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    • 专利摘要:
    Method for the preparation of silica nanoparticles with pores that comprise a surfactant with inherent pharmacological activity. The present invention relates to a method for the preparation of siliceous nanoparticles with pores comprising a surfactant, wherein said surfactant comprises an ester or amide moiety which, upon hydrolysis, liberates I) a compound with pharmaceutical activity, or a salt thereof, and Ii) a compound comprising a carboxyl moiety, a hydroxymethyl moiety or an aminomethyl moiety linked to a hydrocarbon moiety comprising an aliphatic chain of between 7 and 23 carbon atoms, or a salt thereof, Where said method comprises mixing A) said surfactant; y B) at least one compound of the formula (b1) or (b2); y C) at least one compound of the formula si (or3)4. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2579000A1
    申请号:ES201530132
    申请日:2015-02-03
    公开日:2016-08-03
    发明作者:Rafael GARCÍA MUÑOZ；Victoria MORALES PÉREZ；Moisés BALABASQUER PEÑA
    申请人:Universidad Rey Juan Carlos；
    IPC主号:
    专利说明:

    METHOD FOR THE PREPARATION OF SILICAN NANOPARTICLES WITHPORES THAT UNDERSTAND A SURFACTANT WITH ACTIVITYINHERENT PHARMACOLOGICAL FIELD OF THE INVENTION
    The present invention relates to the fields of nanotechnology and pharmacology.
    Specifically, the present invention relates to a method for the preparation of siliceous nanoparticles with pores comprising a surfactant, wherein said surfactant when hydrolyzed, releases a compound with pharmaceutical activity. Furthermore, the present invention relates to the siliceous nanoparticles with pores comprising a surfactant that are obtained as a product of said process, and to the use of said siliceous nanoparticles for the treatment and / or prevention of a medical condition chosen from a disease, a damage, a disability, a disorder, a syndrome, an infection, or a behavior. Also, the present invention relates to a method for the release of the compound with pharmaceutical activity of said siliceous nanoparticles.
    Furthermore, the present invention relates to a pharmaceutical and / or nutraceutical composition comprising said siliceous nanoparticles, a process for the preparation of said composition and the use of said composition for the treatment and / or prevention of a medical condition chosen from a disease, a harm, a disability, a disorder, a syndrome, an infection, or a behavior. STATE OF THE TECHNIQUE
    A particular area of nanotechnology with biomedical / pharmaceutical applications focuses on mesostructured silica nanoparticles as matrices to be used therapeutically as drug carriers. These mesoporous silica materials are characterized by a high pore volume, a narrow distribution of pore sizes, a large surface area and relative ease of functionalization that allows most of the drugs used in clinical practice to be easily introduced into their pores [1-3]. Therefore, the active substance (drug or biologically active material) dissolves, adsorbs, traps
    or is encapsulated [4], and subsequently delivered to the body for a prolonged period of time in a controlled and continuous form of administration.
    The typical route to prepare ordered mesoporous silicas is based on the self-assembly of the inorganic precursor around surfactants as structure directing agents [5, 6]. In the state of the art, pharmaceutical compounds are adsorbed in the pore space that is free of surfactants after calcination or solvent extraction. However, due to the difficulties not only in emptying the entire pore space of the mesoporous surfactant silicas, but also in filling said released space, the percentage of the pore volume occupied with the pharmaceutical compounds is not maximized. In addition, in the case of extraction, residual surfactants may interfere with the supply of pharmaceutical compounds and / or be toxic.
    The state of the art focuses on the control of pore size, pore management, morphology of siliceous particles and, mainly, on the modification of mesoporous walls with functional groups to confer optical, electronic, magnetic and / or mechanical to silica, so that the kinetic release of adsorbed pharmaceutical molecules can be positively or negatively influenced [7-11]. Methods for releasing drugs based on molecular "nanomachines" such as nano-impellers or nano-valves and gate systems [12-17] are also described in the state of the art. However, in said systems the pharmaceutical compounds are adsorbed or partially trapped in the pores, or repelled from the pores, due to electrostatic interactions between said pharmaceutical compounds and the functional groups of the organic compounds comprised in the pores of the silica. . Therefore, neither the occupation of the pores, nor the release of pharmaceutical compounds from said pores, are maximized in said siliceous particles described in the state of the art.
    It is an object of the present invention to provide a method for the preparation of siliceous nanoparticles with pores comprising a surfactant, wherein said surfactant possesses an inherent pharmaceutical activity as a consequence of its composition and / or is a precursor of a compound that possesses a pharmaceutical activity, and where said siliceous nanoparticles comprise a mesoporous silica with a large surface area and a high pore volume, as well as greater robustness and greater stability under thermal and chemical conditions unlike other polymer matrix nanoparticles.
    Furthermore, it is an object of the present invention to provide a method for the preparation of siliceous nanoparticles with pores comprising a surfactant, wherein the occupation of the pores of said siliceous nanoparticles by said surfactant and therefore, by a compound that possesses a pharmaceutical activity 5 and / or a precursor of said compound is maximized. It is also the object of the present invention to simplify the method of preparing siliceous nanoparticles with pores that comprise a compound possessing a pharmaceutical activity and / or a precursor thereof. It is also the object of the present invention to provide a method for the preparation of siliceous nanoparticles with pores that
    10 comprise a surfactant, where the release of said surfactant, that is, of the compound that possesses pharmaceutical activity and / or the precursor of a compound that possesses pharmaceutical activity, from the pores of said siliceous nanoparticles, is maximized for optimal administration of the compound that possesses the pharmaceutical activity. 15 BRIEF DESCRIPTION OF THE INVENTION
    The present invention refers to a method for the preparation of siliceous nanoparticles with pores comprising a surfactant, wherein said surfactant comprises an ester or amide moiety which, when hydrolyzed, releases i) a compound with pharmaceutical activity, or a salt thereof, Y
    Ii) a compound comprising a carboxyl moiety, a hydroxymethyl moiety or an aminomethyl moiety bonded to a hydrocarbon moiety comprising an aliphatic chain of between 7 and 23 carbon atoms, or a salt thereof, wherein said method comprises mixing a) said surfactant; Y
    B) at least one compound of the formula (B1) or (B2) (R1O) (3-g) (OH) gSi- (CH2) hN (R2) (2-j) Hj (B1) [(R1O) (3-g) (OH) gSi- (CH2) hN (R2) (3-k) Hk] + [X] - (B2) where g is an integer between 0 and 3;
    30 h is an integer between 1 and 8; j is an integer between 0 and 2; k is an integer between 0 and 3; R1 is a hydrocarbon moiety comprising between 1 and 8 atoms of
    carbon, with the proviso that when g is a chosen integer of 0
    or 1, each R1 can be the same or different;
    R2 is a hydrocarbon moiety comprising between 1 and 8 atoms of
    carbon, with the proviso that when j is the integer 0 or when k
    it is an integer chosen from 0 or 1, each R2 can be the same or different;
    X is F, Cl, BroI; and c) at least one compound of the formula (C)
    Yes (OR3) 4 (C)
    where
    R3 is a hydrocarbon moiety comprising between 1 and 8 atoms of
    carbon, with the proviso that each R3 can be the same or different.
