WO2015092110A1 - Polymer nanoparticles comprising poly(butyl cyanoacrylate) or poly(ε-caprolactone) for the use thereof in therapy - Google Patents

Abstract

The invention relates to nanoparticles with prolonged release of active substances, to the use of said nanoparticles in therapy, preferably for antitumoral treatment, and to the method for the synthesis of said nanoparticles.

Description

 POLYMER NANOPARTICLES THAT INCLUDE POLI

 (BUTILCIANO ACRYLATE) OR POLYFE-CAPROLACTONE) FOR USE IN

 THERAPY

FIELD OF THE INVENTION The present invention is within the field of medicine, chemistry, biochemistry and immunology, and refers to a system for the transport of biologically active molecules capable of targeting receptors or targets selectively, and in particular to the functionalization of poly (butylcyanoacrylate) (PBCA) or poly (8-caprolactone) (PCL) nanoparticles carrying a drug, preferably 5-fluoruracil. The present invention also relates to the compositions, the preparation process and the uses of the system for the transport of biologically active molecules.

BACKGROUND OF THE INVENTION The need to find effective cancer treatments has increased the lines of research in this area. This has led to the identification of new therapeutic strategies and the development of a large number of new therapeutic agents. The molecules generated usually present some limitations such as: i) they do not arrive in sufficient quantity to the place where the tumor is located; ii) they are not effective enough in the tumor micro-environment; iii) be ineffective in the tumor due to the development of resistance mechanisms; and iv) not be specific enough against a tumor type. These are the reasons for the failure of treatments to certain types of cancer theoretically sensitive to chemotherapeutic agents. A clear example is the use of the anti-tumor drug 5-fluorouracil in the treatment of advanced colorectal cancer, which only induces a global response around 10%. Furthermore, it has been described that the combination of this agent with other antitumor agents has only been able to improve the efficiency around 45% of the cases (Zhang, N. et al., 2008. Molecules 13, 1551-1569).

Among the main causes that justify the failure of antitumor treatment are: i) the unfavorable pharmacokinetics of antitumor agents (characterized by rapid clearance and rapid biodegradation, which lead to a short plasma route) determines the use of highly toxic doses and a rigorous treatment regimen to achieve the desired therapeutic effect; ii) the extensive biodistribution and extravasation of the antitumor molecule in non-zones desired determines its high toxicity; iii) the selectivity of these drugs by the tumor tissue is generally poor; iv) the susceptibility to develop resistance to anticancer cells by tumor cells; and v) the unfavorable physicochemical properties of antitumor agents, for example, their hydrophobia, induce poor accumulation at the site of action (Arias, JL 2008. Molecules 13, 2340-2369; Durán, JDGet al., 2008. J Pharm. Sci. 97, 2948-2983).

With the aim of solving these problems, antitumor agents have been associated with colloidal systems in the treatment of cancer (Arias, JL 2008. Molecules 13, 2340-2369). This association aims to increase the specific accumulation of the drug in the tumor area, and increase the exposure time of cancer cells to these active agents. Other benefits of the exclusive location of chemotherapeutic agents in the target region are the improvement of their pharmacokinetic profile and the decrease in toxicity associated with the extensive biodistribution of these molecules. In addition, colloidal systems can achieve adequate protection of these active ingredients in vitro (during storage) and in vivo (against biodegradation phenomena related mainly to enzyme systems), which will reduce the formation of potentially toxic degradation products (Arias , JL 2008. Molecules 13, 2340-2369; Durán, JDG et al., 2008. J. Pharm. Sci. 97, 2948-2983; Davis et al., 2008. Nal Rev. Drug. Discov. 7 (9) , 771-782), That is why numerous efforts are being focused on the formulation of colloids, based mainly on vesicular systems (liposomes and niosomes) or polymeric, to achieve effective transport of any antitumor to the target area (Arias, JL 2008. Molecules 13, 2340-2369; Choef al., 2008. Clin. Cancer Res. 14, 1310-1316.). However, recent research has proven that this simple association is not always sufficient to specifically direct a drug to any area of the organism, beyond the organs belonging to the endothelial reticulum system (Reddy et al., 2005. J. Phys. Chem . 109, 3355-3363; Couvreur and Vauthier, 2006. Pharm. Res. 23 (7), 1417-1450), It is for all this that important research (with very promising results) is currently underway aimed at the design of conveyor systems drug liabilities (based on the effect of increased permeation and retention) and active drug transport systems at the site of action (based on ligand-receptor interactions, and on the design of nanoparticles sensitive to external stimuli) (Reddy et al., 2005. J. Phys. Chem. 109, 3355-3363; Arias, JL 2008. Molecules 13, 2340-2369).

Magnetic nanoparticles of poly (e-caprolactone) containing a drug for cancer treatment have been described. However, the large size they present these particles make their accumulation in the target region poor, so that the effectiveness of the treatment is impaired (Gang, J. et al., 2007. J. Drug Target. 15 (6), 445-53; Arias , JL et al., 2010. Colloids Suri. B Biointerfaces 75, 204-208).

There are numerous documents that describe the production of poly (butylcyanoacrylate) nanoparticles. Poly (butylcyanoacrylate) (PBCA) particles meet ideal requirements such as biodegradability, the ability to alter drug biodistribution and ease of synthesis and purification (Beck, PH et al., 1994. Eur. J. Pharm. BiopharmÁO , 134-37; Kreuter, J. et al., 1995 Brain Res. 674, 171-74; Schroeder, U. et al., 1996.fíra / ^' n fíes. 1996. 710, 121-24; Couvreur, P . et al., 1979. J. Pharm. Pharmacol. 31: 331-32). The optimal polymerization pH for the formation of said nanoparticles is below 5.0, as well as the high polymerization temperature (60 ^e C) (Behan, N. et al., 2001. Biomaterials 22, 1335-44) .

Within the different biodegradable and biocompatible polymers that are used as transporters, butylcyanacrylate is widely used. There is therefore a need to provide nanoparticles that are of a minimum size that allow a greater accumulation of them in the target region, that minimize the phenomena of recognition and withdrawal thereof by the immune system and therefore improve the effectiveness of the treatment .

Among the recently proposed possibilities to overcome the difficulties of drug administration, the incorporation of active ingredients in small particles stands out. The interaction of these particles with the mucous membranes is affected among other factors by the size of these particles, said interaction increasing with the decrease in particle size. Depending on their size we can classify them in micro- and nano-systems. Among the different types of nanosystems, nanoparticles are of special relevance in the transport of biologically active molecules due to their advantages, such as:

- the protection of the encapsulated drug against enzymatic degradation and the ability to control release until reaching its site of action; - the great penetration capacity in microcapillaries or intracellular compartments or to cross the blood brain barrier due to its nanometric size; - the use of biodegradable polymers for its preparation, which allows the controlled release of the drug for days, weeks or months.

