MX2012012084A - Pharmaceutical compositions. - Google Patents

Abstract

A pharmaceutical composition comprising efavirenz wherein the efavirenz is in the form of nanoparticles.

Description

PHARMACEUTICAL COMPOSITION FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition comprising an antiretroviral drug, to a process for the preparation of such a composition, to therapeutic uses and to a method of treatment using the same.

BACKGROUND OF THE INVENTION Efavirenz is the international unregistered name for the non-nucleoside reverse transcriptase inhibitor (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which belongs to the class of benzoxazinones. The efavirenz presents the following structural formula: Efavirenz is effective in the treatment of human immunodeficiency virus (HIV), which is the retrovirus that causes the progressive destruction of the human immune system that leads to the onset of AIDS. Efavirenz is a very potent reverse transcriptase inhibitor and is effective against the resistance of HIV reverse transcriptase. It is a crystalline lipophilic solid with a partition coefficient in water with logarithmic octanol of 5.4 and an aqueous solubility of 9.0 pg / ml.

Efavirenz is classified in the class II drugs (low solubility, high permeability) of the Biopharmaceutical Classification System. Class II drugs such as efavirenz demonstrate poor gastrointestinal (Gl) absorption due to the inadequate solubility of the drug in Gl tract fluids. Additionally, efavirenz is a crystalline lipophilic solid with an aqueous solubility of 9.0 g / ml and a low intrinsic dissolution rate 1 (IDR) of 0.037 mg / cm2 / min. Drugs with less than 0.1 mg / cm2 / min of IDR have dissolution as a step limiting the rate of absorption, which is further affected by the patient's fasting / feeding state. This, in turn, can affect the peak concentration in plasma. This may affect the peak concentration in plasma, making the calculation of dosage and dosing regimes more complex.

This suggests the importance of improving the dissolution of efavirenz. In addition, most of these new chemical entities, despite their high permeability, are absorbed only in the upper small intestine. Consequently, if these drugs are not completely released in the area of the gastrointestinal tract, they have low bioavailability. Therefore, there is a need to increase the therapeutic dose of the drug in order to obviate this disadvantage; However, increasing the dose can lead to increased side effects of the drug.

It has been reported that various formulations of the prior art improve the solubility of efavirenz in the Gl tract. For example, one of the approaches used is the encapsulation of the drug in cyclodextrins using the 1: 1 molar ratio as described by Indrajit et al in Macromolecular symposia in 2010, 287, 51-59. However, considering the high dose of efavirenz, it is difficult in practice to develop the oral dosage form using cyclodextrins.

Dispersion techniques in solids and PEGylation have been proposed by Madhavi et al. in "Dissolution enhancement of efavirenz by soli dispersion and PEGilation techniques"; International Journal of Pharmaceutical Investigation, 2011 (1), 29-34, in which the drug and the vehicle are added to a common solvent followed by homogenization and evaporation of the solvent to form the solid dispersion of efavirenz. However the recrystallization of amorphous solid dispersions due to the temperature, humidity and the amount of polymer can lead to a reduction in the rate of dissolution, and consequently reduce bioavailability. Additionally, the article also establishes that drug-PEG conjugates at ratios of 1: 1 and 1: 2 in w / w were prepared by dissolving efavirenz and PEG 6000 separately in organic solvent and then pouring the drug solution into the PEG solution. while stirring, incubating the mixture overnight and then evaporating the solvent to give the PEGylated compound. However PEGylation is a complex procedure that requires many stages of processing.

WO99 / 61026 describes a tablet dosage form of efavirenz in which extragranular lactose is added to obtain a stable tablet formulation that is bioequivalent with the capsule formulation of efavirenz. However, the patent does not provide any bioequivalence data.