    Furthermore, the present invention refers to siliceous nanoparticles with pores comprising a surfactant, obtainable by the method of the present invention.
    The present invention also refers to a pharmaceutical and / or nutraceutical composition comprising the siliceous nanoparticles with pores comprising a surfactant, according to the present invention, and at least one excipient.
    Likewise, the present invention refers to siliceous nanoparticles with pores comprising a surfactant according to the present invention, and a pharmaceutical and / or nutraceutical composition according to the present invention, for the treatment and / or prevention of a medical condition chosen from a disease , a harm, a disability, a disorder, a syndrome, an infection, or a behavior.
    The present invention also discloses a process for the preparation of a pharmaceutical and / or nutraceutical composition according to the present invention, which comprises mixing a) siliceous nanoparticles with pores comprising a surfactant according to the
    present invention; and b) at least one excipient.
    Furthermore, the present invention refers to a method for the release of the compound with pharmaceutical activity which comprises treating the siliceous nanoparticles with pores comprising a surfactant according to the present invention, with a fluid, wherein said fluid comprises an esterase enzyme or an amidase enzyme. .
    Likewise, the present invention refers to a method for the production of surfactant-free siliceous nanoparticles comprising the release of a surfactant from the siliceous nanoparticles with pores that comprise it, which comprises subjecting the siliceous nanoparticles with pores comprising a
    5 surfactant, according to the present invention, to calcination at a temperature of at least 200 ° C under vacuum. DESCRIPTION OF THE FIGURES
    Figure 1. Synthesis of N-lauroyl-L-tryptophan from L-tryptophan and lauroyl chloride according to the method described in Example 1.
    Figure 2. Transmission electron microscopy images of the mesostructured siliceous nanoparticles of the present invention prepared according to the methods described in Example 2, wherein said siliceous nanoparticles were made from tetraethoxysilane, with 3-aminopropyltrimethoxysilane (3-aminopropyl trimethoxysilane, APS ) as co-agent director of the structure and A. N-capril-L-tryptophan, B. N-lauroil
    15 L-tryptophan, D. N-palmitoyl-L-tryptophan, and F. N-stearoyl-L-tryptophan, (managing agents of the structure), and with N-trimethoxysilylpropyl-N, N, Ntrimethylammonium chloride (N- trimethoxysilylpropyl-N, N, N-trimethylammonium chloride, TMAPS), as co-directing agent of the structure and C. N-lauroyl-L-tryptophan, and E. N-palmitoylL-tryptophan as surfactants (structure directing agents) . G and H for a
    On the other hand, I and J, on the other, show the scanning electron microscopy (SEM) images of the MSN-2 and MSN-4 sample, respectively.
    Figure 3. Release profiles of different concentrations (mM) of (i) the surfactants of the corresponding mesostructured siliceous nanoparticles, MSN-2 and MSN-3, of the present invention with respect to time (days), in simulated body fluids ( SBF), specifically phosphate buffered saline (PBS) at a pH value of 7.4 and an aqueous solution of 0.1 M NaHCO3 at a pH value of 8.0, and (ii) surfactants of the corresponding mesostructured siliceous nanoparticles, MSN-4 and MSN-5, of the present invention with respect to time (days), in a simulated body fluid (SBF),
    30 specifically an aqueous solution of 0.1 M NaHCO3 at a pH value of 8.0. DETAILED DESCRIPTION OF THE INVENTION
    The present invention refers to a method for the preparation of siliceous nanoparticles with pores (ie, porous siliceous nanoparticles) comprising a surfactant. Said surfactant is a structure directing agent.
    5 of said siliceous nanoparticles with pores. Said surfactant comprises an ester or amide moiety which, when hydrolyzed, releases i) a compound with pharmaceutical activity and ii) a compound comprising a carboxyl moiety, a hydroxymethyl moiety or a
    aminomethyl moiety attached to a hydrocarbon moiety comprising an aliphatic chain of between 7 and 23 carbon atoms.
    Preferably, the hydrocarbon moiety comprises an aliphatic chain of between 9 and 19 carbon atoms, more preferably between 9 and 17 carbon atoms, of the Formula (H1):
    - (CH2) p- (CH = CH-CH2) q- (CH2) r-CH3 Formula (H1)
    15 where p is an integer between 1 and 16; q is an integer between 0 and 6; and r is an integer between 0 and 12. Even more preferably, (H1) is selected from –CH2 (CH2) 7-CH3, –CH2 (CH2) 9-CH3, –CH2 (CH2) 11-CH3, –CH2 ( CH2) 13-CH3, –CH2 (CH2) 15
    20 CH3, –CH2 (CH2) 6-CH = CH- (CH2) 3-CH3, –CH2 (CH2) 6-CH = CH- (CH2) 5-CH3, –CH2 (CH2) 3-CH = CH- (CH2) 8-CH3, –CH2 (CH2) 8-CH = CH- (CH2) 5-CH3, –CH2 (CH2) 6-CH = CH- (CH2) 7-CH3, –CH2 (CH2) 6- (CH = CH-CH2) 2- (CH2) 3-CH3, –CH2 (CH2) 4- (CH = CH-CH2) 3-CH3, - CH2 (CH2) 6- (CH = CH-CH2) 3- CH3, –CH2 (CH2) 3- (CH = CH-CH2) 3- (CH2) 3-CH3 or - CH2 (CH2) 3- (CH = CH-CH2) 4-CH3. Even more preferably, the rest
    A hydrocarbon comprising an aliphatic chain of between 9 and 17 carbon atoms is selected from a moiety of the Formula (H2) or a moiety of the Formula (H3)
    –CH2 (CH2) sCH3 Formula (H2) –CH2 (CH2) tCH = CH (CH2) vCH3 Formula (H3)
    30 where s is an integer between 7 and 15, t is an integer between 3 and 10 and v is an integer between 3 and 10. Even more preferably, (H2) is selected from - CH2 (CH2) 7-CH3, –CH2 (CH2) 9-CH3, –CH2 (CH2) 13-CH3 or –CH2 (CH2) 15-CH3, while (H3) is selected from –CH2 (CH2) 6-CH = CH- (CH2) 7- CH3. When the rest
    The hydrocarbon comprising an aliphatic chain of the present invention comprises a double bond, said double bond can be a cis-stereoisomer or a trans-stereoisomer.