In the case of polymeric nanoparticles, important properties are added such as biocompatibility and biodegradability that allow their use in a wide variety of applications in the medical field. Thus, in the treatment of cancer, for example, polymeric drug transporters are used that allow the transport of the drug selectively minimizing its biodistribution, biological metabolization and the elimination of the drug it carries, allowing a greater therapeutic effect with low toxicity. Nanoparticulate systems based on hydrophilic polymers have been developed for application as drug delivery systems. This is demonstrated by the abundant literature in this field. Numerous works have been published that describe various methods of making hydrophilic nanoparticles based on naturally occurring macromolecules such as albumin nanoparticles (Lin, W. et al., 1994. Pharm. Res., 1 1) and gelatin (Watzke , HJ et al., 1994. Adv. Colloid Interface Sci., 50, 1-14,) and based on polysaccharides such as alginate (Rajaonarivonvy M. et al., 1993. J. Pharm. Sci., 82, 912- 7). However, most of these methods require the use of organic solvents, oils and high temperatures, aspects that greatly limit the exploitation of these systems. In the literature, a multitude of methods for the synthesis of nanoparticles have been described, among the most important are: the continuous emulsion polymerization method in the aqueous phase, the continuous emulsion polymerization method in the organic phase, the interfacial polymerization, the interfacial arrangement of the polymer with solvent evaporation, molecule desolvation and dialysis methods (Marty et al. 1978 Pharm. Acta Helv. 53, 17). Polymerization in monomers in the presence of surfactants above the critical micellar concentration (emulsion polymerization) generally leads to the formation of smaller particles (Bhawal, S. et ai, 2002. Eur. Polym. J. 38, 735- 44).

BRIEF DESCRIPTION OF THE INVENTION

A first aspect of the invention relates to a polymeric nanoparticle, hereafter referred to as a nanoparticle of the invention, obtainable by a method comprising: i) the dissolution of at least one or more biodegradable polymers, in an organic solvent, ii) the addition of the solution obtained in (i) on a mixture comprising an anti-solvent and a surfactant, to obtain a particle iii) the isolation of the particle obtained, where the active ingredient is incorporated by surface association on the nanoparticle obtained after step (iii) or by association inside the polymer matrix during step (i).

In a preferred embodiment of this aspect of the invention, the process further comprises an evaporation step of the organic solvent. In another preferred embodiment of this aspect of the invention, it further comprises a redispersion of the polymeric nanoparticle until the conductivity of the supernatant is less than or equal to 10 με / οηι.

In another preferred embodiment of this aspect of the invention, step (iii) is carried out by centrifugation. In another preferred embodiment of this aspect of the invention, step (ii) is performed sequentially.

In another preferred embodiment of this aspect of the invention, the antisolvent is water or water mixed with an organic solvent.

In another preferred embodiment of this aspect of the invention, the nanoparticle has an average particle size between 55 and 85 nm. In another preferred embodiment of this aspect of the invention, at least one biodegradable polymer is poly (butylcyanacrylate) or poly (8-caprolactone).

In another preferred embodiment of this aspect of the invention, the biodegradable poly (butylcyanoacrylate) polymer has a molecular weight of less than 10,000 Daltons, preferably between 3,000 and 100 Daltons, and even more preferably between 2,000 and 500 Daltons, and even more preferably it is about 1 .500 Daltons, or where the biodegradable poly (8-caprolactone) polymer has a molecular weight of less than 100,000 Daltons, preferably between 5,000 and 45,000 Daltons, and even more preferably between 7 and 20,000 Daltons, and still more preferably it is about 10,000 Daltons. In another preferred embodiment of this aspect of the invention, the nanoparticle comprises as a biodegradable polymer 90% poly (butylcyanacrylate) or 75% poly (8-caprolactone).

In another preferred embodiment of this aspect of the invention, the nanoparticle comprises at least one pyrimidine analog as active ingredient.

In another preferred embodiment of this aspect of the invention, the poly (butylcyanoacrylate) and the pyrimidine analog, or the poly (8-caprolactone) and the pyrimidine analog are in a sufficient ratio to remain associated.

In another preferred embodiment of this aspect of the invention, the ratio sufficient to remain associated with the poly (butylcyanoacrylate) and the pyrimidine analog is a ratio of between 1000: 1 and 1: 100 p / p respectively, preferably it is a ratio of 5: 1 and 15: 1 p / p; or the ratio sufficient to remain associated with poly (8-caprolactone) and the pyrimidine analog is a ratio between 1000: 1 and 1: 100 p / p respectively, preferably it is a ratio between 2: 1 and 10: 1 p / p. In another preferred embodiment of this aspect of the invention, the nanoparticle comprises a% surfactant in a percentage between 0.2% and 5%.

In another preferred embodiment of this aspect of the invention, the surfactant is selected from the list comprising: polysorbate 20, polysorbate 60, polysorbate 80, high or low molecular weight polyvinyl alcohol, polyvinyl pyrrolidone, phosphatidyl choline, lecithins, amphiphilic block copolymers, poloxamers of different types, solutol HS15, sodium glycocholate, sodium taurocholate, sodium tauroglycocholate, sodium taurodeoxycholate, cholesteryl hemisuccinate and tyloxapol.

In another preferred embodiment of this aspect of the invention, the surfactant is an amphiphilic block copolymer, more preferably it is a poloxamer, and even more preferably it is F68 pluronic.

In another preferred embodiment of this aspect of the invention, the pyrimidine analog is selected from the list consisting of cytarabine, fluorouracil (5-fluorouracil or 5- FU), tegafur or ftorafur, carmofur, gemcitabine, capecitabine, azacitidine, decitabine, or any of its corresponding salts, isomers, prodrugs, derivatives or analogs, and combinations thereof. Even more preferably, it is 5-fluorouracil (5-FU), or any of its salts, isomers, prodrugs, derivatives or the like. Even more preferably, the nanoparticle of the invention comprises 5-fluorouracil (5-FU) in a percentage between 0.1% and 25%. A second aspect of the invention relates to a pharmaceutical composition, hereinafter pharmaceutical composition of the invention, comprising the nanoparticle of the invention. In a preferred embodiment of this aspect of the invention, the composition of the invention is a pharmaceutical composition. In another more preferred embodiment of this aspect of the invention it further comprises a pharmaceutically acceptable excipient. Even more preferably, it also comprises another active ingredient.

