Classifications

• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
  • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
  • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels

Definitions

• the present invention refers to a carrier system for weakly water soluble substances comprising (i) a lipid compound, (ii) a cosolvent and (iii) water, with the said system being a liquid constituted of a lyotropic phase in thermodynamic equilibrium, in the form of an L 3 -phase (sponge phase), obtained from stoichiometrically defined proportions.
• the invention also contemplates a process for obtaining the said carrier system for weakly water soluble substances, as well as its use as a carrier medium for weakly water soluble substances, such as pharmaceuticals, pesticides, herbicides, proteins, amino-acids, vitamins, antibiotics and similar substances for the preparation of compositions or as a template for the preparation of high-porosity nanoparticles.
• weakly water soluble substances such as pharmaceuticals, pesticides, herbicides, proteins, amino-acids, vitamins, antibiotics and similar substances for the preparation of compositions or as a template for the preparation of high-porosity nanoparticles.
• lyotropic structures formed when amphiphilic molecules, such as soaps, detergents and lipids, are exposed to water is currently well categorised with their phase diagrams being well known.
• the lyotropic character of the liquid crystal phases is provided by solvent molecules. This is due to the fact that such phases are not evenly distributed, typically being more numerous in one part of the phase than in others.
• micellar Lrphase in a low ⁇ aicohoi/ ⁇ surfactant ratio
• L ⁇ -phase at a higher ratio with the occurrence of the stability domain of the lamellar phase swollen with alcohol
• L 3 - phase characterised by being a narrow region.
• the detergent molecules in the diluted phase organise themselves as micelles, that grow in size and change form (giant micelles or cylindrical forms, depending on the counter-ion, chloride or bromide), with the cetylpyridinium chloride (CPCl) micelles remaining small and globular and the cetylpyridinium bromide (CPBr) micelles growing to form large flexible cylindrical forms.
• Swollen lamellas are formed by the progressive addition of water (termed the L ⁇ -phase) and, following the addition of more alcohol, a phase comes up exhibiting optical isotropy and low viscosity. It is in this phase termed the L 3 -phase that the Jardin group concentrated their efforts.
• DPPC dipalmitoil L-alpha-phosphatidylcholine
• SA stearylamine
• the structure of the DPPC vesicle was not affected by the addition of heparin, while the structure of the heparin/DPPC-SA complex proved to be different from that of the DPPC-SA vesicle.
• the authors of this work concluded that the interaction of heparin with vesicles depends on the nature of the amphiphilics. They also verified that heparin was solubilised in the organic solvent when made up into complexes with vesicles of DODAB or of DPPC-SA. Furthermore, the authors reached the conclusion that although the membranes of polyurethaneurea mixed with complexes of heparin/DODAB or heparin/DPPC-SA are highly non- thrombogenic, they are relatively cytotoxic.
• Short chain alcohols (methanol, ethanol, 1-propanol and 1 -butanol) were added to these vesicles as cosolvents in various concentrations, with these systems being systematically studied in relation to their effect on the stability of the resulting vesicles.
• Measurements by dynamic light scattering indicated that the vesicles formed from one of the IPAs (in other words, dodecyltrimethylammonium dodecyl sulphate) may be effectively stabilised through the addition of appropriate quantities of 1 -propanol and 1- butanol.
• Maximum life cycle times of over a year were observed and of 132 days for vesicles stable in solutions of 1-butanol at 5% and of 1-propanol at 15%, respectively.
• Luisi P. Another group currently dedicated to researching pre-formed vesicle systems is coordinated by Luisi P. (refer to Thomas CF.. Luisi P. L. "Novel properties of DDAB: Matrix effect and interaction with oleate", JOURNAL OF PHYSICAL CHEMISTRY B 108 (31): 11285-11290 (2004)), with their most recent study relating to the interaction of a positively charged surfactant DDAB (didodecyldimethylammonium bromide) with pre-formed vesicles from POPC (l-palmitoil-2-oleoyl-sn-glycero-3-phosphocholine).
• DDAB didodecyldimethylammonium bromide
• Vieira, D. B. and collaborators focussed on another application for surfactant aqueous emulsions.