    In one embodiment of the present invention, the surfactant is synthesized by esterification or amidation of the compound with pharmaceutical activity by a
    5 compound of the formula (G1), (G2) or (G3)HOOC – R4 Formula (G1)HOCH2 – R4 Formula (G2)HnN (R5) (2 - n) CH2 – R4 Formula (G3)
    where
    R4 is a hydrocarbon moiety comprising an aliphatic chain, as already described above, of between 7 and 23 carbon atoms; n is an integer chosen from 1 or 2; and R5 is a hydrocarbon moiety comprising between 1 and 8 carbon atoms. Thus, preferably, R4 is a hydrocarbon moiety comprising an aliphatic chain
    15 of between 9 and 19 carbon atoms, more preferably between 9 and 17 carbon atoms, of the Formula (H1), as already described above. Even more preferably, R4 is a hydrocarbon moiety comprising an aliphatic chain of between 9 and 17 carbon atoms selected from a moiety of the Formula (H2) or a moiety of the Formula (H3), as already described above. Yet
    More preferably, (G1) is selected from HOOC- (CH2) 8-CH3, HOOC- (CH2) 10-CH3, HOOC- (CH2) 14-CH3, HOOC- (CH2) 16-CH3 or HOOC- (CH2 ) 7-CH = CH- (CH2) 7-CH3, while (G2) is selected from HOCH2- (CH2) 8-CH3, HOCH2- (CH2) 10-CH3, HOCH2 (CH2) 14-CH3, HOCH2- ( CH2) 16-CH3 or HOCH2- (CH2) 7-CH = CH- (CH2) 7-CH3, and (G3) is selected from H2NCH2- (CH2) 8-CH3, H2NCH2- (CH2) 10-CH3, H2NCH2 - (CH2) 14-CH3,
    H2NCH2- (CH2) 16-CH3 or H2NCH2- (CH2) 7-CH = CH- (CH2) 7-CH3.
    In a much more preferred embodiment, said surfactant comprises an ester moiety
    or amide which, when hydrolyzed, releases i) a compound with pharmaceutical activity and ii) a compound of the formula (G6), a compound of the formula (G7), or a
    Compound of the formula (G8): HOOC- (CH2) d-CH3 Formula (G6) HOCH2- (CH2) d-CH3 Formula (G7) H2NCH2- (CH2) d-CH3 Formula (G8)
    where d is an integer between 8 and 16. Similarly, in said embodiment the surfactant is synthesized by esterification or amidation of the compound with pharmaceutical activity by a compound of the formula (G6), (G7) or (G8). More preferably, (G6) is selected from HOOC- (CH2) 8-CH3, HOOC- (CH2) 10-CH3, HOOC- (CH2) 14-CH3 or HOOC
    5 (CH2) 16-CH3, while (G7) is selected from HOCH2- (CH2) 8-CH3, HOCH2 (CH2) 10-CH3, HOCH2- (CH2) 14-CH3 or HOCH2- (CH2) 16-CH3 , and (G8) is selected from H2NCH2- (CH2) 8-CH3, H2NCH2- (CH2) 10-CH3, H2NCH2- (CH2) 14-CH3 or H2NCH2- (CH2) 16 -CH3.
    The method of the invention comprises mixing 10 a) the surfactant as already described above; Y
    b) at least one compound of the formula (B1) or (B2) (R1O) (3-g) (OH) gSi- (CH2) hN (R2) (2-j) Hj (B1) [(R1O) ( 3-g) (OH) gSi- (CH2) hN (R2) (3-k) Hk] + [X] - (B2)
    where
    15 g is an integer between 0 and 3; h is an integer between 1 and 8; j is an integer between 0 and 2; k is an integer between 0 and 3; R1 is a hydrocarbon moiety comprising between 1 and 8 atoms of
    20 carbon, with the proviso that when g is an integer chosen from 0 or 1, each R1 can be the same or different; R2 is a hydrocarbon moiety comprising between 1 and 8 carbon atoms, with the proviso that when j is the integer 0 or when k is an integer chosen from 0 or 1, each R2 may be the same or different;
    Xes F, Cl, BroI; and c) at least one compound of the formula (C)
    Si (OR3) 4 (C) where R3 is a hydrocarbon residue comprising between 1 and 8 atoms of
    30 carbon, with the proviso that each R3 can be the same or different.
    The compound of the formula (B1) or (B2) is a co-directing agent for the structure of siliceous nanoparticles. Preferably, in the compound of the formula (B1) or (B2): g is 0; h is an integer between 2 and 6; j is 2; k is 3; R1 is a methyl, ethyl, propyl, butyl, phenyl or benzyl moiety, and all R1 moieties are the same; R2 is a methyl, ethyl, propyl or butyl moiety, and all R2 moieties are the same; and X is Cl or Br. More
    preferably, the compound of the formula (B1) is selected from (R1O) 3Si (CH2) h-NH2, (R1O) 3Si- (CH2) h-NH (CH3) or (R1O) 3Si- (CH2) hN (CH3 ) 2, where h is an integer between 2 and 6 and R1 is a methyl, ethyl or propyl moiety, while the compound of the formula (B2) is selected from [(R1O) 3Si- (CH2) hN (CH3) 3 ] + [X] -, [(R1O) 3Si- (CH2) h-NH (CH3) 2] + [X] -, [(R1O) 3Si- (CH2) hN (CH3) H2] + [X] - or [(R1O) 3Si- (CH2) h-NH3] + [X] -, where h is an integer between 2 and 6, R1 is a methyl, ethyl or propyl moiety, and X is Cl or Br. Still more preferably, the compound of the formula (B1) is selected from (CH3O) 3Si- (CH2) h-NH2, (CH3O) 3Si- (CH2) h-NH (CH3) or (CH3O) 3Si- (CH2) hN ( CH3) 2, where h is an integer between 2 and 6, and the compound of the formula (B2) is selected from [(CH3O) 3Si- (CH2) hN (CH3) 3] + [X] -, [( CH3O) 3Si (CH2) h-NH (CH3) 2] + [X] -, [(CH3O) 3Si- (CH2) hN (CH3) H2] + [X] - or [(CH3O) 3Si- (CH2) h-NH3] + [X] -, where h is an integer between 2 and 6, and X is Cl or Br. In one embodiment d In the present invention, the compound of the formula B1 is (R1O) 3Si- (CH2) h-NH2 and the compound of the formula B2 is [(R1O) 3Si- (CH2) hN (R2) 3] + [X] - where h is an integer between 2 and 6; R1 is a methyl, ethyl, propyl or butyl moiety; R2 is a methyl, ethyl, propyl or butyl moiety; and X is Cl or Br and where residues R1 are equal to each other, and residues R2 are equal to each other.