In another preferred embodiment of this aspect of the invention, the pharmaceutical composition is formulated for parenteral use, preferably for intravenous, intraarterial, intratumoral, intramuscular or subcutaneous use.

In another preferred embodiment of this aspect of the invention, the pharmaceutical composition is in solid form for oral administration, preferably in tablets or capsules.

A third aspect of the invention relates to the use of the nanoparticle of the invention or of the composition of the invention in the preparation of a medicament, or alternatively, to the nanoparticle of the invention or the composition of the invention for use as a medicament. .

A fourth aspect of the invention relates to the use of the nanoparticle of the invention or of the composition of the invention in the preparation of a medicament for the treatment of cancer, or alternatively, to the nanoparticle of the invention or the composition of the invention for for the treatment of cancer. In a preferred embodiment of this aspect of the invention, the cancer is colorectal cancer.

A fifth aspect of the invention relates to a process for the synthesis of a nanoparticle with an average size of less than 100 nm, preferably less than 75 nm, comprising one or more degradable polymers, one or more active ingredients and at least one surfactant. , where at least one biodegradable polymer is poly (butylcyanoacrylate) or poly (£ -caprolactone) and where at least one active ingredient is 5-fluorouracil and which consists of: i) the dissolution of one or more biodegradable polymers, in an organic solvent. ii) the addition of the solution obtained in (i) on a mixture comprising an anti-solvent and a surfactant iii) the isolation of the obtained particle, where the active ingredient is incorporated by surface association on the nanoparticle obtained after stage (iii) or by association within the polymer matrix during stage (i).

DESCRIPTION OF THE FIGURES

Fig. 1. Molecular structure of poly (£ -caprolactone) (a) and poly (butylcyanoacrylate) (b).

Fig. 2. Visualization by electron microscope of the nanoparticles of poly (butylcyanoacrylate) (a) and poly (£ -caprolactone) (b). Bar length: 1 μηι (a), and 200 nm (b). Fig. 3. In vitro cytotoxicity of poly (butylcyanoacrylate) (a) and poly (£ -caprolactone) (b) in a range of concentrations (0.1-20 μΜ) on the MC38, CCD-18, HCT-15, HT lines -29 and T84 derived from colon cancer after three days of incubation with the agents described. Data represent the mean ± SD of four experiments. PBCA and PCL showed no toxicity in the lines tested at the concentrations necessary for use with the antitumor drug and after 72 hours of treatment. Therefore, these nanoparticles have a fine compatibility.

Fig. 4. In vitro cytotoxicity of NP 5-FU-poly (butylcyanoacrylate) compared to the free 5-FU agent in colon cancer lines in T84 (a), HT-29 (b), HCT-15 (c), CCD-18 (d), and MC38 (e). The degree of growth inhibition was measured in 72 hours using the SRB assay. The survival percentage was determined by normalizing the absorbance of the controls at 100%. In addition, NP and 5-FU free are used together to demonstrate non-interaction. Data are represented as mean ± SD of the crops in quadruplicate.

Fig. 5. In vitro cytotoxicity of NP 5-FU-poly (£ -caprolactone) compared to the free 5-FU agent in colon cancer lines T84 (a), HT-29 (b), HCT- 15 (c), CCD-18 (d), and MC38 (e). The degree of growth inhibition was measured in 72 hours using the SRB assay. The survival percentage was determined by normalizing the absorbance of the controls at 100%. In addition, NP and 5-FU free are used together to demonstrate non-interaction. Data are represented as mean ± SD of the crops in quadruplicate.

Fig. 6. Inhibition of the growth of a tumor induced subcutaneously by inoculation of a line derived from colon cancer. The tumors were treated with Np 5-FU-poly (butylcyanoacrylate) (a) and Np 5-FU-poly (£ -caprolactone) (b) and were compared with the treatment with free 5-FU and no load Np. The graph shows a statistically significant reduction in tumor volume of mice treated with 5-FU-poly (butylcyanoacrylate) (a) or Np 5-FU-poly (£ -caprolactone) (b) in relation to untreated tumors, treated with empty NP or treated 5-FU free. Data represent a mean ± SEM (n = 10).

Fig. 7. Survival study of mice carrying subcutaneous tumor colon cancer treated with Np 5-FU-poly (butylcyanoacrylate) (a) and Np 5-FU-poly (£ - caprolactone) (b) compared to 5-FU free and Np without load, by performing the Kaplan-Meier curves Data were analyzed according to the survival of the mice with the treatment applied to each group (n = 10). The comparison between the treatment groups was made using the log-rank test (p <0.05).

DETAILED DESCRIPTION OF THE INVENTION The inventors of the present invention have developed nanoparticles that behave as an excellent pyrimidine analog transport system, and in particular 5-fluorouracil. The nanoparticles of the invention allow optimal vehiculization of the anticancer agent, achieve high extravasation in the tumor mass and, in turn, the release of the drug is more controlled. In addition, studies of in vitro antitumor efficacy have demonstrated a very significant increase in the antitumor activity of this drug when it is vehiculized through the nanoparticles of the invention.

Therefore, a first aspect of the invention relates to a polymeric nanoparticle, hereafter referred to as a nanoparticle of the invention, obtainable by a process comprising: i) the dissolution of at least one or more biodegradable polymers, in an organic solvent, ii) the addition of the solution obtained in (i) on a mixture comprising an anti-solvent and a surfactant, to obtain a particle iii) the isolation of the obtained particle, where the active ingredient is incorporated by surface association on the nanoparticle obtained afterwards of stage (iii) or by association within the polymer matrix during stage (i). The superficial association consists in the incorporation by adsorption of the drug, in the case of the examples the antitumor drug 5-fluorouracil, on the surface of the previously obtained polymeric nanoparticles. In the association inside the polymer matrix, the active ingredient is incorporated into the nanoparticles by absorption.

In a preferred embodiment of this aspect of the invention, the process further comprises an evaporation step of the organic solvent.

In another preferred embodiment of this aspect of the invention, it further comprises a redispersion of the polymeric nanoparticle until the conductivity of the supernatant is less than or equal to 10 με / οηι.

The conductivity of the supernatant obtained can be determined, for example but not limited to 25.0-0.5 ^e C using a Crison micropH 2001 conductivity meter (Spain). The redispersion of the sediment obtained after centrifugation of the nanoparticles can be carried out, for example but not limited to, by adding double-distilled water to this sediment and exposing this mixture (at 25.0-0.5 ^e C) to ultrasound (450 W, Branson 5200E4 ultrasonic bath, USA).