US6555133 B2 provides better oral dosage formulations of efavirenz containing one or more superdisintegrants that improve the dissolution rate of the drug in the gastrointestinal tract thereby improving the speed and extent of drug absorption in the gastrointestinal tract. the body. However, the use of more of a super-disintegrant such as sodium starch glycolate can lead to a negative effect on the disintegration of the tablets due to the formation of a viscous gel layer formed by sodium starch glycolate that can form a barrier thick for further penetration of the disintegration medium and hide the disintegration of the tablets [Development of Fast Dispersible Aceclofenac Tablets: Effect of Functionality of Superdisintegrant, C. Mallikarjuna Setty et al .; Received February 7, 2007; revised on January 16, 2008; accepted March 12, 2008].

Therefore, improving the solubility of efavirenz and thereby its oral bioavailability while reducing the dose of drug is one of the most promising aspects especially for the oral drug delivery system. Is It is desirable to provide efavirenz compositions that show better bioavailability compared to the prior art formulations. Therefore there is still a need not covered to develop an efavirenz formulation with better solubility and dissolution properties of the drug.

BRIEF DESCRIPTION OF THE INVENTION The aim of the present invention is to provide a pharmaceutical composition of efavirenz which has improved solubility and dissolution.

Another objective of the present invention is to provide a method of manufacturing a pharmaceutical composition comprising efavirenz.

According to one aspect of the invention there is provided a composition comprising efavirenz in the particulate form, in which substantially all particles have a particle size less than or equal to 1 micrometer.

In a preferred embodiment the composition additionally comprises at least one surface stabilizer, at least one viscosity-reinforcing agent and at least one polymer, in which substantially all the particles have a particle size less than or equal to 1 micrometer.

In a preferred embodiment all the particles have a particle size greater than 1 nanometer.

The composition described above may comprise a pharmaceutical composition, or may be used to form a pharmaceutical composition.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising efavirenz or a pharmaceutically acceptable salt, solvate, derivative, hydrate, polymorph, or mixtures thereof in which the particle size of efavirenz is in a range nanometer According to another aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition comprising efavirenz or a pharmaceutically acceptable salt, solvate, derivative, hydrate, polymorph, or mixtures thereof in which the particle size of Efavirenz is in a nanometer range.

According to yet another aspect of the present invention there is provided a method of treatment using a pharmaceutical composition according to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the dissolution profile of the nano-sized efavirenz composition prepared in accordance with the present invention versus the prior art composition.

DETAILED DESCRIPTION OF THE INVENTION Efavirenz is a class II drug that has low solubility and low dissolution.

Bioavailability is the degree to which a drug begins to be available for the target tissue after administration. Many factors can affect the bioavailability including the dosage form, the particle size, various properties, for example, the dissolution rate of the drug. The low bioavailability is a major problem that is found in the development of pharmaceutical compositions, particularly for those that contain an active principle that is poorly soluble in water. Drugs that are poorly soluble in water, that is, those that have a solubility less than about 10 mg / ml, tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. Therefore the development of efavirenz formulations is a challenge for an inventor. The inventors of the present invention have surprisingly found that the dissolving property of efavirenz has greatly improved reducing the particle size of efavirenz to nanometric size thus leading to better absorption and bioavailability of the drug from the Gl tract.

The present invention thus provides a pharmaceutical composition comprising efavirenz in nanometric form and a process for the preparation thereof.

The term "efavirenz" as used in this invention throughout the specification and claims is used broadly to include not only efavirenz but its pharmaceutically acceptable salts, solvates, derivatives, prodrugs, racemic mixtures and polymorphs thereof.

The nano-ionization of hydrophobic drugs usually involves the production of nano-sized crystals of drug by chemical precipitation [bottom-up technology] or disintegration [top-down technology]. Different methods can be used to reduce the particle size of hydrophobic drugs for example: Huabing Chen et al, describe the various procedures for developing nanoformulations in "Nanonization strategies forpoorly water-soluble drugs", Drug Discovery Today, Volume 00, number 00 , March 2010.

The nanoparticles of the present invention can be obtained by any of the methods such as, but not limited to, trituration, precipitation and homogenization.

