described in 1), the following conditions were used:

Apparatus: paddle device (USP type 2);

Dissolution medium: 0.025% (w/v) polysorbate 20 (Tween ^® 20) in 0.01 M HCl

Volume: 900 ml

Temperature: 37ºC

Rotation speed: 75 rpm;

Sampling time points: 5, 10, 15, 20, 30, 45 and 60 minutes.

Rilpivirine HCl was measured by HPLC:

Conditions for performing HPLC:

Column: X-terra, RP18, 50mm x 4.6mm ID, 3.5µm particle size or equivalent

Column temperature: Heating or room temperature, or 35 ± 3 ^o C

Flow rate: 1.2 ml/min

Injection volume: 50 µl

Detection: UV at 280 nm

Mobile phase: A: 10 mM ammonium acetate pH4.0

B: acetonitrile

Elution mode: isocratic, (mobile phase A: Mobile phase B) (45:55)

Analysis duration: 2.5 min ^a

^a Retention time (guide): Approximately 1.7 minutes for rilpivirine HCl

Dissolution results after 45 minutes (%) (A dissolution % of at least 80% after 45 minutes is considered acceptable for clinical trials) (Study ID 151187: 65 tablets in 40 cm3 ^LDPE bottle with 2 g desiccant; child-resistant polypropylene cap).

Storage conditions Duration of the test Dissolution after 45 minutes (%) Original 97 Light according to ICH ^a , without protection ^b 8 hours 100 Light according to ICH ^a , with protection ^c 8 hours 101 5ºC 1 month
3 months 101
101 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 100
102
100
101
102 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 100
97
99
100
103 40ºC/75%RH 1 month
2 months
3 months
6 months 99
99
102
98 50ºC 1 month 102

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

Dissolution results after 45 minutes (%) (study ID 151188: 65 tablets in 75 cm3 ^LDPE bottle with 2 g desiccant; child-resistant polypropylene cap)

Storage conditions Duration of the test Dissolution after 45 minutes (%) Start 100 Light according to ICH ^a , without protection ^b 8 hours 101 Light according to ICH ^a , with protection ^c 8 hours 98 5ºC 1 month
3 months 104
102 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 99
100
100
98
99 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 103
102
97
104
103 40ºC/75%RH 1 month
2 months
3 months
6 months 101
97
100
98 50ºC 1 month 97

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

4) Appearance

The appearance of the product was also assessed (visually) and was found to be acceptable: round tablets from white to off-white in colour.

5) Time required for decay

The disintegration of the product was assessed according to Ph. Eur.<2.9.1>.

Disintegration time results (minutes) (study ID 151187: 65 tablets in 40 cm3 ^LDPE bottle with 2 g desiccant; child-resistant polypropylene cap)

Storage conditions Duration of the test Decay duration (minutes; 1 means greater than or equal to 30 seconds; 0 means less than 30 seconds) Original 1 Light according to ICH ^a , without protection ^b 8 hours 1 Light according to ICH ^a , with protection ^c 8 hours 1 5ºC 1 month
3 months 1
1 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 1
1
1
1
0 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 1
1
1
1
0 40ºC/75%RH 1 month
2 months
3 months
6 months 1
0
0
0 50ºC 1 month 1

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

Disintegration time results (minutes) (study ID 151188: 65 tablets in 75 cm3 ^LDPE bottle with 2 g desiccant; child-resistant polypropylene cap)

Storage conditions Duration of the test Decay duration (minutes; 1 means greater than or equal to 30 seconds; 0 means less than 30 seconds) Start 1 Light according to ICH ^a , without protection ^b 8 hours 1 Light according to ICH ^a , with protection ^c 8 hours 1 5ºC 1 month
3 months 1
1 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 1
1
1
1
1 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 1
1
1
0
0 40ºC/75%RH 1 month
2 months
3 months
6 months 1
1
1
0 50ºC 1 month 1

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

6) Fineness of dispersion

The fineness of dispersion was determined according to Ph.eur.<2.9.1>. The criterion for compliance was considered to be passing through a sieve with a mesh size of 710 µm.

The product stored as indicated in the tables above meets the requirements of the dispersion fineness test.

7) Water content

Water content was determined by the Karl Fischer method in accordance with USP <291> method I/EP <2.5.12>.

Results for water content (% w/w) (study ID 151187: 65 tablets in 40 cm3 ^LDPE bottle with 2 g desiccant; child-resistant PP cap)

Storage conditions Duration of the test Water content (% w/w) Start 2.5 Light according to ICH ^a , without protection ^b 8 hours 2,2 Light according to ICH ^a , with protection ^c 8 hours 1.8 5ºC 1 month
3 months 2,3
1.9 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 2.5
1.7
1.9
1.7
1.7 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 2.6
1.9
1.9
1.9
1.9 40ºC/75%RH 1 month
2 months
3 months
6 months 2.1
1.9
1.8
2.1 50ºC 1 month 2.0

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

Results for water content (% w/w) (study ID 151188: 65 tablets in 75 cm3 ^LDPE bottle with 2 g desiccant; child-resistant PP cap)

Storage conditions Duration of the test Water content (% w/w) Start 2,2 Light according to ICH ^a , without protection ^b 8 hours 2,3 Light according to ICH ^a , with protection ^c 8 hours 1.8 5ºC 1 month
3 months 2,2
1.6 25ºC/60%RH 1 month
3 months
6 months
9 months
12 months 2.1
1.7
1.9
1.9
1.7 30ºC/75%RH 1 month
3 months
6 months
9 months
12 months 2,2
2,2
1.9
1.8
2.0 40ºC/75%RH 1 month
2 months
3 months
6 months 2,2
1.9
1.9
2,3 50ºC 1 month 1.9

^a : integrated energy source in the near UV region of at least 200 ^W h/ ^m2 , general illumination of at least 1200 klux h

^b : tablets in a Petri dish were directly exposed to light according to ICH

^c : tablets packed in the original container were exposed to light according to ICH

8) Homogeneity of composition

The composition homogeneity was determined according to Ph. Eur. <2.9.40> or USP <905>. The conditions of the dosage homogeneity requirements were met (the acceptance index of the first 10 standard dosage forms was less than or equal to L1 (L1: not more than 15.0).

