• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    The present invention relates to an antimicrobial system comprising support particles functionalized with at least one antimicrobial compound of natural origin. The particles are preferably selected from the group consisting of mesoporous particles of silicon oxide with a particle size comprised between 0.01 and 7 μm and a pore size comprised between 1 and 20 nm, and amorphous silicon oxide particles with a particle size comprised between 0.01 and 30 μm, while the antimicrobial compound is preferably selected from the group consisting of carvacrol, cinnamaldehyde, perillaldehyde, eugenol, thymol, vanillin, gallic acid and ferulic acid. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2549685A1
    申请号:ES201531075
    申请日:2015-07-21
    公开日:2015-10-30
    发明作者:José Manuel BARAT BAVIERA；María Dolores Marcos Martínez；Ramón Martínez Mañez；Edgar PÉREZ ESTEVE；María RUIZ RICO；Félix Sancenón Galarza
    申请人:Universidad Politecnica de Valencia；
    IPC主号:
    专利说明:

    ANTIMICROBIAL SYSTEM
    Field of the Invention
    The present invention relates to the field ofantimicrobial compounds, and more specifically to systemsantimicrobials for the administration of saidcompounds.
    Background of the invention
    Plant metabolites such as compoundsessential oils and organic acids assets ofplant extracts show antimicrobial activitytested against various fungi and bacteria(“Antimicrobial gallic acid from Caesalpinia mimosoidesLamk. " Food Chemistry, 100 (3), 1044-1048, 2007; “Essentialoils in food preservation: mode of action, synergies, andinteractions with food matrix components ”. Frontiers inMicrobiology, 3, 2012). The use of these extracts, as well asof the active compounds thereof, as agentsantimicrobials in food, coatings and containers areHe has studied extensively in recent years (“Essentialoils: their antibacterial properties and potentialapplications in foods - a review ”. International journal offood microbiology, 94 (3), 223-253, 2004).
    The main limitations of the use of this type ofcompounds are their solubility, theirvolatility, as well as the modification oforganoleptic characteristics of food afterincorporation, mainly the strong smell that prevents itsuse at effective concentrations for the conservation offood.
    Recently it has begun to study theencapsulation of this type of particulate compounds
    mesoporous silicon oxide as a form ofalternative administration
    Mesoporous particles of silicon oxide, or PMS,they are considered in the literature as materialsbiocompatibles, as shown for example fromstudy conducted by Wehling et al. (“A critical study:Assessment of the effect of silica particles from 15 to 500nm on bacterial viability ”. Environmental Pollution, 176,292-299, 2013), in which the effect ofsilicon oxide particles with a size includedbetween 15 and 500 nm on bacterial viability. Theresults established that the particles did not showinhibitory properties regardless of their sizeparticle. Other investigations in which it has beenestablished the antibacterial effect of charged particlesthey also showed that the unloaded media did not haveinhibitory activity on the microorganisms studied.
    The load of antimicrobial compounds insideof the pores of the mesoporous oxide particles ofSilicon has been studied extensively. For example, in thearticle by Izquierdo-Barba et al. (“Incorporation ofantimicrobial compounds in mesoporous silica filmmonolith. " Biomaterials, 30 (29), 5729-5736, 2009), areencapsulated the LL-37 antimicrobial peptide, as well aschlorhexidine, in mesoporous silicon oxide and thecontrolled release thereof by anchoring–SH groups on the surface of silicon oxide. Bothcharged particles showed bactericidal activity againstto gram-positive and gram-negative bacteria, themost toxic chlorhexidine charged particles according tohemolysis assays, lactate dehydrogenase releaseand cell viability.
    On the other hand, nitroimidazole PA-824 was encapsulated, which
    has high antituberculous activity, in particlesmesoporous silicon oxide getting an improvement ofits solubility, and therefore, its bioavailability. WithoutHowever, the antibacterial activity of this compoundencapsulated was not greater than the effect produced by thefree compound. The absence of improvement in activity coulddue to difficulties during the release of PA-824from the mesoporous particles as a result ofmolecules that can interfere in the cellular environment(“Encapsulation of anti-tuberculosis drugs withinmesoporous silica and intracellular antibacterialactivities ” Nanomaterials, 4, 813-826, 2014).
    An example of compound encapsulationNatural antimicrobial plant extracts is theallyl isothiocyanate. This antibacterial compoundnatural could be used in food, but presentsproblems related to its volatility, spicy taste andpoor water solubility The encapsulation ofthis compound in mesoporous oxide particles ofsilicon and a controlled release of theallyl isothiocyanate modulated as a function ofpore size distribution. The propertiesantibacterials of said compound were maintained afteradsorption and desorption processes (“Controlled release ofallyl isothiocyanate for bacteria growth management ”. FoodControl, 23 (2), 478-484, 2012).