According to an embodiment of the present invention, the trituration process comprises the dispersion of efavirenz particles in a liquid dispersion medium in which efavirenz is poorly soluble, followed by the application of mechanical means in the presence of grinding media such as beads. grinding to reduce the particle size of efavirenz to the desired average particle size.

According to another embodiment of the present invention, the precipitation process involves the formation of nano-sized particles of crystalline or semi-crystalline efavirenz by nucleation and the growth of drug crystals. In a typical procedure, the drug molecules are first dissolved in an appropriate organic solvent such as acetone, tetrahydrofuran or N-methyl-2-pyrrolidone at a supersaturation concentration to allow nucleation of the drug seeds. The drug nanocrystals are then formed by adding the organic mixture to an antisolvent such as water in the presence of stabilizers such as Tween 80, poloxamer 188 or lecithin. The choice of solvents and stabilizers and the mixing procedure are key factors in controlling the size and stability of the drug nanocrystals.

According to another embodiment of the present invention, the homogenization process involves passing a suspension of crystalline efavirenz and stabilizers through the narrow slot of a high pressure homogenizer 50000-200000 kPa (500-2000 bar). The pressure generates powerful disruptive forces such as cavitation, collision and shear, which disintegrate the coarse particles into nanoparticles.

According to a further embodiment of the present invention, the lyophilization drying process involves atomization of an aqueous efavirenz solution in a spray chamber filled with a cryogenic liquid (liquid nitrogen) or halocarbon refrigerant such as chlorofluorocarbon or fluorocarbon. The water is removed by sublimation once the liquid drops solidify.

According to yet another embodiment of the present invention, the supercritical fluid technology process involves the controlled crystallization of efavirenz from the dispersion in supercritical fluids, carbon dioxide.

According to another embodiment of the present invention, the emulsion / double solvent evaporation technique procedure involves the preparation of oil / water (o / w) emulsions with subsequent removal of the oil phase by evaporation. The emulsions are prepared by emulsifying the organic phase containing efavirenz, polymer and organic solvent in an aqueous solution containing emulsifier. He Organic solvent diffuses out of the polymer phase to the aqueous phase and then evaporates, forming polymeric nanoparticles loaded with efavirenz.

According to a further embodiment of the present invention, the method of PRINT (Particle replication in non-wetting templates) involves the use of a low surface energy fiuoropoiimeric mold that allows high resolution printing lithography to manufacture a variety of organic particles. PRINT can precisely manipulate the particle size of efavirenz by varying from 20 nm to more than 100 nm.

According to another embodiment of the present invention, the thermal condensation process involves the use of capillary aerosol generator (CAG) to produce aerosols of submicron to nanometer size by condensation at high concentration from efavirenz solutions.

According to yet another embodiment of the present invention, the ultrasound procedure involves the application of ultrasound during particle synthesis or precipitation, which leads to smaller efavirenz particles and greater uniformity in size.

According to another embodiment of the present invention, the spray drying process involves supplying the feed solution at room temperature and pumping it through the nozzle where it is atomized with the gas from the nozzle. The atomized solution is then dried by preheating the drying gas in a special chamber to remove moisture from the system water, thus forming dried particles of efavirenz.

According to a preferred embodiment of the present invention, the nanonization of efavirenz involves the trituration to nano-size of efavirenz with at least one surface stabilizer, at least one viscosity-reinforcing agent and at least one polymer.

The efavirenz crushed to nanometric size according to the present invention shows a particle size less than or equal to 5 μm, preferably less than or equal to 3 μm, more preferably less than or equal to 1 μm.

The present invention thus provides a pharmaceutical composition comprising crushed efavirenz granules to nanometer size in which the granules comprise at least one surface stabilizer, at least one viscosity-reinforcing agent and at least one polymer together with efavirenz and optionally other pharmaceutically acceptable vehicles.