• AMB amphotericin B
• DODAB dioctadecyldimethylammonium bromide
• miniemulsion Droplet Size Using Capillary Hydrodynamic
• patent US 6.251.416 describes a limpid uniphasic aqueous microemulsion of an agriculturally active pyretroid insecticide, where the said microemulsion is capable of releasing a great quantity of active substance and the concentrate of the microemulsion consisting of (weight ratio): (a) 0.015-4% of N-methylpirrolidone; (b) 0.005-2% of N- octylpyrrolidone; (c) 0.05-1.5% of a polymer surfactant in an ethoxylated/propoxylated (EO/PO) box; (d) 0.04-6% of ethoxylated castor oil or a tristyryl phenol ethoxylate, and (e) 0.0005-0.6% of a phosphate ester with a pH buffer.
• EO/PO ethoxylated/propoxylated
• Document US 6,469,084 describes a process for the preparation of an aqueous composition that acquires the form of a gel at a given temperature.
• the process is characterised by the fact of placing a water soluble associative polymer constituted of a main hydrophilic chain and hydrophobic lateral groups into contact with at least one surfactant in a bilayer form when it is in solution under the same conditions of temperature and concentration.
• the compositions in gel or liquid form comprise vesicles, and more particularly liposomes.
• the process provides the means of considerably varying the viscosity of an aqueous composition containing an associative polymer by means of introducing a surfactant into the composition and selecting the conditions in which this surfactant is in a bilayer form.
• Another important application of the liquid crystal phase is in particle coating.
• patent US 5,531,925 describes particles, especially colloidal particles, comprising (A) an interior phase of (1) a lyotropic non- lamellar liquid crystal phase selected from the group consisting of a reverse cubic liquid crystal phase and a reverse hexagonal liquid crystal phase or (2) a homogenous L 3 -phase or any combination of these, and (B) a surface phase (1) selected from the group consisting of a lamellar crystal phase and a lamellar liquid crystal phase, or (2) an L 3 -phase or any combination of the same, with the said surface phase and the said interior phase being distinct.
• A an interior phase of (1) a lyotropic non- lamellar liquid crystal phase selected from the group consisting of a reverse cubic liquid crystal phase and a reverse hexagonal liquid crystal phase or (2) a homogenous L 3 -phase or any combination of these
• B a surface phase (1) selected from the group consisting of a lamellar crystal phase and a lamellar liquid crystal phase, or (2) an L 3 -phase or any combination of the same
• these particles are appropriated as particles or systems for the delivery of pharmaceuticals and in other medical and non-medical applications and that the structure of L 3 is constituted of multi-connected bilayers forming a bicontinuous structure of high connectivity, which may be contemplated as a disordered counterpart compared to the cubic phases.
• patent US 6,482,517 describes a particle coated in a non-lamellar crystalline material including an internal matrix nucleus having at least one nano-structured liquid phase or a combination of the same for use in the delivery of active agents, such as medicines, nutrients, pesticides, etc. It is mentioned that the particles may be used to release one or more materials in an selected environment and that the L 3 -phase is considered as a bicontinuous phase, being similar to the cubic phase, but not having the long-spectrum order that is characteristic of the cubic phase.
• Non-lamellar such as a non-lamellar crystalline material, non-lamellar amorphous material or non-lamellar semi-crystalline material including an internal matrix nucleus having at least one nano-structured liquid phase or at least one nano-structured liquid crystal phase or a combination of both, to be used in the delivery of active agents, such as medicines, nutrients, pesticides, etc.
• the nano-structured matrix material may be: (a) a nano-structured L 1 -phase material, (b) a nano-structured L 2 -phase material, (c) a nano-structured micro- emulsion or (d) a nano-structured L 3 -phase material.
• the document does not mention the DODAB lipid as being a component of the L 3 -phase.
• Patent US 6,991 ,809 describes a particle comprising a first volume of hydrophobic domain rich material with adjustable dissolution and solubilisation characteristics and a second volume of a nano-structured non-lamellar crystalline material. It is mentioned that the nano-structured non-lamellar crystalline material is capable of remaining in equilibrium with a polar solvent or a water immiscible solvent or with both.