In another preferred embodiment of this aspect of the invention, step (iii) is carried out by centrifugation.

In another preferred embodiment of this aspect of the invention, step (ii) is performed sequentially.

In another preferred embodiment of this aspect of the invention, the antisolvent is water or water mixed with an organic solvent.

In another preferred embodiment of this aspect of the invention, the nanoparticle has an average particle size of between 30 and 500 nm, more preferably between 30 and 999 nm, and even more preferably between 55 and 85 nm.

In another preferred embodiment of this aspect of the invention, at least one biodegradable polymer is poly (butylcyanacrylate) or poly (e-caprolactone).

In another preferred embodiment of this aspect of the invention, the biodegradable poly (butylcyanoacrylate) polymer has a molecular weight of less than 10,000 Daltons, preferably between 3,000 and 100 Daltons, and even more preferably between 2,000 and 500 Daltons, and even more preferably it is about 1 .500 Daltons, or where the biodegradable poly (8-caprolactone) polymer has a molecular weight of less than 100,000 Daltons, preferably between 5,000 and 45,000 Daltons, and even more preferably between 7 and 20,000 Daltons, and even more preferably is about 10,000 Daltons.

In another preferred embodiment of this aspect of the invention, the nanoparticle comprises as a biodegradable polymer 90% poly (butylcyanacrylate) or 75% poly (8-caprolactone).

In another preferred embodiment of this aspect of the invention, the nanoparticle comprises at least one pyrimidine analog as active ingredient.

In another preferred embodiment of this aspect of the invention, the poly (butylcyanoacrylate) and the pyrimidine analog, or the poly (8-caprolactone) and the pyrimidine analog are in a sufficient ratio to remain associated.

In another preferred embodiment of this aspect of the invention, the ratio sufficient to remain associated with the poly (butylcyanoacrylate) and the pyrimidine analog is a ratio of between 1000: 1 and 1: 100 p / p respectively, preferably it is a ratio of 5: 1 and 15: 1 p / p; or the ratio sufficient to remain associated with poly (8-caprolactone) and the pyrimidine analog is a ratio between 1000: 1 and 1: 100 p / p respectively, preferably it is a ratio between 2: 1 and 10: 1 p / p.

In another preferred embodiment of this aspect of the invention, the nanoparticle comprises a% surfactant in a percentage between 0.2% and 5%. In another preferred embodiment of this aspect of the invention, the surfactant is selected from the list comprising: polysorbate 20, polysorbate 60, polysorbate 80, high or low molecular weight polyvinyl alcohol, polyvinyl pyrrolidone, phosphatidyl choline, lecithins, amphiphilic block copolymers, poloxamers of different types, solutol HS15, sodium glycocholate, sodium taurocholate, sodium tauroglycocholate, sodium taurodeoxycholate, cholesteryl hemisuccinate and tyloxapol.

In another preferred embodiment of this aspect of the invention, the surfactant is an amphiphilic block copolymer, more preferably it is a poloxamer, and even more preferably it is F68 pluronic.

In another preferred embodiment of this aspect of the invention, the pyrimidine analog is selected from the list consisting of cytarabine, fluorouracil (5-fluorouracil or 5- FU), tegafur or ftorafur, carmofur, gemcitabine, capecitabine, azacitidine, decitabine, or any of its corresponding salts, isomers, prodrugs, derivatives or analogs, and combinations thereof. Even more preferably, it is 5-fluorouracil (5-FU), or any of its salts, isomers, prodrugs, derivatives or the like. Even more preferably, the nanoparticle of the invention comprises 5-fluorouracil (5-FU) in a percentage between 0.1% and 25%.

The "pyrimidine analogues" constitute a well defined group in the ATC code or System of Anatomical, Therapeutic, Chemical Classification (instituted by the World Health Organization, and adopted in Europe). They belong to section ATC L01, section of the ATC classification system within group L, corresponding to antineoplastic and immunomodulating agents. Specifically they are classified as L01 BC Pyrimidine analogues, and in the latest update of 201 1 includes:

- L01 BC01 cytarabine

- L01 BC02 Fluoracil

- L01 BC03 tegafur

- L01 BC04 carmofur - L01 BC05 gemcitabine

- L01 BC06 Capecitabine

- L01 BC07 azacitidine

- L01 BC08 decitabine

- L01 BC52 fluoracil, combinations - L01 BC53 tegafur, combinations

In this specification, fluorouracil, 5-fluorouracil (5-FU), or 5- Fluoropyrimidine-2,4-dione, a compound with CAS number 51-21-8, of formula (I)

Formula (I) or any of its salts, isomers, prodrugs, derivatives or the like.

In this report, cytarabine, Ara-C, arabinofuranosylcytosine; arabinosylcytosine, cytosine arabinoside, or 4-amino-1 - [(2R, 3S, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl] pyrimidin-2-one, a compound with CAS number 147-94-4, of formula (II)

Fórmula (II) o cualquiera de sus sales, isómeros, profármacos, derivados o análogos.

Formula (II) or any of its salts, isomers, prodrugs, derivatives or the like.

Tegafur, or (RS) -5-fluoro-1 - (tetrahydrofuran-2- yl) pyrimidine-2,4 (1 H, 3H) -dione, a compound with CAS number 17902-23-7 , of formula

or any of its salts, isomers, prodrugs, derivatives or the like. In this specification, carmofur, HCFU or 5-fluoro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide, a compound with CAS number 61422-45-5, of formula (IV)

Formula (IV)

or any of its salts, isomers, prodrugs, derivatives or the like.

Gemcitabine, or 4-amino-1 - (2-deoxy-2,2-difluoro ^ -D-erythro-pentofuranosyl) pyrimidin-2 (1 H) -on, a compound with CAS number 95058- 81 -4, of formula (V)

Formula (V) or any of its salts, isomers, prodrugs, derivatives or the like.

In this specification capecitabine, or pentyl [1 - (3,4-dihydroxy-5- methyltetra idrofuran-2-yl) -5-fluoro-2-oxo-1 H- pyrimidin-4-yl] carbamate, is understood as a compound with CAS number 154361 -50-9, of formula (VI)

Formula (VI) or any of its salts, isomers, prodrugs, derivatives or the like.

Azacitidine, or 4-amino-1 ^ -D-ribofuranosyl-1, 3,5-triazin-2 (1 H) -one, a compound with CAS number 320-67-2, of formula ( VII)

Formula (VII) or any of its salts, isomers, prodrugs, derivatives or the like.