    However, although the encapsulation of compoundsactive inside mesoporous particlesprovides advantages for example in terms of releasecontrolled and sustained compound, these techniques do notThey are completely satisfactory. For example, adisadvantage presented by this type of technique is thatactive compounds, once released from the particles
    mesoporous, remain free in the environment and thereforethey have the same disadvantages as said compoundsadministered individually (for example, asto volatility, unpleasant taste, etc.). On the other hand,when the released compounds disperse in the environment, noa substantial concentration thereof is obtained inA specific area of interest. Additionally, theintroduction of the aforementioned compounds withinthe pores is not always possible due to relationships ofpolarity and ratio of pore and compound sizes. Byon the other hand the use of porous substances with large poresdiameter hinders its closure and therefore theeffective encapsulation of the added compound.
    In the case of administration to a patient (maybe a human being or be another animal species) byexample for the treatment of a disease, theactive compounds, once released, can be absorbed intoThe patient's organism. This prevents or reduces the actionof those compounds in later areas of the tractgastrointestinal, such as in the large intestine orin the blind
    Therefore, the need still exists in the artof an alternative antimicrobial system that allowsobtain a substantial concentration of an active compoundIn an area of interest. In addition, it would be desirable for theantimicrobial system allows masking and reducingless partially certain undesirable properties ofantimicrobial compounds (for example taste and smellunpleasant ...), for example in the case of applicationsfood
    Summary of the inventionTo solve the problems of the prior art and
    ensure property maintenanceantimicrobial, the present invention proposes anchorageof the antimicrobial compounds on the surface ofsupport particles.
    In the beginning, said anchorage or functionalizationcan greatly decrease antimicrobial activityof the antimicrobial compounds, since the groupsmore reactive functions, which are usuallyanchor to the solid, they are what give them their natureantimicrobial However, the inventors have discoverednow surprisingly that in certain groupsspecific antimicrobial compounds of originnaturally, there is no such decrease in activity atanchor them on a solid support, but it is observed thatthis activity is maintained or increased. Even in the case ofmaintain the same antimicrobial activity, the anchoring ofthe compounds on a solid support will provideadditional advantages such as odor masking andunpleasant flavors, for example.
    Thus, the present invention discloses a systemantimicrobial comprising support particlesassociated with at least one antimicrobial compound ofnatural origin According to the present invention, the compoundsantimicrobials are not loaded inside the pores ofsupport particles as is the case in the artprevious, but they are functionalized on the surface ofsaid particles. In this way, the compounds remainanchored to the support particles and are not released in themedium, which provides a number of advantages withregarding the antimicrobial systems of the techniqueprevious.
    Thus, since antimicrobial compounds are notrelease in the environment, properties are masked
    undesirable thereof such as smell and tasteunpleasant, its volatility is reduced, etc. Also giventhat these compounds do not disperse in the medium to which theysupply, its concentration increases at the site ofadministration of the particles and therefore theamount of said compounds to be provided forGet a given effect.
    On the other hand, when the compounds remainpermanently attached to the mesoporous particles, itprevents its absorption in the intestinal tract whenThey administer to a patient. This favors the action ofantimicrobial compounds in posterior areas of the tract
    gastrointestinal, suchhowheintestinethickor the
    blind.
    According arealizationfavoritefromthePresent
    invention, the support particles employed in theantimicrobial system are mesoporous oxide particlesof silicon with a particle size between
    0.01 and 7 ym and with a pore size between 1 and 20 nm.
    According to another embodiment of the invention, the support particles are amorphous silicon oxide particles with a particle size between 0.01 and 30 µm.
    On the other hand, according to a preferred embodiment of thepresent invention, the antimicrobial compound employed inthe antimicrobial system is selected from the groupconsisting of active compounds present in oilsvegetable essentials (for example, carvacrol,cinnamaldehyde, perillaldehyde, eugenol, thymol and vanillin)and organic acids present in the aqueous phase of extractsvegetables (for example, gallic acid and ferulic acid).
    Brief description of the figures
    The present invention will be better understood withReference to the following drawings.
    Figure 1 shows two bar graphs in whichL. innocua inhibition obtained withfree vanillin (control) and with functionalized vanillinon support particles, depending on theconcentration.
    Figure 2 shows two bar graphs in whichL. innocua inhibition obtained withfree carvacrol (control) and with functionalized carvacrolon support particles, depending on theconcentration.