• Liquid crystal phases also find applications in obtaining ceramic materials with enhanced qualities.
• patent US 6,638,885 describes a mesoporous ceramic material with a pore size diameter in the range of approximately 10-100 nm produced in templates with a precursor ceramic as a lyotropic liquid crystal L 3 -phase consisting of a random three-dimensional non- periodic network of a multiply connected continuous membrane. It mentions that a preferred process produces a inesoporous ceramic material that involves the production of a lyotropic liquid crystal L 3 -phase template by the mixture of a surfactant, a co-surfactant and hydrochloric acid.
• This template is then coated with an inorganic ceramic precursor by adding tetramethoxysilane (TMOS) or tetraethoxysilane (TEOS) to the L 3 -phase which is followed by the conversion of the coated template to ceramic by the removal of any liquids.
• TMOS tetramethoxysilane
• TEOS tetraethoxysilane
• the L 3 -phase is a thermodynamically stable phase composed of the surfactant cetylpyridinium chloride (CpCl, mono-hydrated 1 - hexadecylpyridinium chloride, C 16 H 33 (N + )C 5 H 5 (Cr)-H 2 O); of the co-surfactant hexanol (C 6 H 13 OH, ca.
• the surfactants are selected from the group consisting of cetyltrimethylammonium bromide (CTAB), Brij 30.TM. (tetraethylene glycol monododecyl ether) and cetylpyridinium chloride (CPC).
• CTC cetyltrimethylammonium bromide
• the alcohols are moderately polar such as 1 -pentanol, 1 -hexanol, 1 -heptanol, 1 -octanol.
• the micelle are composed of a quaternary amine cation, for example, hexadecyltrimethylammonium (HDTMA) or octadecyltrimethylammonium (ODTMA); and the vesicles are composed of lipids with positive charges, for example, didodecyldimethylammonium bromide (DDAB) or dioctadecyldimethylammonium bromide (DDOB), wherein the micelle or vesicles containing the herbicide are in turn absorbed in a clay mineral having a negative charge.
• DDAB didodecyldimethylammonium bromide
• DDOB dioctadecyldimethylammonium bromide
• the stability and other desirable characteristics of carrier systems for weakly water soluble substances may be enhanced by establishing a relation between the lipid compound and the cosolvent for obtaining a stable lyotropic mixture being, preferentially, of low toxicity, that may be used as a vehicle for the active substance or as a template for depositing inorganic materials, that preferentially give origin to particulate surfaces, and more preferentially, nano-particles.
• the systems thus determined possess an improved capability for solubilising weakly water soluble compounds, such as pharmaceuticals, herbicides, fungicides and similar substances intending application through the compositions to which they are incorporated by delivery to a selected environment, such as an organism, the soil or the similar.
• a first embodiment of the present invention refers to a carrier system for weakly water soluble substances comprising (i) a lipid; (ii) a cosolvent and (iii) water, with the quantity of (ii) in relation to (ii) being determined stoichiometrically for the formation of an L 3 -phase.
• the lipid component may be natural or synthetic, provided it has a conformation that allows the thermodynamically stable accommodation of a weakly water soluble substance, being, preferentially, synthetic and selected from the group consisting of dioctadecyldimethylammonium bromide (DODAB) and dioctadeldimethylammoniun chloride (DODAC).
• the cosolvent component is an organic compound with a polar group selected from the group consisting of hydroxyl, cetone, carboxyl, ester, aldehyde and amide.
• the cosolvent is a hydroxylate compound, preferentially an alcohol with up to eight carbon atoms, more preferentially the alcohol is a straight chain mono-hydroxylate alcohol.
• the molar ratio between the lipid and the cosolvent varies between 1 :12 and 0.0 01 : 1.
• the preferred alcohols are 1-ethanol, 1-propanol, 1- butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, more preferentially, 1- butanol, 1-pentanol, 1-hexanol, 1 -heptanol, 1-octanol, and yet more preferentially, 1-pentanol.