The term "surface stabilizer" according to the present inventions means a surfactant that is capable of stabilizing the highest surface charge of the ground nano-sized drug. Any surfactant is suitable, being able to be amphoteric, non-ionic, cationic or anionic. Suitable surfactants may be included in the solid dosage form as provided in the present invention. Non-limiting examples of anionic, cationic, non-ionic and amphoteric groups include, polysorbates; sodium dodecyl sulfate (sodium lauryl sulphate); lauryldimethylamine oxide; sodium docusate; cetyltrimethylammonium bromide (C ); polyethoxylated alcohols; polyoxyethylene sorbitan; octoxynol; N, oxide, dimethyldodecylamine N-oxide; hexadecyltrimethylammonium bromide, polyoxyl 10 lauryl ether, Brij, bile salts, (sodium deoxycholate, sodium cholate), polyoxylic castor oil; Nonylphenol ethoxylate; cyclodextrins; lecithin; methylbenzethonium chloride; carboxylates; sulfonates; petroleum sulfonate; alkylbenzenesulfonates; naphthalenesulfonates; olefin sulfonates; sulfates of alkyl, sulfates, oils and natural sulphated fats, sulphated esters; sulphated alkanolamides; alkylphenols, ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic acid esters; polyethylene glycol esters; anhydrosorbitol ester and its ethoxylated derivatives, glycol esters of fatty acids; carboxylic acid amides; monoalkanolamine condensates; polyoxyethylene and fatty acid amides; quaternary ammonium salts; amines with amide bonds, polyoxyethylene alkylamines and alicyclic,?,?,?,? tetrakisethylenediamines, 2-alkyl-1-hydroxyethyl-2-imidazolines, N-coco-3-aminopropionic acid / sodium salt thereof, disodium salt of disodium N-tallow-3-iminodipropionate; N-carboxymethyl-n-dimethyl-n-9-octadecenylammonium hydroxide; Sodium salt of n-cocoamidetil-n-hydroxyethylglycine etc.

The term "viscosity builder" means excipients that are capable of stabilizing nano-sized particles by increasing the viscosity of the formulation and thus avoiding the physical interaction of nanoparticles under the operating conditions employed. Examples of such excipients are sugar derivatives, such as lactose, sucrose, sucrose, hydrolyzed starch (maltodextrin) and the like. Mixtures are also suitable.

Suitable examples of polymers include, but are not limited to, cellulose derivatives such as hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, polymers of methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethylhydroxyethylcellulose; acrylics such as acrylic acid, acrylamide, and polymers and copolymers of maleic anhydride. Polymer combinations are also suitable.

The present invention provides a process for preparing a pharmaceutical composition, the method comprising the steps of: homogenizing a drug, at least one surfactant, at least one viscosity-reinforcing agent, at least one polymer, to produce a homogenized dispersion of the drug in the surfactant, the viscosity-reinforcing agent and the polymer; crushing the homogenized dispersion of step one to nanometric size to produce a nano-sized crushed suspension; adsorbing the suspension ground to a nanometer in a vehicle to form granules.

In one embodiment the percentage weight of the active ingredient in the suspension ranges from 5% to 60% w / w.

The granules can be encapsulated in capsules or be pressed into tablets or can be provided as bags or provided as powders for reconstitution.

The solid dosage form according to the present invention may optionally be coated. More preferably, the formulation can be sealed with coating and additionally coated with film.

Alternatively, the nano-sized slurry can be used to formulate liquid dosage forms as a suspension.

The term vehicle used in this invention includes one or more pharmaceutically acceptable ingredients, but not limited thereto, carriers, diluents or fillers, binders, lubricants, slip agents and disintegrants.

Non-limiting examples of pharmaceutically acceptable carriers, diluents or fillers suitable for use in the solid dosage form as provided by the present invention include lactose (eg, lyophilized lactose, α-lactose, β-lactose), lactose available under the name Commercial Tablettose, various grades of lactose under the trade name Pharmatose or other commercially available forms of lactose, lactitol, sucrose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (e.g., microcrystalline cellulose available with the trade name Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (poorly substituted), hydroxypropylmethylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives a, modified starches or starches (including potato starch, wheat starch, corn starch and rice starch) and the like.