    Figure 3 shows TEM photomicrographs ofultra-thin sections of L. innocua in the presence ofMCM-41 particles functionalized with active compounds.
    Detailed description of the preferred embodiments
    As mentioned earlier, thisinvention relates to an antimicrobial systemconsisting of functionalized support particles in itssurface with at least one antimicrobial compound ofnatural origin
    According to an embodiment of the present invention theantimicrobial system comprises support particlesfunctionalized with an antimicrobial compound of originNatural anchored on its surface.
    According to another embodiment of the present invention theantimicrobial system comprises support particlesfunctionalized with two or more antimicrobial compounds ofnatural origin different anchored on its surface, ofso that the system facilitates the simultaneous action of bothantimicrobial compounds
    According to a preferred embodiment, the particles of
    Support are mesoporous silicon oxide particles with a particle size between 0.01 and 7 µm, preferably between 0.1 and 1.5 µm; and a pore size between 1 and 20 nm, preferably between 2 and 8
    5 nm More preferably, the silicon oxide mesoporous particles are preferably selected from MCM-41, SBA-15 and UVM-7.
    According to another preferred embodiment, the support particles are amorphous silicon oxide particles with a particle size between 0.01 and 30 µm, preferably between 3 and 4 µm.
    On the other hand, the antimicrobial compound of originnatural functionalized on the support particles willpreferably select from compounds obtained from
    15 extracts of vegetable essential oils (for example, carvacrol, cinnamaldehyde, perillaldehyde, eugenol, thymol and vanillin) and of organic acids obtained in the aqueous phase of plant extracts (for example, gallic acid and ferulic acid). More preferably, the compound
    20 functionalized antimicrobial on the support particles is selected from the group consisting of carvacrol and vanillin.
    The following are illustrative, but not limiting, examples to facilitate understanding of the present invention.
    Examples Example 1: First, the functionalization of vanillin on MCM-41 mesoporous microparticles as well as its antimicrobial activity was studied. To do this, in vitro tests of
    bacterial viability of Listeria innocua againstmesoporous particles functionalized with vanillin as wellLike vanillin free. The survival of the microorganismin the absence of particles or active compound (controlpositive) was established as 100% of the population forCalculate survival in treated samples.
    For this, the different suspensions were preparedof particles or free vanillin in culture broth (brothsoya tryptone) to which the inoculum was addedmicrobial to get an initial population ofapproximately 106 CFU / mL. Said were incubatedsuspensions with orbital agitation (150 rpm) at 37 ° C for2 h. After this period, the planting of theserial dilutions in selective medium and incubation during48 h, with subsequent count of the forming units ofcolonies (CFU) and calculation of percent inhibition.
    In the attached figure 1 the percentages ofinhibition obtained with different concentrations offree vanillin (graphic on the left) and vanillinfunctionalized on MCM-41 particles (graph ofright) on Listeria innocua crops. As you canshown in figure 1, the antimicrobial activity ofvanillin is enhanced after anchorage to the support incomparison with the results of free vanillin. TheFree vanillin produces a total inhibition ofmicroorganism at a concentration of 4 mg / mL. But nevertheless,vanillin functionalization on MCM41 particles produces a reduction in inhibitory concentration,producing total inhibition at a concentration ofonly 2.5 mg / mL anchored vanillin.
    Indeed, the concentration of vanillin in asmall space thanks to the functionalization onMCM-41 particles greatly increases the capacity
    antimicrobial systems against the presence offree vanillin.
    Therefore, vanillin functionalization onMCM-41 particles almost halves the concentrationof active compound necessary to obtain an inhibition100% in a culture of L. innocua. In addition, saidfunctionalized support particles can be suspendedeasily in aqueous media thus improving solubilityof vanillin, and have little characteristic smellof the active compound.
    In the experiences a test ofinhibition of microorganisms bynon-functionalized particles, and noinhibitory effect
    Example 2:
    A study similar to that described in theExample 1 to determine the antimicrobial activity offunctionalized carvacrol on MCM-41 microparticles incomparison with free carvacrol.
    The attached figure 2 shows the percentages ofinhibition obtained with different concentrations offree carvacrol (graphic on the left) and carvacrolfunctionalized on MCM-41 particles (graph ofright) on Listeria innocua crops.
    As seen in Figure 2, the activityCarvacrol antimicrobial is maintained after anchorageon the silicon oxide microparticles thereofway as in the previous example.
    Similar results have been obtained as well.described above in examples 1 and 2 usingsupport particles of different sizes (data notshown).
    Example 3:
    A study was conducted using electron microscopyof transmission (TEM) on the possible mechanism of actionof functionalized antimicrobial compounds onsupport particles. Figure 3 presents the changesmorphological of L. innocua cells treated withMCM-41 functionalized particles.