• a second embodiment of the invention provides a process for obtaining a carrier system for weakly water soluble substances consisting of a lipid/cosolvent/water system, with the said process being characterised by comprising the stages of: (a) dispersing the lipid component in water at a concentration sufficient to form the L 3 -phase; (b) the careful addition of the cosolvent to the dispersion obtained in (a) in a quantity necessary for the formation of the L 3 -phase; (c) heating the mixture obtained in (b) to temperature T L3 for the time sufficient for the appearance of a transparent stable lyotropic phase with an L 3 -phase structure; and (d) cooling the mixture and letting it stand for sufficient time to attain equilibrium and the complete formation of the L 3 -phase corresponding to the carrier system for weakly water soluble substances of the present invention.
• the concentration of the lipid component for obtaining the L 3 -phase is of up to 10 mM, preferentially, of up to 5 mM.
• the concentration of the cosolvent is such that the molar ratio between the lipid and the cosolvent varies between 1 : 12 and 0.0 01 : 1.
• the temperature T L3 for heating the mixture for the formation of the L 3 -phase depends on the lipid used or, in other words, depends on its T m .
• the temperature does not exceed 70° C, more 5 preferentially, the heating temperature is 65° C and the lipid is DODAB or DODAC.
• a third embodiment of the invention refers to the use of the carrier system for weakly water soluble substances of the invention as a vehicle for pharmaceutical compositions, herbicides, insecticide compositions and the similar.
• a fourth embodiment of the invention refers to the use of the carrier system for weakly water soluble substances in the release of delivery of these substances in a selected environment, with such substances being selected from the group consisting of polymers, biological materials and mineral matter.
• a fifth embodiment of the invention refers to the use of the carrier 20. system for weakly water soluble substances of the invention in the covering of surfaces, preferentially with particles and more preferentially with nano- particles.
• Figure 1 shows, schematically, the L 3 -phase structure that is
• Figure 2 illustrates the definition of T L3 for the DODAB lipid.
• Figure 3 illustrates the formation of the isotropic phase formed DODAB and n-pentanol in a region of greater concentration (milky phase).
• (1) layer of cosolvent and
• (2) isotropic phase of surfactant and cosolvent, in a region of greater concentration.
• Figure 4 illustrates the sequential modification of the structures for the
• DODAB/n-pentanol/water system through the monitoring of this modification using differential scanning: (a) spectrum of the dispersion of DODAB in hot water; (b) spectrum of the mixed micelle of DODAB and n-pentanol and (c) L 3 - phase of the DODAB/n-pentanol/water system showing the bilayer signal.
• Figure 5 illustrates, in accordance with the invention, the graph-form representation of the calculation of the quantity of cosolvent (alcohol) for obtaining the L 3 -phase for the DODAB system (1.5 mM)/alcohol/water.
• Figure 6 illustrates the formation region of the L 3 -phase graphically, through absorbance measurement (measured at 450 nm), in accordance with the quantity of cosolvent (alcohol) for obtaining the L 3 -phase for the DODAB system (1.5 mM)/alcohol/water.
• Figure 7 shows the use of the carrier system for weakly water soluble substances in the solubilisation of amphotericin B.
• Lipid in the context of the invention, means a double-chain natural or synthetic organic compound, structured with a hydrophilic head and a hydrophobic tail, with the hydrophobic tail having a three-dimensional arrangement constituted of chains that define an expandable space to allow the thermodynamically stable accommodation of a weakly water soluble substance.
• Cosolvent Organic compounds having polar groups at not less than one of its extremities, which serve as “spacers” of the lipid chains.
• L 3 -Phase in the context of the invention, means a bicontinuous liquid crystal phase having an orientation order (nematic), optical isotropy of low viscosity (transparent), frequently termed "sponge phase”.
• L ⁇ and L 3 phases is induced by varying the temperature, salt concentration and the surfactant/cosurfactant ratio. This transition occurs in equilibrium between thermodinamically stable phases.
• temperature TL 3 is the temperature between 5 to 20° C above temperature T m (transition temperature of the lipid phase, from gel to liquid crystal) (see Figure
• DODAB DODAB
• thermodinamically stable in the context of this invention, means a system at the lowest possible energy state.