Slip agents and typical lubricants may also be included in the solid dosage form, as provided by the present invention. Non-limiting examples include stearic acid and pharmaceutically acceptable salts or esters thereof (eg, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metal stearates), talc, waxes (eg, microcrystalline waxes) and glycerides, oil light mineral, PEG, silicic acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and / or magnesium aluminometasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil), or mixtures thereof or any other suitable lubricant.

Suitably one or more binders are also present in the solid dosage form as provided by the present invention and are non-limiting examples of suitable binders, for example, polyvinylpyrrolidone (also known as povidone), polyethylene glycol (s), acacia , alginic acid, agar, calcium carrageenan, cellulose derivatives such as ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or mixtures thereof or any other suitable binder .

Suitable disintegrants may also be present in the formulation according to the present invention, including but not limited to these hydroxylpropylcellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified by examples of fillers and also carboxymethylstarch, hydroxylpropylamidon, modified starch; crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or its equivalents and any combination thereof.

In one embodiment of the present invention there is provided a method of preparing a pharmaceutical composition according to the present invention, said method comprising the step of homogenizing the dispersion of efavirenz, docusate sodium, sucrose, HPMC. 2 ° Crush the homogenized dispersion of stage one to nanometric size. 3o Adsorb the nano-sized ground suspension of step 2 into a mixture of lactose monohydrate, microcrystalline cellulose and crospovidone to form granules.

In yet another preferred embodiment of the present invention there is provided a method of preparing a pharmaceutical composition, the method comprising: (1) preparing a dispersion of efavirenz with sodium docusate, HPMC, sodium lauryl sulfate and sucrose in purified water in agitation conditions (2). Homogenization of the stage (1) dispersion and then crushing to nanometric size of the homogenized dispersion (3) Adsorption of the crushed drug to nanometric size by spraying the crushed suspension to nanometric size in a mixture of lactose monohydrate, microcrystalline cellulose and crospovidone in granulator fluidized bed. (4) Drying and combination of the obtained granules. (5) Lubrication of the granules and finally pressing into tablets (6) The tablets obtained were sealed and then covered with film.

The composition of efavirenz crushed to nanometric size prepared in accordance with the present invention showed a dissolution profile demonstrating an improvement over the prior art composition as evidenced in Figure 1. This could further lead to a considerably better biocompatibility of the active ingredient compared to that obtained with the compositions of the prior art. Additionally, as can be seen from the dissolution data, an adequate dose of efavirenz that can be administered according to the present invention can be in the range of about 300 mg to about 600 mg, which can lead to reduced side effects of the active principle .

Further provided with the present invention is a solid dosage form substantially as described below, for use in the treatment of disorders or conditions that respond to, or are avoided, improved or eliminated with the administration of efavirenz. More preferably, a solid dosage form, substantially as described below, is further provided with the present invention for use in the treatment of human immunodeficiency virus [HIV]. Efavirenz is also used in combination with other antiretroviral agents as part of an extended post-exposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to significant risk.

It can be appreciated from the aforementioned method of describing treatment according to the present invention that it may be beneficial to provide, recommend or label a solid dosage form according to the present invention for administration with one or more other therapeutically active compounds used. for the treatment of HIV infection.

The present invention is further explained with the following non-limiting examples and with the help of the dissolution profile of efavirenz tablets prepared according to the present invention with innovative tablets.

The following example is only illustrative of the invention and is not intended to limit the scope of the present invention in any way.

Example 1 Formula: Process: 1. A dispersion of efavirenz was prepared with sodium docusate, HPMC, sodium laurisulfate and sucrose in purified water under stirring conditions. 2. The previous dispersion was homogenized and then crushed to nanometric size. 3. The suspension of crushed drug was adsorbed to nanometric size by spraying in mixture of lactose monohydrate, microcrystalline cellulose and crospovidone in a fluidized bed granulator.

. The granules obtained were sifted and lubricated 5. The lubricated granules were pressed into tablets 6. The tablets obtained were sealed and then film coated.