    It can be seen that the treated cells havesevere damage to its morphology with membrane rupture andcell wall as well as loss of componentsintracellular These results confirm thatactive compounds functionalized on particles ofsupport have as their main target the outer envelopecell phone, just like when they appear in yourFree form.
    Example 4 (comparative example):
    Caprylic acid anchoring was studied onmesoporous particles of MCM-41. Caprylic acid is amedium chain fatty acid with proven activityantimicrobial against a broad spectrum ofmicroorganisms, but whose use is limited by the
    intense odortorancid.Byit,beraisedhow
    alternative heanchoredof theacidcaprilicon
    microparticles MCM-41withheobjectivefromkeepthe
    antimicrobial activity of fatty acid avoidingsensory rejection associated with its administration in formfree. Anchoring of fatty acid was carried out bythe reaction between the terminal carboxylic group thereof andthe amino group previously immobilized on the MCM41 support, obtaining a support with hydrocarbon chains withthe terminal methyl group. However, this mechanism of
    anchored greatly decreased the propertiesantimicrobials thereof, requiring large amountsof functionalized support to partially inhibit abacterial culture (results not shown).
    Therefore, it is shown that not all compoundsnaturally occurring antimicrobials have an activityenhanced antimicrobial through functionalizationon mesoporous particles disclosed hereininvention, as well as the functionalization methodused to anchor them is decisive forthe maintenance of its antimicrobial activity.
    Indeed, it is known that antimicrobial activityof said compounds is due to certain functional groupsin its molecular structure, and therefore, the modification ofsaid structure can modify the propertiesantimicrobial thereof. In particular, theactive essential oil compounds owe their activityantimicrobial the presence of free hydroxyl groups and theblocking these functional groups causes the loss ofinhibitory effect (“Antimicrobial activity of carvacrolrelated to its chemical structure ”. Letters in AppliedMicrobiology, 43 (2), 149-154, 2006).
    Example 5 (comparative example):
    However, the anchoring of caprylic acid onMCM-41 mesoporous particles according to the present invention,through a different functional group than the one used in thecomparative example 4, will provide an increase or atless maintenance of the activity of this compoundantimicrobial
    For the preparation of this material the route offunctionalization used consisted of a first step in thethat the inorganic support was functionalized with amino groups.
    In a second step, the amino groups were reactedwith succinic anhydride, producing materials with ahigh density of carboxylic acids on its surfaceexternal and finally the 8-hydroxycaprylic acid was anchored
    5 by an esterification reaction.
    The material obtained by this method presentedhydrocarbon chains with the terminal carboxylic groupon its surface. The tests performed showed thatsaid support maintained the antimicrobial activity of the acid
    10 caprylic in the same range as the free compound.
    权利要求:
    Claims (8)
    [1]
    one. Antimicrobial system consisting of particles ofsupport functionalized on its surface with at leastan antimicrobial compound of natural origin.
    [2]
    2. System according to claim 1, characterized bythat the antimicrobial compound is selected fromgroup consisting of carvacrol, cinnamaldehyde,perillaldehyde, eugenol, thymol, vanillin, acidgallic acid, caprylic acid and ferulic acid.
    [3]
    3. System according to claim 2, characterized bythat the antimicrobial compound is selected fromgroup consisting of carvacrol and vanillin.
    [4]
    Four. System according to any one of claims 1 to3, characterized in that the particles are selectedof the group consisting of mesoporous particles ofsilicon oxide with a particle size
    between 0.01 and 7 µm and a pore size between 1 and 20 nm, and amorphous silicon oxide particles with a particle size between 0.01 and 30 µm.
    [5]
    5. System according to claim 4, characterized bythat the particles are mesoporous oxide particlesof silicon with a particle size comprised
    between 0.1 and 1.5 m.
    [6]
    6. System according to any of claims 4 and5, characterized in that the particles are particlesmesoporous silicon oxide with a pore sizebetween 2 and 8 nm.
    [7]
    7. System according to any of claims 4 to6, characterized in that the particles are selectedof MCM-41, SBA-15 and UVM-7.
    [8]
    8. System according to any one of claims 1 to
    3, characterized in that the particles are amorphous silicon oxide particles with a particle size between 3 and 4 µm.
    Inhibition (%)
    A 100 B100
    90
    Inhibition (%)
    20 10
    10 0
    0 2 2.5 3 3.5 4 0.1 0.15 0.3 2.5 5
    Free vanillin (mg / mL) Anchored vanillin (mg / mL)
    FIG. one
    FIG. 3
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