• micellar structures When dissolved in water. These structures include globules, cylindrical or discoid bodies, as well as vesicles (non-micellar structures). These primary structures may organise themselves on a macroscopic scale in a manner that the entire system may become organised even in diluted solutions containing approximately 1 % of surfactant.
• the morphology of the aggregates formed by the self-molding of the lipid molecules in solution and the evolution of this morphology with additives (cosolvents), such as medium chain alcohols, ketones, esters, and amides, is the physicochemical phenomenon that forms the basis of the present invention.
• the substances with surfactant activity in solution may result in systems with opposite characteristics.
• the systems are microemulsions containing much water, much oil and a moderate quantity of surfactant mixture (surfactant + cosolvent).
• surfactant + cosolvent a moderate quantity of surfactant mixture
• the hydrophilic and hydrophobic mediums have a symmetric role and are not submitted to local restrictions, with the exception of density restrictions.
• Such systems are separated by a surfactant film that has its own mechanical properties (for example, spontaneous curvature) and elastic resistance to extra folding and, furthermore, incorporate the majority of surfactant and cosolvent molecules.
• the lamellar L ⁇ -phase is a birefringent phase with an one-dimensional arrangement of bilayers stacked in esmetic order, or, in other words, a liquid crystal in which the molecules are ordered in parallel layers.
• the second consists of bilayers interconnected in the three dimensions and is known as the sponge phase (L 3 -phase).
• the present invention refers to obtaining this L 3 -phase from a mixture of lipid, cosolvent and water, in stoichiometrically defined proportions.
• the lipid used in the present invention is an amphiphilic substance capable of forming a thermodynamically stable sponge phase and possesses a three-dimensional arrangement constituted of chains that define an expandable space by means of the cosolvent action, to allow the thermodynamically stable accommodation of a weakly water soluble substance.
• the lipid is a synthetic substance, such as, for example, dioctadecyldimethylammonium bromide (DODAB) or dioctadecyldimethylammonium chloride (DODAC), which are both synthetic double-chain lipids having surfactant activity that allow the progressive addition of short and medium chain linear alcohols.
• DODAB dioctadecyldimethylammonium bromide
• DODAC dioctadecyldimethylammonium chloride
• the sponge phase is formed spontaneously without secondary aggregation in relation to time and remains in thermodynamic equilibrium.
• the L 3 -phase is important in the synthesis of new mesostructured inorganic materials that use lyotropic systems as templates, in the crystallisation of transmembrane proteins, in the transportation of pharmaceuticals and other bioactive molecules, in the coating of particles and especially nano-particles, amongst others.
• the system of the present invention was developed through the observation that when organic compounds containing polar groups, such as, for example, alcohols with two or more carbon atoms, enter into contact with a dispersion containing closed lipid vesicles, such as, for example, DODAB or DODAC, a white interface zone is formed in a few minutes as a result of the spontaneous transition of the bilayer vesicles (closed, unilamellar, translucid) into miniemulsions, with the said white (milky) interface zone consisting of an isotropic phase formed by the lipid (for example, DODAB) and by the cosolvent (for example, n-pentanol) in a region of greater concentration (refer to Figure 3). With heating and the correct lipid:cosolvent proportion, the intended L 3 -phase is formed.
• Figure 4 illustrates the sequential change of these structures.
• the cosolvent molecules appear to have two fundamental roles, namely:
• the organised insertion in the vesicle providing means for the expandability of the hydrophobic part of the lipid (for example, the two paraffinic long chains in the case of the DODAB molecule) and (2) filling up the inside of the two nanometric "drops" that compose the mixed micelles that occur in the region of greater concentration of the lipid (for example, DODAB).
• the closed vesicles with a broad size distribution (in the range of 700-1200 nm) transform themselves spontaneously through the addition of a cosolvent, into stable miniemulsions, with a narrow size distribution (of approximately 250 nm), stabilised by a positive charge.
• Microcalorimetric scanning data reveals the disappearance of the typical DODAB vesicle bilayer.
• the mixture of 1-pentanol (cosolvent) with pre-formed vesicles of 5mM DODAB (lipid) form a white intermediary phase (refer to Figure 3) which, when diluted in an adequate proportion, give origin to a thermodynamically stable isotropic phase.