The composition described in 1) has been tested in a Phase I, open-label, randomized (Williams design), four-period crossover trial in healthy HIV-negative adults aged 18-55 years (Study TMC278IFD1008; NCT02561936). In the first part of the study, water-dispersible tablets (10 tablets containing 2.5 mg rilpivirine base equivalent) were taken after a standard breakfast (Treatment C) and compared with the ^Edurant® comparator tablet taken after a standard breakfast (Treatment A). In the second part of the study, water-dispersible tablets (10 tablets containing 2.5 mg rilpivirine base equivalent) were taken after a standard breakfast or on an empty stomach, or dispersed in orange juice (an acidic drink) and taken after a standard breakfast, or dispersed in water and taken with yoghurt.

Venous blood samples were collected for 168 hours post-dose to determine plasma rilpivirine concentrations. Plasma rilpivirine bioassay was performed using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1.0 ng/mL.

Taste attractiveness was assessed using a taste questionnaire that rated bitterness, sweetness, and taste, as well as overall acceptability using a four-point rating scale, and overall taste using a five-point hedonic visual rating scale.

Administration of the dispersible tablet was generally safe and well tolerated in both fed and fasted conditions. Rilpivirine exposure was higher than the comparative 25 mg ^Edurant® tablet after a standard breakfast (Treatment C versus Treatment A).

The bioavailability of the dispersible tablet taken on an empty stomach was lower than when taken with a standard breakfast. When taken with yogurt alone, bioavailability was lower compared to a normal calorie, normal fat breakfast. Dispersion of the tablet in orange juice increased bioavailability compared to water. Overall, the tablets demonstrated good bioavailability, acceptable palatability, and were well tolerated.

Treatment A Treatment C C _max (ng/ml) 96.1 (±25.6) 121 (±26.2) AUC _0-last (ng*h per ml) 3592 (±1156) 4310 (±1147) AUC _0-infinite (ng*h per ml) 3411 (±1449) 4367 (±1106)

Claims (50)

1. A dispersible composition for use in the treatment of HIV infection in pediatric and/or geriatric populations, having granular and extragranular fractions, wherein the fractions contain the following ingredients by weight based on the total weight of the composition: Granular fraction 2.75 mg rilpivirine hydrochloride salt from 1% to 8% diluent from 0.01 to 2.5% wetting agent from 0 to 10% binder from 0.1% to 5% baking powder Extragranular fraction from 35% to 87% diluent 1% to 5% baking powder from 0.01 to 2.5% wetting agent from 0 to 5% lubricant; wherein the extragranular fraction diluent comprises a first diluent which is microcrystalline cellulose and a second diluent which is mannitol; and wherein the composition comprises, by weight based on the total weight of the composition, from 35% to 70% microcrystalline cellulose. 2. The composition according to claim 1, wherein the composition contains, by weight based on the total weight of the composition, from 35% to 50% microcrystalline cellulose. 3. The composition according to claim 1, wherein the granular fraction makes up to 50% by weight of the total weight of the composition. 4. The composition according to claim 3, wherein the granular fraction is from 5 to 20% by weight of the composition. 5. The composition according to any one of claims 1 or 2, wherein the extra-granular fraction makes up to 95% by weight of the total weight of the composition. 6. The composition according to claim 5, wherein the extra-granular fraction makes up from 50 to 95% by weight of the composition. 7. The composition according to claim 1, wherein the granular and extra-granular fractions contain the following ingredients by weight based on the total weight of the composition: Granular fraction 2.75 mg rilpivirine hydrochloride salt from 5 to 8% diluent from 0.01 to 1.5% wetting agent from 0.1 to 2% binder from 0.1 to 2% baking powder Extragranular fraction from 70 to 87% diluent 2 to 5% baking powder from 0.1 to 1.5% wetting agent from 1 to 3% lubricant. 8. The composition according to item 1, having the following composition: Rilpivirine hydrochloride 2.75 mg Lactose monohydrate Croscarmellose sodium Polyvinylpyrrolidone (eg Povidone K30) Polysorbate 20 Total: 8.73 mg Mannitol Microcrystalline cellulose Sodium Lauryl Sulfate Croscarmellose sodium Sodium stearyl fumarate Total: 100 mg. 9. A composition according to any one of claims 1-7 for use in the treatment of HIV infection in the pediatric population. 10. The composition according to claim 9, wherein the composition is administered in water, milk, orange juice, yogurt or applesauce. 11. A method for producing a composition according to any of paragraphs 1-8, which includes: (a) obtaining a granular fraction using components of the granular fraction as defined in any of claims 1 to 8, using a binder solution containing a binder as defined in any of claims 1 to 8; (b) obtaining an extra-granular fraction using the components of the extra-granular fraction as defined in any of paragraphs 1-8, and the use of these fractions to obtain the composition.