Herein is understood as decitabine, or 4-amino-1 - (2-deoxy-bD-erythropentofuranosyl) -1, 3,5-triazin-2 (1 H) -one, a compound with CAS number 2353- 33-5, of formula (VIII)

Fórmula (VIII) o cualquiera de sus sales, isómeros, profármacos, derivados o análogos.

Formula (VIII) or any of its salts, isomers, prodrugs, derivatives or the like.

As used herein, the term "derivative" includes both pharmaceutically acceptable compounds, including derivatives of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), and / or (VIII), which may be used in the manufacture of a medicament, as pharmaceutically acceptable derivatives, since these may be useful in the preparation of pharmaceutically acceptable derivatives.

Also, within the scope of this invention are the prodrugs of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), and / or (VIII) . The term "prodrug" as used herein includes any compound derived from the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), and / or (VIII), for example, esters, including esters of carboxylic acids, amino acid esters, phosphate esters, sulphonate esters of metal salts, carbamates, amides, etc., which, when administered to an individual, are capable of providing, directly or indirectly, the effect of the compound of formula (I) on said individual. Advantageously, said derivative is a compound that increases the bioavailability of the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), and / or (VIII), when administered to an individual or that enhances the release of the compound of formula (I) (II), (III), (IV), (V), (VI), (VII), and / or (VIII), in a biological compartment The nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (I) (II), (III), (IV), (V), (VI), (VII), and / or (VIII), in a biological compartment of an individual. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.

In particular, the nanoparticle synthesis process of the invention of poly (butylcyanoacrylate) or poly (8-caprolactone) is based on the interfacial arrangement method of polymers.

The interfacial arrangement of polymers is a process for the preparation of biodegradable nanoparticles, or nanospheres. In this method, the biodegradable polymer is first dissolved in an organic solvent, for example acetone or dichloromethane. The resulting organic solution is poured under stirring into the water containing surfactant, such as a polaxamer, with which the aqueous phase immediately becomes a milky solution, indicating the formation of nanoparticles. The organic solvent is removed under reduced pressure. The colloidal suspension formed is concentrated to the desired volume. The use of the interfacial arrangement of polymers for the synthesis of the nanoparticles of the invention entails several advantages. In addition to being a simple and fast synthesis, it allows nanoparticles with very relevant characteristics to be obtained such as: a very small size colloidal system with very low average sizes The process allows a much higher drug load, which among other advantages allows the quantity of polymeric material administered be smaller. All this allows: i) that the mass to be administered from the transport system is not very high to obtain a significant (antitumor) effect, compared to what happens with other colloids previously proposed in other works; and, in addition, ii) an intimate and very prolonged contact between the therapeutic molecule (antitumor) and the target cells (tumor).

The nanoparticles of the present invention may include other active ingredients, such as, but not limited to, those used in the treatment of cardiovascular diseases (eg, arteriosclerosis, thrombosis), metabolic diseases (eg, diabetes), chronic inflammatory diseases (eg, arthritis, allergic asthma, uveitis), neurodegenerative diseases (Alzheimer's, Parkinson's), or infectious diseases, among others.

A second aspect of the invention relates to a pharmaceutical composition, hereinafter pharmaceutical composition of the invention, comprising the nanoparticle of the invention. In a preferred embodiment of this aspect of the invention, the composition of the invention is a pharmaceutical composition. In another more preferred embodiment of this aspect of the invention it further comprises a pharmaceutically acceptable excipient. Even more preferably, it also comprises another active ingredient.

In another preferred embodiment of this aspect of the invention, the pharmaceutical composition is formulated for parenteral use, preferably for intravenous, intraarterial, intratumoral, intramuscular or subcutaneous use.

In another preferred embodiment of this aspect of the invention, the pharmaceutical composition is in solid form for oral administration, preferably in tablets or capsules. A third aspect of the invention relates to the use of the nanoparticle of the invention or of the composition of the invention in the preparation of a medicament, or alternatively, to the nanoparticle of the invention or the composition of the invention for use as a medicament. . Both the polymeric nanoparticle of the invention and the pharmaceutical composition of the invention are useful in therapy. Preferably, they are useful for the preparation of a medicament for the treatment of cancer, and more preferably the cancer is selected from the list consisting of: Hodgkin and non-Hodgkin lymphoma, breast cancer, ovarian cancer, testicular cancer, acute leukemia , soft tissue sarcoma, lung cancer, urinary bladder cancer, gastric cancer, thyroid cancer, hepatocarcinoma, Wilms tumor or neuroblastoma, among others, and even more preferably, for the treatment of colon cancer.

Therefore, a fourth aspect of the invention relates to the use of the nanoparticle of the invention or of the composition of the invention in the preparation of a medicament for the treatment of cancer, or alternatively, to the nanoparticle of the invention or the composition of the invention for the treatment of cancer. In a preferred embodiment of this aspect of the invention, the cancer is colorectal cancer.

A fifth aspect of the invention relates to a process for the synthesis of a nanoparticle with an average size of less than 100 nm, preferably less than 75 nm, comprising one or more degradable polymers, one or more active ingredients and at least one surfactant. , where at least one biodegradable polymer is poly (butylcyanoacrylate) or poly (£ -caprolactone) and where at least one active ingredient is 5-fluorouracil and which consists of: i) the dissolution of one or more biodegradable polymers, in an organic solvent. ii) the addition of the solution obtained in (i) on a mixture comprising an anti-solvent and a surfactant iii) the isolation of the obtained particle, where the active ingredient is incorporated by surface association on the nanoparticle obtained after step (iii) ) or by association within the polymer matrix during step (i).

The photon correlation spectroscopy (PCS: Photon Correlation Spectroscopy) method can be used to measure the particle size of the nanoparticles of the invention.

The term biodegradable polymer refers to an organic macromolecule (consisting of small molecules called monomers) that is capable of being destroyed (degraded) in vivo under certain physiological conditions. In this way, it is metabolized and eliminated from the body. This destruction occurs mainly under the action of certain enzymes or enzyme systems, e.g. eg, phospholipase A2, phospholipase C specific for phosphatidylinositol, transglutaminase, alkaline phosphatase, metalloproteinase, esterases, etc. Some biodegradable polymers are also sensitive to slightly acidic pHs (eg, pH 6.6 characteristic of tumor interstitium) or temperature. As used herein, the term "organic solvent" refers to any organic compound, or mixtures of organic compounds, capable of dissolving poly (butylcyanacrylate) or poly (£ -caprolactone). Representative examples include alcohols, hydrocarbons, halogenated compounds, ethers and acetone. Particular examples of organic solvents are ethyl acetate, acetone, acetonitrile (MeCN), benzene, chloroform, methylene chloride, dichloromethane (DCM), 1: 1 mixtures of dichloromethane: chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1 , 4-dioxane, protic polar solvents, diethyl ether, tetrahydrofuran (THF), toluene and (ethanol, methanol, n-butanol, npropanol and isopropanol (IPA)).