Example 2 Formula: Process: 1. A dispersion of efavirenz was prepared with sodium docusate, HPMC, sodium laurisulfate and sucrose in purified water under stirring conditions. 2. The previous dispersion was homogenized and then crushed to nanometric size. 3. The suspension of crushed drug was adsorbed to nanometric size by spraying in mixture of lactose monohydrate, microcrystalline cellulose and crospovidone in a fluidized bed granulator. 4. The granules obtained were sifted and lubricated 5. The lubricated granules were pressed into tablets 6. The tablets obtained were sealed and then film coated.

Example 3. Dissolution of a composition according to the invention and a composition according to the prior art.

In accordance with the present invention a dissolution study was carried out in an aqueous medium containing a surfactant, 2% SLS. The paddle procedure (US Pharmacopoeia) was used under the following conditions: volume of medium 1000 ml; medium temperature: 37 ° C; speed of rotation of the blades 50 rpm; Samples taken: every 10 minutes.

Table 1 : The composition according to the present invention consisted of 300 mg tablets of efavirenz prepared according to example 2. The prior art composition contained efavirenz [600mg], croscarmellose sodium, hydroxypropic cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose , and sodium lauryl sulfate.

The results obtained are shown graphically in figure 1 in which the dissolution percentage is shown. As shown in Table 1 and Figure 1, approximately 75% of the active ingredient of the composition of nanometer size dissolved in 10 minutes and almost 100% of the active ingredient dissolved within one hour while the formulation of the technique previous only 88% was dissolved in one hour. These results clearly show that the compositions of the present invention have a dissolution profile which is clearly better than the composition of the prior art.

It will be readily apparent to one skilled in the art that variable substitutions and modifications may be made to the invention described herein without departing from the spirit of the invention. Therefore, it should be understood that although the present invention has been specifically described with the preferred embodiments and those skilled in the art may resort to optional features, modification and variation of the concepts described in this invention, such modifications and variations are considered which are within the scope of the invention.

It is to be understood that the phraseology and terminology is used in this invention for descriptive purposes and should not be understood as limiting. The use of "include", "understand" or "have" and variations thereof in this invention is understood to comprise the elements enumerated above and equivalents thereof as well as additional elements.

It should be noted that as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

Claims (35)

1. A composition comprising efavirenz in the form of particles, characterized in that substantially all particles have a particle size less than or equal to 1 micrometer.

2. The composition according to claim 1, characterized in that it further comprises at least one surface stabilizer, at least one viscosity-reinforcing agent and at least one polymer, in which substantially all the particles have a particle size less than or equal to 1 micrometer

3. The composition according to claim 2, characterized in that the surface stabilizer is a surfactant.

4. The composition according to claim 3, characterized in that the surfactant is an amphoteric, nonionic, cationic or anionic surfactant.

5. The composition according to claim 3 or 4, characterized in that the surfactant is a polysorbate; sodium dodecyl sulfate (sodium laurisulfate); lauryldimethylamine oxide; sodium docusate; cetyltrimethylammonium bromide (C ); a polyethoxylated alcohol; a polyoxyethylene sorbitan; octoxynol; N, N-dimethyldodecylamine N-oxide; hexadecyltrimethylammonium bromide, polyoxyl 10 lauryl ether, Brij, a bile salt, such as sodium deoxycholate or sodium cholate; a polyoxylic castor oil; Nonylphenol ethoxylate; a cyclodextrin; lecithin; methylbenzethonium chloride; a carboxylate; a sulfonate; a petroleum sulfonate; an alkylbenzene sulfonate; a naphthalenesulfonate; and olefin sulfonate; a sulfate surfactant; an alkyl sulfate; a sulfated natural oil or fat; a sulfated ester; a sulfated alkanolamide; an alkylphenol, optionally ethoxylated and sulfated; an ethoxylated aliphatic alcohol; polyoxyethylene; a carboxylic ester; a polyethylene glycol ester; an anhydrosorbitol ester or an ethoxylated derivative thereof; a glycol ester of a fatty acid; a carboxylic acid amide; a monoalkanolamine condensate; a polyoxyethylene amide and fatty acid amide; a quaternary ammonium salt; an amine with amide bonds; a polyoxyethylenealkylamine; an alicyclic polyoxyethyleneamine; a ?,?,?,? substituted tetrakisethylenediamine; a 2-alkyl-1-hydroxyethyl-2-imidazoline; N-coco-3-aminopropionic acid or a sodium salt thereof; disodium salt of N-tallow-3-iminodipropionate disodium; N-carboxymethyl-n-dimethyl-n-9-octadecenylammonium hydroxide; n-cocoamidethyl-n-hydroxyethylglycine sodium salt; or mixtures thereof.