    Preferably, in the compound of the formula (C), R 3 is a hydrocarbon moiety comprising between 1 and 6 carbon atoms, more preferably between 1 and 4 carbon atoms. Even more preferable, the compound of the formula (C) is selected from Si (OCH3) 4, Si (OCH2CH3) 4, Si (OCH3) 1 (OCH2CH3) 3, Si (OCH3) 2 (OCH2CH3) 2, Si (OCH3 ) 3 (OCH2CH3) 1, Yes (OCH2CH2CH3) 4, Yes (OCH2CH2CH2CH3) 4, Yes [OCH (CH3) CH2CH3] 4, Yes [OCH2CH (CH3) 2] 4 or Yes [OC (CH3) 3] 4.
    In a preferred embodiment, the molar ratio compound (C): compound (B1) or (B2): surfactant is when the molar ratio of compound (C) is 10 to 20, the molar ratio of compound (B1) or (B2 ) is 0.5 to 2, and the molar ratio of surfactant is 0.5 to 2.0. Preferably, the molar ratio of compound (C) is 10 to 12, the molar ratio of compound (B1) or (B2) is 0.8 to 1.5, and the molar ratio of surfactant is 0.8 to 1.5
    The compound with pharmaceutical activity is a compound comprising at least one ionizable or ionic moiety and a hydroxy (-OH), amino (-NH2) and / or carboxyl (-COOH) moiety, or a salt thereof. In a preferred embodiment, said compound with pharmaceutical activity is an amino acid and / or a neurotransmitter, more preferably an L-amino acid and / or a monoamine neurotransmitter, wherein said
    amino acid and / or said neurotransmitter comprises at least one ionizable or ionic moiety and a hydroxy, amino and / or carboxyl moiety. The ionizable or ionic moiety can be ionized to generate a cationic moiety or an anionic moiety. Preferably, the ionizable or ionic moiety is a carboxylic acid, an amine, an imine, an azide, a nitrate, a nitro compound, a sulphonic acid, a sulfinic acid, a phosphonate, a phosphate, or a salt of any of these remains. More preferably, the ionizable or ionic moiety is a carboxylic acid, an amine, or a salt of any of these moieties. In addition, said compound with pharmaceutical activity is preferably a drug that meets these structural requirements and is administered in the long term, ie for at least two weeks. Even more preferably said compound with pharmaceutical activity is selected from Ltriptophan, 5-hydroxy-L-tryptophan, serotonin, 5-hydroxyindoleacetic acid, dopamine, norepinephrine, adrenaline, tyramine, tyrosine, levodopa, gamma-aminobutyric acid, glycine, glutamic acid, somatostatin, substance P, the regulated transcription protein of cocaine and amphetamine or an opioid peptide. Preferably said opioid peptide is selected from an endorphin (such as α-endorphin, β-endorphin, γendorphine, α-neo-endorphin or β-neo-endorphin), an enkephalin (such as Met-enkephalin
    or Leu-enkephalin), proopiomelanocortin, adrenorphine, amidorphine, leumorphine, dinorphine A, dinorphine B, endomorphine-1, endomorphine-2, opiorphine, spinorphine,
    20 hemorrhain-4 or valorine. Even more preferably said compound with pharmaceutical activity is selected from L-tryptophan, serotonin, dopamine, norepinephrine, tyrosine, levodopa, gamma-aminobutyric acid, endomorphine-1, endomorphine-2, Metencephalin or Leu-enkephalin; especially, even more preferably, said compound with pharmaceutical activity is selected from L-tryptophan or serotonin.
    Thus, the approach used in the present invention is based on the synthesis of surface active agents (surfactants) with a dual function. The first function is to act as structure directing agents (template), which allow to prepare well-ordered mesoporous siliceous nanoparticles with high surface area and pore volume, and with greater robustness and stability under thermal and chemical conditions, to
    30 difference from other nanoparticles. The second function is to possess an inherent pharmacological activity as a result of its synthesis from a compound with pharmaceutical activity. Thus, the design of the surfactants involves the association of a part of a compound with pharmaceutical activity with a hydrocarbon moiety through a covalent bond, as described above,
    35 that has a therapeutic effect once released in the body. Thus, the loading of conveniently modified drugs acts as a template that directs the mesostructure of the siliceous nanoparticles. Therefore, the porous siliceous system is fully occupied with the potential drug unlike the works described in the literature, in which the drug is adsorbed or partially trapped in the channels. In addition, the surfactant remains protected, as a precursor of the compound with pharmaceutical activity, in the pores of the siliceous nanoparticles until said surfactant is released more or less constantly and controlled over several weeks and even for several months. In fact, the release of the surfactant can be controlled depending on the length of the aliphatic chain, so the longer the aliphatic chain, the longer the release of the surfactant and, therefore, the release of the compound with pharmaceutical activity.
    Therefore, the present invention also relates to siliceous nanoparticles obtainable by the method of the present invention. Said siliceous nanoparticles have pores comprising a surfactant as already described above. Furthermore, for the purposes of the present invention, the term "nanoparticles" is defined as a particle with a dimension of at least between 1 and 1000 nm.
    Preferably, the siliceous nanoparticles of the invention have: a) a BET surface after calcination, of at least 200 ± 6 m2 / g, more preferably of at least 300 ± 9 m2 / g, still more preferably of at least 500 ± 15 m2 / g (to determine the textural properties of the materials, the nitrogen adsorption / desorption technique has been used at a constant temperature of 77 K. The subsequent mathematical treatment of the resulting isotherm allows estimating the different textural parameters. Nitrogen adsorption it was carried out in a Micromeritics TRISTAR 3000 equipment, after degassing the samples, keeping them under vacuum at a temperature of 300 ° C for 4 hours according to the method disclosed in [18]); b) an average pore diameter between 2 ± 0.06 and 6 ± 0.18 nm, more preferably between 3 ± 0.09 and 5 ± 0.15 nm (measured by the adsorption / desorption isotherms of N2 with a device TRISTAR 3000 according to the method disclosed in [19]); and c) an average pore volume between 0.3 ± 0.009 and 0.6 ± 0.018 cm3 / g (determined from adsorption-desorption isotherms of N2 with a TRISTAR 3000 equipment according to the method disclosed in [19]).