The term "anti-solvent" refers to a liquid which, when mixed with a solvent in which a solute dissolves, that is, poly (butylcyanacrylate) or poly (£ -caprolactone), reduces the ability of the organic solvent to dissolve the solute. . Thus, when an antisolvent is mixed with a solution of a solute in an organic solvent, the solubility of the solute can be reduced to the point where it precipitates in the solution. The solvent must be sufficiently miscible with the organic solvent. It will be appreciated that miscibility can be controlled by varying one or more parameters, within which the solvency between the system and the solvent can be kept at a sufficiently low temperature so that the two liquids are not particularly miscible (during storage , for example), and as the temperature rises the two liquids become miscible and so the nanoparticles can be formed. The preferred antisolvent is an aqueous solution, although acidified aqueous solutions, such as a 2% (v / v) acetic acid solution in water, may also be preset.

The term "surfactant" agent, or surfactant, refers to surface active agents that have a structure characterized by a hydrophilic polar group and a hydrophobic tail. These active surface molecules generally have a long chain with at least eight carbon atoms. Surfactants are effective in modifying the properties of the interface, such as interfacial tension, at very low concentrations. Surfactants are also characterized by being able to modify surface thermodynamic properties (eg, hydrophobia), light scattering properties and solute solubilization. Specifically, a Increased surfactant concentration tends to significantly reduce surface tension, until it reaches a breakpoint known as the critical micellar concentration (CMC).

Any effective surfactant can be used in the practice of the present invention, including anionic, nonionic and cationic surfactants. Specific surfactants useful for the present invention are polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol of high or low molecular weight, polyvinyl pyrrolidone, phosphatidyl choline, lecithins, poloxamers, solutol HS15, sodium glycocholate, sodium taurocholate, sodium tachocholantoic sodium, tauroglodeoxide sodium Cholesteryl hemisphecinate and tyloxapol, preferably polysorbate 80. The most preferred surfactants are polaxamers, preferably a copolymer of poly (propylene oxide) and poly (ethylene oxide), and more preferably pluronic ^® F-68.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention.

EXAMPLES OF THE INVENTION Characterization of nanoparticles. Specifications of its synthesis

Caprolactone: The synthesis procedure is based on the interfacial arrangement method of poly (£ -caprolactone) (PCL), which involves precipitation of this polymer in aqueous medium. The synthesis process of ροΝ (ε-caprolactone) nanoparticles involves the addition of 5 ml of a 0.3% (w / v) solution of polymer in dichloromethane over 25 ml of an aqueous solution of pluronic ^® F-68 of 2 % (p / v).

The volume of the organic phase where the polymer is dissolved can be up to 50 ml (the volume is in relation to the polymer, so increasing the amount of polymer), more preferably 30 ml, and even more preferably up to 20 ml, the organic phase can also be constituted by acetone or ethyl acetate; Similarly, the volume of the aqueous phase can be up to 200 ml, much more preferably 120 ml, and even more preferably up to 100 ml (generally about 4 times the organic phase). The surfactant used can also be dextran-70, while the concentration of agent used Surfactant can vary from 0.5 to 3% (w / v). From approximately 1% (w / v) the formation of the particles with the characteristics of the patent is achieved. At concentrations greater than 5% foam is formed. Under any of these conditions the particle size always remains below 100 nm (mean diameter: 70 ± 15 nm, polydispersion index less than 1).

The organic phase is added to the aqueous phase under mechanical agitation (10,000 rpm), which is maintained for 3 hours to ensure the total precipitation of the polymer in the form of nanoparticles. The mechanical stirring speed can range from 900 rpm to 20,000 rpm, even more preferably from 1000 rpm to 18000 rpm, while the stirring can extend from 0.5 hours to 7 hours, more preferably from 1 to 6 hours.

The organic phase is completely eliminated by evaporation with the help of a rotary evaporator. Finally, the nanoparticles are cleaned using the necessary number of centrifugation cycles (1000 rpm for 30 minutes) and redispersion in double-distilled water so that the obtained supernatant is transparent and has a conductivity of less than 10 με / οηι. To obtain the PCL nanoparticles loaded with 5-FU, the antitumor drug is dissolved in the organic phase (molar concentrations used from 10 ^{~ 7} to 10 ^{~ 2} M). Thus, a greater absorption in the polymer matrix is achieved, compared to its dissolution in the aqueous phase. For example, for the concentration of 5-FU that provides maximum drug vehiculization under the developed synthesis conditions, the entrapment efficiency values (entrapment efficiency,%) of 5-FU in the nanoparticles are: 82% if 5 -FU dissolves in the organic phase (where the dissolved polymer is also found), and 66% if 5-FU dissolves in the aqueous phase. Otherwise, the preparation procedure coincides with the synthesis routine described previously.

Cyanoacrylate: The synthesis procedure is based on the interfacial arrangement method of the butylcyanoacrylate monomer, which involves supolymerization in an aqueous medium. The synthesis process consists in the addition of 0.1 ml of an acetone solution containing a concentration of 1% (w / v) of monomer over 10 ml of an aqueous solution of 10 ^"4 N HCI containing 1% (p / v) of pluronic ^® F-68. The volume of the organic phase where the monomer is dissolved can be up to 12 ml, more preferably up to 10 ml, the organic phase can also be made up of ethanol; Similarly, the volume of the aqueous phase can be up to 600 ml, preferably up to 500 ml. The surfactant used can also be dextran-70 or poly (ethylene glycol) 4000, while the concentration of surfactant used can vary from 0.2 to 5% (w / v). Under any of these conditions the particle size always remains below 100 nm (mean diameter: 75 ± 10 nm, polydispersion index less than 1. The organic phase is added to the aqueous phase under mechanical agitation (10,000 rpm) , which is maintained for 6 hours to ensure the complete transformation of the monomer into polymer nanoparticles.To complete the reaction, a sufficient amount of a base (eg, 1 M NaOH, 1 M KOH) is added to neutralize (pH 7 ) the polymerization medium.