6. The composition according to any of the preceding claims, characterized in that the surfactant is sodium docusate and / or sodium laurisulfate.

7. The composition according to any of the preceding claims, characterized in that the viscosity-reinforcing agent is lactose; sucrose; saccharose; a hydrolyzed starch, such as maltodextrin; or mixtures thereof.

8. The composition according to claim 7, characterized in that the viscosity-reinforcing agent is sucrose.

9. The composition according to any of the preceding claims, characterized in that the polymer is hydroxypropylcellulose; hydroxymethylcellulose; hydroxypropylmethylcellulose; a methylcellulose polymer; hydroxyethylcellulose; sodium carboxymethylcellulose; carboxymethylenehydroxyethylcellulose and / or carboxymethylhydroxyethylcellulose; an acrylic polymer, such as acrylic acid, acrylamide, and polymers and copolymers of maleic anhydride; or a combination thereof; or mixtures thereof.

10. The composition according to claim 9, characterized in that the polymer is hydroxypropylmethylcellulose.

11. The composition according to any of the preceding claims, characterized in that all the particles have substantially a particle size greater than 1 nanometer.

12. The composition according to any one of the preceding claims, characterized in that it additionally comprises a pharmaceutically acceptable carrier, wherein said particles have been adsorbed on the surface of the vehicle.

13. A pharmaceutical composition, characterized in that it comprises the composition as claimed in any of claims 1 to 12.

14. The pharmaceutical composition according to claim 13, characterized in that the vehicle comprises: one or more diluents or fillers; one or more binders; one or more lubricants; one or more slip agents; one or more disintegrants; or a mixture of them.

15. The pharmaceutical composition according to claim 13 or 14, characterized in that the carrier comprises lactose monohydrate, microcrystalline cellulose and crospovidone or mixtures thereof.

16. The pharmaceutical composition according to claim 13, 14 or 15, characterized in that it is in the form of a tablet dosage form, a powder dosage form, a capsule dosage form, a liquid dosage form.

17. A process for the preparation of a pharmaceutical composition, characterized in that it comprises the steps of: homogenizing the efavirenz, at least one surface stabilizer, at least one viscosity-reinforcing agent and at least one polymer to produce a homogenized dispersion of the efavirenz in the surfactant, the viscosity-reinforcing agent and the polymer; shredding said homogenized dispersion to produce a suspension of particles having a particle size less than or equal to 1 micrometer; Y adsorb the crushed suspension in a vehicle to form granules.

18. The process according to claim 17, characterized in that the granules are pressed to form tablets, or are encapsulated in capsules, or are provided as a powder dosage form.

19. The process according to claim 17, characterized in that the granules are used to form a liquid dosage formulation.

20. The process according to any of claims 17 to 19, characterized in that the surface stabilizer is a surfactant.

21. The method according to claim 20, characterized in that the surfactant is an amphoteric, nonionic, cationic or anionic surfactant.