    In one embodiment, the proportion of surfactant in the siliceous nanoparticles obtainable by the method of the invention is between 20% to 50% by weight with respect to the silica, preferably between 30% to 40% by weight with Regarding silica.
    In a more preferred embodiment of the siliceous nanoparticles of the invention already described, the nanoparticles are in the form of spherical or ellipsoidal sheaths comprising transverse walls that go from end to end of the siliceous wall surrounding the sheath, where the nanoparticles are divided internally by walls with lamellar structure that separate the interior of the
    10 particles in different internal cavities (micropores and macropores, and above all, mesopores), and where the interior of the internal cavities comprises the surfactant. The walls provide stability to the material, like the beams of a house, and prevent the nanoparticles from collapsing. Additionally, the external walls of the siliceous nanoparticles, the walls with lamellar structure that form the
    15 inside the internal cavities of the siliceous nanoparticles, and said internal cavities of the siliceous nanoparticles can comprise the surfactant with inherent pharmacological activity. For the purposes of the present invention, the term "micropore" is defined as a pore with a dimension of up to 1.99 nm, the term "mesopore" as a pore with a dimension between 2.00 and 50 nm and the term
    20 "macropore" as a pore with a dimension of at least 51 nm, provided that a micropore, mesopore or macropore cannot exceed the maximum size of the nanoparticles of the invention.
    The present invention also relates to a pharmaceutical and / or nutraceutical composition comprising siliceous nanoparticles with pores comprising
    25 a surfactant, as described above, and at least one excipient. Likewise, the present invention relates to a process for the preparation of said pharmaceutical and / or nutraceutical composition, which comprises mixing a) said siliceous nanoparticles with pores comprising a surfactant; and b) said at least one excipient.
    The excipient can be selected from binders, fillers, disintegrators, lubricants, coaters, sweeteners, flavorings, colorants, transporters, antioxidants, compactors, stabilizers, etc. and combinations thereof. Likewise, the siliceous nanoparticles with pores comprising a surfactant, according to the invention, can be part of pharmaceutical or nutraceutical compositions, in
    35 combination with other active ingredients. In a preferred embodiment, the pharmaceutical and / or nutraceutical composition of the present invention comprises at least two different compounds of Formula I, described herein.
    The present invention also relates to siliceous nanoparticles with pores comprising a surfactant, and to a pharmaceutical and / or nutraceutical composition comprising said siliceous nanoparticles, for the treatment and / or prevention of a medical condition. Thus, for the purposes of the present invention, the term nutraceutical is defined as a compound that is ingested periodically as a food or as a food supplement and that serves to treat and / or prevent said medical condition. Said medical condition is a disease, a damage, a disability, a disorder, a syndrome, an infection, or a behavior. Thus, the pharmaceutical activity of the compound serves to treat and / or prevent a disease, a damage, a disability, a disorder, a syndrome, an infection, or a behavior. Preferably said medical condition is a medical condition that is related to an imbalance in the production of neurotransmitters (such as, for example, serotonin) and / or with an abnormal protein structure (and function). A non-exhaustive list of examples of such conditions includes: mental or nervous system diseases such as epilepsy, drug dependence, drug withdrawal syndrome, cognitive disorders, eating disorders (such as anorexia, bulimia) autism, anxiety disorders , 20 attention deficit disorder with hyperactivity, amnesia, sleep disorders (such as insomnia, narcolepsy), neuropsychiatric disorders (such as schizophrenia, Tourette's syndrome, bipolar disorder, depression, hallucination, obsessive disorder) compulsive), hypochondria, manias, pain, paranoia, phobias, psychosis, neurodegenerative diseases (such as, for example,
    25 Alzheimer's, Huntington or Parkinson's disease), stress (such as post-traumatic stress disorder); carcinoid syndrome, metabolic diseases (such as, for example, heart disease, obesity, consumption of excess carbohydrates, uremia); growth disorders (such as growth hormone deficiency).
    The present invention also relates to a method for the release of the compound with pharmaceutical activity, which comprises treating the siliceous nanoparticles with pores comprising a surfactant, as described above, with a fluid, wherein said fluid comprises an esterase enzyme or a Amidase enzyme Said fluid acts as a means to release the surfactant from the pores of
    35 siliceous nanoparticles by simple diffusion and / or capillary action, while
    said enzyme breaks the C-O or C-N covalent bond of the ester or surfactant amide respectively, to release the compound with pharmaceutical activity. Preferably, said fluid is a body fluid, such as bloodstream fluid, or a fluid within an organ, such as a pancreatic fluid comprising enzymes [20] such as trypsin, which could hydrolyze said ester or covalent bond of the amide that connects the hydrocarbon moiety with the moiety belonging to the compound with pharmaceutical activity. More preferably, said fluid is a body fluid.
    Similarly, the present invention relates to a method for the release of siliceous nanoparticles from a surfactant, which comprises subjecting siliceous nanoparticles with pores comprising a surfactant, according to claim 5 of the present invention, to calcining using a temperature at least 500 ° C under vacuum. Preferably, the calcination is carried out at a temperature of at least 550 ° C under vacuum. Optionally, the siliceous nanoparticles with pores comprising a surfactant may be dispersed in a fluid for at least one month before drying and subjected to such calcination.
    The siliceous nanoparticles obtained by said method are released from the surfactant. Preferably, said siliceous nanoparticles comprise less than 5% by weight (5 wt.%) Of said surfactant, more preferably less than 1% by weight (1 wt.%) Of said surfactant, still more preferably less than 0.1% in weight (0.1 wt.%) of said surfactant, with respect to the total weight of said siliceous nanoparticles once subjected to calcination. The novelty of the nanoparticles resides in the transverse walls that go from end to end of the siliceous wall that surrounds the sheath. Thus, nanoparticles in the form of spherical sheaths (described in bibliography) or ellipsoidal are internally divided by porous walls with lamellar-like structure that separate the interior of the particles into different internal cavities. The cavities are separated by transverse walls that prevent the structures from collapsing.
    Finally, the present invention refers to a method for the treatment and / or prevention of a medical condition chosen from a disease, a damage, a disability, a disorder, a syndrome, an infection or a behavior, in humans and animals, which It comprises administering to the patient a therapeutically effective amount of siliceous nanoparticles with pores comprising a surfactant according to the present invention. Furthermore, the present invention refers to a method for the treatment and / or prevention of a medical condition chosen from a disease, a damage, a disability, a disorder, a syndrome, an infection or a behavior, in humans and animals, which comprises administering to the patient a therapeutically effective amount of the siliceous nanoparticles with pores comprising a surfactant of the present invention, as described above. For the purposes of the present invention, "therapeutically effective amount" is understood as that which reverses a disease, a damage, a disability, a disorder, a syndrome, an infection or a behavior without showing adverse side effects or, if produced, these are acceptable based on the criteria defined by the regulatory agencies in pharmaceutical matters.