The mechanical stirring speed can range from 800 rpm to 20,000 rpm, and more preferably from 1000 rpm to 18,000 rpm, while the stirring can extend from 0.5 to 12 hours. The organic phase is completely eliminated by evaporation with the help of a rotary evaporator. Finally, the nanoparticles are cleaned using the necessary number of centrifugation cycles (1000 rpm for 30 minutes) and redispersion in double-distilled water so that the obtained supernatant is transparent and has a conductivity of less than 10 με / οηι.

To obtain PBCA nanoparticles loaded with 5-fluorouracil (5-FU), the antitumor drug is dissolved in the organic phase (molar concentrations used from 10 ^{~ 7} to 10 ^{~ 2} M). Thus, a greater absorption in the polymer matrix is achieved, compared to its dissolution in the aqueous phase. For example, for the concentration of 5-FU that provides maximum drug vehiculization under the developed synthesis conditions, the entrapment efficiency values (entrapment efficiency,%) of 5-FU in the nanoparticles are: 73% if 5 -FU dissolves in the organic phase (where the dissolved polymer is also found), and 59% if 5-FU dissolves in the aqueous phase. Otherwise, the preparation procedure coincides with the synthesis routine described previously. Finally, the concentration of HCI set in the polymerization medium also influences the vehicleization of 5-FU by PBCA nanoparticles. Specifically, it is possible to incorporate this antitumor agent in the nanoparticles when the values of HCI concentration is between 10 ^"5 and 10 ^{" 2} N, preferably 10 ^"4 N (entrapment efficiency: 73%, versus the minimum obtained for a concentration of HCI 10 ^{" 2} N: 18%). Therefore, it can be said that the modification of the pH influences the absorption of 5-FU by the nanoparticles. Specifically, the pH determines the polymerization kinetics of the monomer, which is governed by the amount of hydroxyl ions present in the medium. As this concentration is lower (acidic polymerization media, high concentrations of HCI), the polymerization rate decreases and, thus, drug absorption. That is, the faster the polymerization reaction passes, the more 5-FU (hydrophilic drug) will be trapped in the hydrophobic nanomatrix of PBCA, since it will not have room to escape to the aqueous medium where the process takes place. On the other hand, an excessively rapid polymerization kinetics (existing at concentrations of HCI below 10 ^"5 N, pH 6 and higher) leads to a poor process of formation of PBCA nanoparticles, mainly obtaining solid irrigated macroags that do not serve as 5-FU transporting nanosystems.

Cytotoxicity Study

 The new PBCA nanoparticle without drug showed no toxicity in the colon-derived cell lines that were tested (T84, HT-29 and CCD-18, MC-38) after an incubation time of 72 h (Fig. 3a) and at any of the concentrations tested (Fig. 3a). On the other hand, the new PCL nanoparticle without drug also showed no toxicity in the same colon-derived cell lines tested (T84, HT-29 and CCD-18, MC-38) and with the same incubation times (Fig. 3b) and concentrations (Fig. 3b). These concentrations include those suitable for use with drug loading in in vivo experiences indicating the possible use of the new agent as a therapeutic drug.

Antiproliferative effect of poly (butylcyanoacrylate) and poly (s-caprolactone) loaded with 5-fluorouracil.

With all the nanoparticles and with all cell lines, an increase in the antiproliferative effect was obtained at 72 h of incubation (Fig. 4) in relation to the use of the 5-fluorouracil agent without nanoparticle.

- The nanoparticle PBCA-5-FU is able to reduce the IC50 value (dose that eliminates 50% of the cells in the culture) with respect to 5-FU treatment. This implies a huge improvement in the antitumor activity of the agent. PBCA-5-FU (1 mM) induced an increase of 61, 9%, 35% and 62.2% of Rl in cancer cells of colonT-84, HT-29 and HCT-15, respectively (p <0.05) and therefore a significant reduction in the IC50 value of 5-FU compared to free 5-FU, which implies the possibility of reducing the dose of drug to get the same effect. We must highlight the 70.2% increase in Rl in the MC-38 line with the same nanoparticle (PBCA-5-FU) using it at 0.03 mM (Fig. 4).

- The PCL-5-FU nanoparticles behaved similarly to PBCA-5- FU. The Np of PCL-5-FU reached a maximum level of Rl% inhibition in relation to free 5-FU at the concentration of 0.1 mM for T84 (61.9%), 1 mM for HT-29 (27 , 5%), HCT-15 (69.3%) and CCD-18 (38.24%) and 0.03 mM for MC-38 (76.2%) (p <0.05) (Fig. 5 ).

Behavior of nanoparticles against p-qlicoproteína.

Our results show that our nanoparticles do not prevent this efflux pump from acting on 5-FU.

In vivo tumor growth inhibition with poly (butylcyanoacrylate) v ροΙΚε-caprolactone) nanoparticles loaded with 5-fluorouracil. Treatment with nanoparticles loaded with 5-FU in mice with induced colon tumors with a 45-day follow-up demonstrated a significant reduction in their volume (Fig. 6).

 - Thus, PBCA-5-FU is able to significantly reduce the volume of the tumor (p value <0.05) with respect to 5-FU from day 27 until the end of the experiment (Fig. 6). Specifically this reduction was 50.8% on day 45. The group of mice treated with PCL-5-FU also presented a significant reduction in tumor volume to compare with 5-FU (p value <0.05) since on day 27 until the last day of treatment (Fig. 6).

 - PCL-5-FU the result was even better with a 64.4% reduction in tumor volume on day 45 compared to 5-FU. PCL-5-FU achieves a greater significant reduction in tumor volume than PBCA-5-FU (p-value <0.05).

 -On the other hand, the groups of mice treated with PBCA and PCL nanoparticles without drugs, do not differ significantly with the control group, indicating that there is no in vivo toxicity of these nanoparticles.

Survival of the mice. Despite a considerable reduction in tumor volume, 5-FU fails to increase the likelihood of survival of mice treated with this drug compared to control mice and those treated with the nanoparticle without drug (Fig. 7). However, this does not happen with mice treated with nanoparticles that carry 5-FU.

 According to the log-rank test there are significant differences in survival times (p-value <0.05) between mice treated with PBCA-5-FU (Fig. 5) and PCL-5-FU (Fig. 7) and groups of control mice, treated with 5-FU and treated with drug-free nanoparticles. These groups showed no significant differences between survival times, even in the case of mice treated with 5-FU (p value> 0.05). This shows that, in addition to increasing the reduction in tumor volume, nanoparticles are also able to improve the survival of mice.