22. The process according to claim 20 or 21, characterized in that the surfactant is a polysorbate; sodium dyl sulfate (sodium lauryl sulphate); lauryldimethylamine oxide; sodium docusate; cetyltrimethylammonium bromide (C ); a polyethoxylated alcohol; a polyoxyethylene sorbitan; octoxynol; N-oxide N-dimethyldylamine; hexadecyltrimethylammonium bromide, polyoxyl 10 lauryl ether, Brij, a bile salt, such as sodium deoxycholate or sodium cholate; a polyoxylic castor oil; Nonylphenol ethoxylate; a cycltrin; lecithin; methylbenzethonium chloride; a carboxylate; a sulfonate; a petroleum sulfonate; an alkylbenzene sulfonate; a naphthalenesulfonate; and olefin sulfonate; a sulfate surfactant; an alkyl sulfate; a sulfated natural oil or fat; a sulfated ester; a sulfated alkanolamide; an alkylphenol, optionally ethoxylated and sulfated; an ethoxylated aliphatic alcohol; polyoxyethylene; a carboxylic ester; a polyethylene glycol ester; an anhydrosorbitol ester or an ethoxylated derivative thereof; a glycol ester of a fatty acid; a carboxylic acid amide; a monoalkanolamine condensate; a polyoxyethylene amide and fatty acid amide; a quaternary ammonium salt; an amine with amide bonds; a polyoxyethylenealkylamine; an alicyclic polyoxyethyleneamine; a ?,?,?,? substituted tetrakisethylenediamine; a 2-alkyl-1-hydroxyethyl-2-imidazoline; N-coco-3-aminopropionic acid or a sodium salt thereof; disodium salt of N-tallow-3-iminodipropionate disodium; N-carboxymethyl-n-dimethyl-n-9-octadecenylammonium hydroxide; n-cocoamidethyl-n-hydroxyethylglycine sodium salt; or mixtures thereof.

23. The process according to claim 20, 21 or 22, characterized in that the surfactant is sodium docusil and / or sodium lauryl sulfate.

24. The process according to any of claims 19 to 23, characterized in that the viscosity-reinforcing agent is lactose; sucrose; saccharose; a hydrolyzed starch, such as maltodextrin; or a mixture of them.

25. The process according to claim 24, characterized in that the viscosity-reinforcing agent is sucrose.

26. The process according to any of claims 17 to 25, characterized in that the polymer is hydroxypropylcellulose; hydroxymethylcellulose; hydroxypropylmethylcellulose; a methylcellulose polymer; hydroxyethylcellulose; sodium carboxymethylcellulose; carboxymethylenehydroxyethylcellulose and / or carboxymethylhydroxyethylcellulose; an acrylic polymer, such as acrylic acid, acrylamide, and polymers and copolymers of maleic anhydride; or a combination thereof; or a mixture of them.

27. The process according to claim 26, characterized in that the polymer is hydroxypropylmethylcellulose.

28. The process according to any of the preceding claims, characterized in that all the particles have substantially a particle size greater than 1 nanometer.

29. The method according to any of claims 17 to 28, characterized in that the vehicle comprises: one or more diluents or fillers; one or more binders; one or more lubricants; one or more slip agents; one or more disintegrants; or a mixture of them.

30. The process according to any of claims 17 to 29, characterized in that the carrier comprises lactose monohydrate, microcrystalline cellulose and crospovidone or mixtures thereof.

31. The process according to any of claims 17 to 30, characterized in that the ground suspension is adsorbed on the particles by spraying the suspension on the granules in a fluidized bed granulator.

32. The process according to any of claims 17 to 31, characterized in that it also comprises the steps of drying and combining the granules after the adsorption step of the ground suspension.

33. A composition characterized in that it comprises efavirenz in the form of particles, in which substantially all particles have a particle size less than or equal to 1 micrometer, for use in the treatment of HIV.

34. The use of a composition comprising efavirenz in the form of particles, in which substantially all particles have a particle size less than or equal to 1 micrometer, for the manufacture of a medicament for the treatment of HIV.

35. An HIV treatment method, characterized in that it comprises the administration of a therapeutically effective amount of a composition comprising efavirenz in the particulate form, in which substantially all particles have a particle size less than or equal to 1 micrometer. PHARMACEUTICAL COMPOSITIONS A pharmaceutical composition comprising efavirenz in which efavirenz is in the form of nanoparticles.