    The administration of the siliceous nanoparticles with pores comprising a surfactant according to the present invention, can be carried out by any route such as, for example: enteral route (through the digestive system), oral route (by pills, capsules, granules, emulsions , tablets or syrups), rectal (through suppositories or enemas), topical (through creams or patches), inhalation, parenteral, intravenous, intramuscular or subcutaneous, as indicated above or by any pharmaceutically acceptable form . The siliceous nanoparticles with pores comprising a surfactant described in the present invention, also have the ability to be administered orally, intraperitoneally, intravenously, subcutaneously or topically, lacking apparent side effects at nutraceutical or pharmaceutical doses. EXAMPLES
    The amino acid L-tryptophan was chosen as a compound model with pharmaceutical activity. L-Tryptophan, as a precursor of serotonin, contributes to mental balance and has positive effects on well-being, and therefore is essential for the human body.
    Example 1: Method to exemplify the synthesis of surfactants.
    The preparation of a surfactant (structure directing agent) was carried out by amidation of L-tryptophan as a model of compound with pharmaceutical activity, with lauroyl chloride, a chloride of a carboxylic acid, giving rise to the corresponding amide, N-lauroyl -L-tryptophan, shown in Figure 1.
    The L-tryptophan (10.0 mmol) was resuspended in 12.0 mL of a mixture of 5.0 mL of water and 7.0 mL of 1,4-dioxane and sodium hydroxide (20.0 mmol) was added to dissolution. While the solution was maintained at 0 ° C, sodium hydroxide (15.0 mmol) dissolved in 2.0 mL of water, and lauroyl chloride (10.0 mmol) were added simultaneously dropwise, mixing continuously for approximately 10 minutes. Mixing was continued at 0 ° C for 2 hours. Then, water and hydrochloric acid (6M) were added to the mixture until the pH was adjusted to 1. The acidified aqueous phase was extracted with diethyl ether, and the organic phases, once combined, washed with water. The solvent was evaporated in vacuo to provide the crude product.
    Example 2: Methods to exemplify the synthesis of siliceous nanoparticles with porosity of meso-macroscopic type.
    In the following examples, the positively charged amino or ammonium moiety of the co-directing agents of the structure, 3-aminopropyltrimethoxysilane (3-aminopropyl trimethoxysilane, APS) and N-trimethoxysilylpropyl-N, N, N-trimethylammonium chloride, ( N-trimethoxysilylpropyl-N, N, N-trimethylammonium chloride, TMAPS) interacts electrostatically with the rest of the surfactant (the head) to form micelles. Subsequently, the source of silica, tetraethoxysilane (tetraethoxylsilane, TEOS), condenses around these micelles to form an inorganic silica mesh [21
    - 2. 3].
    i) Example of the synthesis of siliceous nanoparticles with APS as co-agent for the structure.
    The surfactant (1 mmol) was dispersed in deionized water to obtain a concentration of 1% by weight (1 wt.%) Under stirring at 80 ° C overnight. The mixture was cooled to 60 ° C before adding APS (1.65 mmol). 5 minutes later TEOS (11.8 mmol) was added and the silica gel resulting from the solution was mixed for 10 minutes at 60 ° C. The reaction gel was maintained without stirring at 60 ° C for 1 day and at 100 ° C for another 3 days. The precipitate was filtered, washed with water and dried to provide the siliceous nanoparticles.
    ii) Example of the synthesis of siliceous nanoparticles with TMAPS as co-director of the structure.
    The surfactant (1 mmol) was dispersed in deionized water to obtain a concentration of 1% by weight (1 wt.%). The mixture was heated to 70 ° C and NaOH (1mmol) was added. A mixture of TMAPS [50% by weight (50 wt.%) In methanol, 1 mmol] and TEOS (15 mmol) was then added and stirred to obtain a gel with a molar ratio of TEOS / TMAPS / surfactant / H2O from 15: 1: 1: 2153. After 10 minutes, stirring was stopped and the mixture was aged at 70 ° C for 2 days. He
    The precipitate was filtered, washed with water (100 mL) and dried overnight at room temperature, to provide the siliceous nanoparticles.
    Example 3: Characterization of siliceous nanoparticles with a porosity of the meso-macroscopic type.
    The periodic structure of inorganic silica meshes was determined by
    10 X-ray diffraction. X-ray diffraction patterns (XRD) were obtained by using a Philips X´PERT MPD diffractometer equipped with Cu Kα radiation. Before and after calcination, well resolved peaks were observed around 2θ = 1.5 to 2 °. These peaks correspond to the reflection of the basal plane d100 based on a two-dimensional hexagonal unit cell of
    15 p6mm symmetry confirming the formation of highly mesostructured nanoparticles.
    The textural properties of the calcined mesoporous siliceous nanoparticles (ie, those that do not comprise the surfactant) and uncalcined (ie, those comprising the surfactant) were obtained by adsorption isotherms20 desorption of N2 at –196 ° C. The calcined samples were measured with a Micromeritics TRISTAR 3000 instrument. Previously, the samples were degassed at 300 ° C. These measurements allowed determining the BET surface areas (Brunauer-Emmett-Teller), the pore size distribution, and the values of the total pore volume, which are summarized in Table 1. The BET surface areas were calculated
    25 applying the Brunauer-Emmet-Teller equation (BET). A cylindrical geometry of the pores was assumed for the calculation of the size distribution of the mesopores using the BJH model.
    Table 1. Textural properties of mesoporous siliceous nanoparticles (NP) obtained according to the methods of Example 2 with an L-tryptophan N-amide as a surfactant and APS or TMAPS as a co-directing agent of the structure.