 Conclusion: The original development of two new nanoparticles of poly (butylcyanoacrylate) and poly (£ -caprolactone) that associated with the 5-FU agent have been demonstrated both in vitro and in vivo:

 1) Increase the antiproliferative activity of the drug by up to 61.9% by measuring the% RI - relative growth inhibition - in tumor cells derived from colon cancer and in relation to the 5-fluorouracil agent

 2) Reduce up to 50.8% the volume of colon cancer tumors developed in mice in relation to the activity of the 5-fluorouracil agent without nanoparticle.

 3) Significantly increase the survival time of mice with tumors in relation to treatment with that of the 5-fluorouracil agent without nanoparticle.

 4) The nanoparticles you develop do not show any toxicity.

Claims

one . - A polymeric nanoparticle obtainable by a process comprising: i) the dissolution of at least one or more biodegradable polymers, in an organic solvent, ii) the addition of the solution obtained in (i) on a mixture comprising an anti-solvent and a surfactant, to obtain a particle iii) the isolation of the obtained particle, where the active ingredient is incorporated by surface association on the nanoparticle obtained after stage (iii) or by association inside the polymer matrix during stage (i ). 2. - The polymeric nanoparticle according to the preceding claim, wherein the process further comprises an evaporation step of the organic solvent. 3. - The polymeric nanoparticle according to any of claims 1-2, wherein step (iii) is carried out by centrifugation. 4. The polymeric nanoparticle according to any of claims 1 -3, which further comprises a redispersion of the polymeric nanoparticle until the conductivity of the supernatant is less than or equal to 10 με / οηι. 5. The polymeric nanoparticle according to any of claims 1-4, wherein step (ii) is carried out sequentially. 6. The polymeric nanoparticle according to any of claims 1-5, wherein the antisolvent is water or water mixed with an organic solvent. 7. - The polymeric nanoparticle according to any one of claims 1-6, characterized in that the nanoparticle has an average particle size between 30 and 500 nm, more preferably between 30 and 999 nm, and even more preferably between 55 and 85 nm 8. - The polymeric nanoparticle according to claims 1-7, wherein the at least one biodegradable polymer is poly (butylcyanacrylate) or poly (e-caprolactone). 9. - The polymeric nanoparticle according to any one of claims 1-8, wherein the biodegradable poly (butylcyanoacrylate) polymer has a molecular weight of less than 10,000 Daltons, preferably between 3,000 and 100 Daltons, and even more preferably between 2,000 and 500 Daltons, and even more preferably it is about about 1,500 Daltons, or where the biodegradable polymer of poly (s-caprolactone) has a molecular weight of less than 100,000 Daltons, preferably between 5,000 and 45,000 Daltons, and even more preferably between 7 and 20,000 Daltons, and even more preferably it is about 10,000 Daltons. 10. - The polymeric nanoparticle according to any one of claims 1-9, comprising as biodegradable polymer 90% poly (butylcyanacrylate) or 75% poly (8-caprolactone). eleven . - The polymeric nanoparticle according to any of claims 1-10, which comprises at least one pyrimidine analogue as active ingredient. 12. - The polymeric nanoparticle according to any of claims 1 -1 1, wherein the poly (butylcyanoacrylate) and the pyrimidine analogue, or the poly (8-caprolactone) and the pyrimidine analogue are in a sufficient ratio to remain associated. 13. - The polymeric nanoparticle according to claim 12, wherein the ratio sufficient to remain associated with the poly (butylcyanoacrylate) and the pyrimidine analog is a ratio between 1000: 1 and 1: 100 p / p respectively, preferably it is a ratio between 5: 1 and 15: 1 p / p; or the ratio sufficient to remain associated with poly (8-caprolactone) and the pyrimidine analog is a ratio between 1000: 1 and 1: 100 p / p respectively, preferably it is a ratio between 2: 1 and 10: 1 p / p. 14. The polymeric nanoparticle according to any of claims 1-13, which comprises a% surfactant in a percentage between 0.2% and 5%. 15. - The nanoparticle according to any of claims 1-14, wherein the surfactant is selected from the list comprising: polysorbate 20, polysorbate 60, polysorbate 80, high or low molecular weight polyvinyl alcohol, polyvinyl pyrrolidone, phosphatidyl choline, lecithins, copolymers in amphiphilic blocks, poloxamers of different types, solutol HS15, sodium glycocholate, sodium taurocholate, sodium tauroglycocholate, sodium taurodeoxycholate, cholesteryl hemisuccinate and tyloxapol. 16. The polymeric nanoparticle according to any of claims 1-15, wherein the surfactant is an amphiphilic block copolymer. 17. The nanoparticle according to any of claims 1-16, wherein the surfactant is an amphiphilic block copolymer is a poloxamer. 18. - The nanoparticle according to any of claims 1-17, wherein the poloxamer is pluronic F68. 19. - The polymeric nanoparticle according to any one of claims 1-18, wherein the pyrimidine analog is selected from the list consisting of cytarabine, fluorouracil (5-fluorouracil or 5-FU), tegafur or ftorafur, carmofur, gemcitabine, capecitabine , azacitidine, decitabine, any of its salts, isomers, prodrugs, derivatives or corresponding analogs, and combinations thereof. 20. - The polymeric nanoparticle according to any of the preceding claims, wherein the pyrimidine analog is 5-fluorouracil (5-FU), or any of its salts, isomers, prodrugs, derivatives or the like. twenty-one . - The polymeric nanoparticle according to any of the preceding claims, which comprises 5-fluorouracil in a percentage between 0.1% and 25%. 22. - A composition comprising a nanoparticle according to any of claims 1-21. 23. The composition according to claim 22, further comprising a pharmaceutically acceptable excipient. 24. - The composition according to any of claims 22-23, which further comprises another active ingredient. 25. - The use of the pharmaceutical composition according to any of claims 22-24, in the preparation of a medicament. 26. - The use of the pharmaceutical composition according to any of claims 22-24, in the preparation of a medicament for the treatment of cancer. 27. - The use of the pharmaceutical composition according to the preceding claim, wherein the cancer is colon cancer. 28.- A method for the synthesis of a polymeric nanoparticle with an average size of less than 100 nm, preferably less than 75 nm, comprising one or more degradable polymers, one or more active ingredients and at least one surfactant, where the at least A biodegradable polymer is poly (butylcyanoacrylate) or ροΝ (ε-caprolactone) and where at least one active substance is a pyrimidine analogue, and which comprises: i) the dissolution of at least one or more biodegradable polymers, in an organic solvent, ii) the addition of the solution obtained in (i) on a mixture comprising an anti-solvent and a surfactant, to obtain a particle iii) the isolation of the particle obtained, where the active ingredient is incorporated by surface association on the nanoparticle obtained after step (iii) or by association inside the polymer matrix during step (i).