    NP N-Amido ofAgentArea ofDiameterVolume
    L-tryptophan co-director of the structureBET surface (m2 / g)pore medium (nm)pore medium (cm3 / g)
    MSN-1 goatAPS3953.90.38
    MSN-2 lauroilAPS2553.90.29
    MSN-3 lauroilTMAPS5433.00.48
    MSN-4 palmitoilAPS1544.40.15
    MSN-5 palmitoilTMAPS2913.00.30
    MSN-6 stearoilAPS3473.70.44
    MSN-7 oleoylAPS3673.90.39
    5 The adsorption-desorption curves of N2 are found in the group of type IV isotherms, according to the IUPAC classification, typical of mesoporous solids. The slope detected in the adsorption branch around P / P0 = 0.5 corresponding to the capillary condensation of nitrogen in uniform pores, provides evidence for the formation of mesostructured solid materials. This
    The conclusion is based on the narrow distribution of the pore size detected in these materials. The BET surface area and pore volume increase as the hydrocarbon residue decreases, while the pore diameter decreases with the same factor. As for the co-directing agents of the structure, the use of TMAPS instead of APS increases the volume of the pores
    15 and the BET surface, and the pore diameter decreases.
    Transmission electron microscopy (TEM) images were obtained with a PHILIPS TECHNAI 20 to 200 kV microscope. The samples were sprayed, dispersed in acetone, and deposited on a copper grid covered in coal. In Figure 2, the TEM images reveal that these materials are mainly spherical in shape, with a range of outside diameters of 100 to 600 nm. Figure 2 also shows the TEM images obtained for the synthesized materials using different combinations of a surfactant (L-tryptophan Namido) as the structure directing agent and a structure directing co-agent. You can see the mesoporous structures obtained with these 25 materials, where spherical nanoparticles are internally divided
    porous walls both vermiform and lamellar structure, which separate the interior of the particles in different cavities.
    When APS is used as a co-directing agent of the structure, the formation of silica of the "hollow sheath" type (hollow-shell) is induced. The formation mechanism can be explained as a consequence of an organic-in-water emulsification process (oil-in-water) that forms spontaneously. In the reaction medium, the hydrophobic surfactant, grouped in the form of micelles, and water form an interface, around which siliceous species condense.
    The 13C CP-MAS NMR spectra in solid state obtained for uncalcined NPs (i.e., comprising the surfactant and the co-directing agent of the structure) show a low screened chemical shift of approximately 171 ppm corresponding to quaternary carbons in the carbonyl groups of the synthesized amide, and constitutes the evidence that the surfactant acts as a template for the preparation of well-ordered mesostructured nanoparticles. The spectra also show different peaks in the most shielded chemical shift in a range of 5 to 10 ppm corresponding to the aliphatic carbons of the hydrocarbon moiety of the surfactant.
    Thus, a meso-structured and well-ordered silica with high surface areas and pore volume was obtained, from a new template. In addition, this template is constituted by a modified drug model (L-tryptophan) that can remain inside the cavities of the porous silica.
    Example 4: Compound release assay with in vitro pharmaceutical activity.
    The use of siliceous nanoparticles as a drug delivery vehicle was investigated. For this purpose, surfactant release experiments of Example 1 were carried out of the pores of the mesoporous silica nanoparticles of the invention.
    In vitro tests for the release of compounds with pharmaceutical activity were carried out, using sterilized dialysis bags with a molecular weight limit of 10,000 Da of the dialyzer. Samples of siliceous nanoparticles with a porosity of the meso-macroscopic type comprising a surfactant within said pores (0.1 g), were dispersed in release media (2 mL), and then the solutions were placed in dialysis bags pre-treated PBS was used
    (phosphate-buffered saline, phosphate buffered saline) at pH 7.4 and a 0.1 M aqueous solution of NaHCO3 pH 8.0 to simulate body fluids (simulated body fluids, SBF). The dialysis bags, once sealed, were placed in flasks and the release medium (100 mL) was added. These conveniently capped flasks 5 were shaken at a speed of 100 rpm at 37 ° C. At determined time intervals, 1 mL samples were taken from the release media to measure the concentration of the surfactant released by the UV-vis absorption technique. Once measured, the samples were returned to the corresponding release media in each flask. The concentration of the surfactant of Example 1 (N-lauroyl-L10 tryptophan) charged to the siliceous mesoporous nanoparticles MSN-2 and MSN-3 respectively prepared according to Example 2 i) (APS) and 2 ii) (TMAPS) was plotted against release time, at pH 7.4 and pH 8.0, as shown in Figure 3. Figure 3 also shows the concentration of N-palmitoyl-L-tryptophan loaded in the siliceous mesoporous nanoparticles MSN-4 and MSN -5
    Respectively prepared according to Example 2 i) (APS) and 2 ii) (TMAPS) against the release time, at pH 8.0.
    The release of the surfactant occurs continuously and progressively over time, and depending on the length of the corresponding fatty acid chain, and the pH used, the release time extends from 1 to 20 months. In no case is the typical immediate release of the drug that occurs when it is found on the outer surface of the siliceous materials. At pH 8.0 the release is faster than at pH 7.4. In addition, the more carbon atoms the aliphatic chain of the hydrocarbon moiety of the surfactant comprises, the more slowly said surfactant is released. These results indicate that it is possible
    25 lengthen or reduce the release time of drugs, improving the control of their administration.
    These drug vehicles have important advantages over the state of the art, because the template that directs the mesostructure of the siliceous nanoparticles, and therefore completely fills the porous structure of said
    30 nanoparticles, is at the same time the pharmacological active substance or a precursor thereof, which will be released in the body for several weeks. REFERENCES
    1. T. Kresge, M.E. Leonowicz, W.J. Roth, J.C. Vartuli, J.S. Beck; Nature 1992, 359, 710-712.
    2. D. Zhao, Q. Huo, J. Feng, B. F. Chmelka, G. D. Stucky; J. Am. Chem. Soc. 5 1998, 120, 6024-6036.
    3. J. Y. Ying, C. P. Mehnert, M. S. Wong; Angew Chem., Int. Ed. 1999, 38, 56 -
    77.
    4. J. Kreuter; in Encyclopedia of Pharmaceutical Technology; Marcel Dekker: New York, 1994; pp. 165.
    10 5. US2010008990.
    6. US2002197206.
    7. M. Vallet-Regi, F. Balas, D. Arcos; Angew Chem., Int. Ed. 2007, 46, 7548-7558.
    8. C.-H. Lee, L.-W. Lo, C.-Y. Mou, C.-S. Yang; Adv. Funct. Mater. 2008, 18, 15 3283-3292.
    9. M. Liong, S. Angelos, E. Choi, K. Patel, J.F. Stoddart, J.I. Zink; J. Mater. Chem .; 2009, 19, 6251-6257.
    10. S. Angelos, E. Choi, F. Vogtle, L. DeCola, J. I. Zink; J. Phys. Chem. C 2007, 111, 6589-6592.
    20 11. S. Saha, K.C.F. Leung, T.D. Nguyen, J.F. Stoddart, J.I. Zink; Adv. Funct. Mater. 2007, 17, 685-693.
    12. J. Zhang, D. Desai, J.M. Rosenholm; Adv. Funct. Mater. 2014, 24, 2352-2360.
    13. J. Lu, E. Choi, F. Tamanoi, J.I. Zink; Small 2008, 4, 421-426
    25 14. T.D. Nguyen, K.C.F. Leung, M. Liong, C.D. Pentecost, J.F. Stoddart, J.I. Zink; Org. Lett. 2006, 8, 3363-3366.
    15. C. Park, K. Oh, S.C. Lee, C. Kim; Angew Chem., Int. Ed. 2007, 46, 1455-1457.
    16. Q. Yang, S. Wang, P. Fan, L. Wang, Y. Di, K. Lin, F.-S. Xiao; Chem. Mater. 30 2005, 17, 5999-6003.
    17. R. Casasus, M.D. Marcos, R. Martinez-Manez, J.V. Ros-Lis, J. Soto,
    THE. Villaescusa, P. Amoros, D. Beltran, C. Guillem, J. Latorre; J. Am. Chem. Soc. 2004, 126, 8612-8616.
    18. S. Brunauer, P.H. Emmett, E., Teller, J. Am. Chem. Soc. 1938, 60, 309.
    35 19. E.P. Barrett, L.G. Joyner, P.P. Halenda, J. Am. Chem. Soc. 1951, 73, 373. 20 J.A. Saez, B. Escuder, J.F. Miravet; Tetrahedron 2010, 66, 2614-2618.
    twenty-one. S. Che, Z. Liu, T. Ohsuna, K. Sakamoto, O. Terasaki, T. Tatsumi; Nature 2004, 429, 281-284.
    22 H. Qiu, Y. Inoue, S. Che; Angew Chem. Int. Ed. 2009, 48, 3069-3072.
    40 23. A.E. Garcia-Bennett, N. Kupferschmidt, Y. Sakamoto, S. Che, O. Terasaki; Angew Chem. Int. Ed. 2005, 44, 5317-5322.
    权利要求:
    Claims (13)
    [1]
    1. Method for the preparation of siliceous nanoparticles with pores comprising a surfactant, wherein said surfactant comprises a moiety
    5 ester or amide which, when hydrolyzed, releases i) a compound with pharmaceutical activity, or a salt thereof, and ii) a compound comprising a carboxyl moiety, a moiety
    hydroxymethyl or an aminomethyl moiety attached to a hydrocarbon moiety comprising an aliphatic chain of between 7 and 23 atoms of
    Carbon, or a salt thereof, wherein said method comprises mixing a) said surfactant; and b) at least one compound of the formula (B1) or (B2)
    (R1O) (3 - g) (OH) gSi- (CH2) h-N (R2) (2 - j) Hj (B1)
    [[R1O] (3-g) (OH) gSi- (CH2) h-N (R2) (3-k) Hk] + [X] - (B2) where g is an integer between 0 and 3; h is an integer between 1 and 8; j is an integer between 0 and 2;
    20 k is an integer between 0 and 3; R1 is a hydrocarbon moiety comprising between 1 and 8 carbon atoms, with the proviso that when g is an integer chosen from 0 or 1, each R1 may be the same or different; R2 is a hydrocarbon moiety comprising between 1 and 8 atoms of
    Carbon, with the proviso that when j is the integer number 0, or when k is an integer chosen from 0 or 1, each R2 may be the same or different; X is F, Cl, BroI; and
    c) at least one compound of the formula (C)
    30 Si (OR3) 4 (C) where R3 is a hydrocarbon moiety comprising between 1 and 8 carbon atoms, with the proviso that each R3 can be the same or different.
    [2]
    2. The method according to claim 1, wherein the surfactant is synthesized by esterification or amidation of the compound with pharmaceutical activity by a compound of the formula (G1), (G2) or (G3)
    HOOC – R4 (G1)5 HO – R4 (G2)
    HnN (R5) (2-n) -R4 (G3) where R4 is a hydrocarbon moiety comprising an aliphatic chain of between 7 and 23 carbon atoms;
    10 n is an integer chosen from 1 or 2; and R5 is a hydrocarbon moiety comprising between 1 and 8 carbon atoms.
    [3]
    3. The method according to any of claims 1 or 2, wherein the
    The compound with pharmaceutical activity comprises at least one ionizable or ionic moiety and a hydroxy, amino and / or carboxyl moiety.
    [4]
    4. The method according to any one of claims 1 to 3, wherein the compound of the formula B1 is 20 (R1O) 3Si- (CH2) h-NH2 (B1) and the compound of the formula B2 is
    [(R1O) 3Si- (CH2) h-N (R2) 3] + [X] - (B2) where h is an integer between 2 and 6; R1 is a methyl, ethyl, propyl moiety
    or butyl; R2 is a methyl, ethyl, propyl or butyl moiety; and X is Cl or Br and where 25 each remainder R1 is equal and each remainder R2 is equal.
    [5]
    5. Siliceous nanoparticles with pores comprising a surfactant, obtainable by the method of any of claims 1 to 4.
    6. Siliceous nanoparticles with pores comprising a surfactant according to claim 5, for the treatment and / or prevention of a medical condition chosen from a disease, a damage, a disability, a disorder, a syndrome, an infection, or a behavior.
    [7]
    7. Pharmaceutical and / or nutraceutical composition comprising siliceous nanoparticles with pores comprising a surfactant, according to any of claims 5 or 6, and at least one excipient.
    5. Pharmaceutical and / or nutraceutical composition according to claim 7, for the treatment and / or prevention of a medical condition chosen from a disease, a damage, a disability, a disorder, a syndrome, an infection or a behavior.
    9. Process for the preparation of a pharmaceutical and / or nutraceutical composition according to any one of claims 7 or 8, which comprises mixing a) siliceous nanoparticles with pores comprising a surfactant,
    according to any of claims 5 or 6; and 15 b) at least one excipient.
    [10]
    10. A method for the release of the compound with pharmaceutical activity comprising treating the siliceous nanoparticles with pores comprising a surfactant according to any of claims 5 or 6, with a fluid,
    20 wherein said fluid comprises an esterase enzyme or an amidase enzyme.

    Figure 1
    L-tryptophan
    1,4-dioxane NaOH, H2O lauroyl chloride 0 ° C, 2 hours
    N-lauroyl-L-tryptophan

    Figure 2
     Figure 3
    drug released(mmol drug)
    [0]
    0.5
    [0]
    0.4
    [0]
    0.3
    [0]
    0.2
    [0]
    0.1
    [0]
    0.0
    0 30 60 90 120 150 180 210 t (days)
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