• the DODAB compound (dioctadecyldimethylammonium bromide) is a synthetic double-chain lipid of a quaternary ammonium salt. Molecules of DODAB form vesicles when dispersed in water above the transition phase temperature T m (gelto liquid crystal) (refer to Figure 2). Since the T n , of the aqueous dispersion of DODAB is between 44.8 and 45.5° C, it is believed the DODAB vesicles are in a gel state when at room temperature.
• the cosolvents used in the present invention are organic compounds containing functional groups capable of interacting with the lipid to obtain the lyotropic phase, L 3 -phase or sponge phase of the invention.
• hydroxyl for example, alcohols containing at least two carbon atoms, preferably, between two and eight carbon atoms
• ketone for example, ketones C 2 -C 8
• carboxyl for example, carboxylic acids C 2 -C 8
• amide for example, amides C 2 -C 8
• ester for example, esters C 2 -C 8
• aldehyde for example, aldehydes C 2 -C 8
• the cosolvents used in the present invention are straight chain alcohols containing a hydroxyl at one extremity.
• the cosolvent of the ternary system of the present invention is selected from the group consisting of n-ethanol, n-propanol, n- butanol, n-pentanol, n-hexanol, n-heptanol ou n-octanol. Combined with the lipids, the cosolvents are capable of forming mixed micelles.
• the system comprises as the lipid, DODAB, as the cosolvent, a straight chain alcohol with 2 to 8 carbon atoms and water.
• DODAB lipidxosolvent
• Table 1 shows the compatibility of the values calculated and empirical for determining the maximum volume of alcohol for obtaining the L 3 -phase with a DODAB/alcohol/water system for a constant DODAB concentration of 1.5 mM. This accord may also be seen graphically in Figures 5 and 6.
• Table 1 Maximum quantity of alcohol added to the DODAB/water dispersion for obtaining the L 3 -phase, related to the carbon atoms of the alcohol.
• Vesicles or liposomes consist of closed bilayer lipids surrounding an aqueous nucleus and presenting themselves as folded membranes around three-dimensional structures, similar to micelle, but with two layers of molecules. Vesicles are formed by self-templating so as to protect the hydrophobic chains of water.
• DODAB vesicle system is an example of spontaneous vesiculation, or, in other words, the vesicles are formed by the simple addition of the lipid to water and heating above the transition phase temperature (T m ).
• the sponge phase is formed as a "fused" bilayer phase with each fusion occurring by means of narrowed bonds (refer to Figure 1).
• the transparency of the system occurs because these deformations are dynamic.
• An L ⁇ -phase is formed before each L 3 -phase.
• the sequence occurs: vesicles — » progressively smaller vesicles — > L ⁇ -phase, and — > finally, L 3 -phase.
• This modification of the structures may be monitored by analysis of differential scanning calorimetry (DSC), as illustrsted in Figure 4.
• DSC differential scanning calorimetry
• the transporter system of the present invention differs radically from all known systems, such as that of Benton and Miller (1983) who worked with anionic surfactants (in a surfactant/alcohol/water system) with concentrations of approximately 10% in weight.
• the concentration varies preferentially between 0.5 and 10 mM, which is the equivalent, in the case of the lipid being DODAB, to approximately 0.01 to 0.2% in weight. In other words, a concentration up to 100 times less, approximately. This difference is most important, especially when the carrier system for weakly water soluble substances is used for pharmaceutical compositions, in which the safety requirements with regard toxicity are extremely high.
• the carrier systems for weakly water soluble substances may be obtained by a process comprising the stages of: (a) dispersing the lipid component in water at a concentration sufficient to form the L 3 -phase; (b) the careful addition of the cosolvent to the dispersion obtained in (a) in a quantity necessary for the formation of the L 3 -phase; (c) heating the mixture obtained in (b) to temperature T L3 for the time sufficient for the appearance of a transparent stable lyotropic phase with an L 3 -phase structure; and (d) cooling the mixture and letting it stand for sufficient time to attain equilibrium and the complete formation of the L 3 -phase corresponding to the carrier system for weakly water soluble substances.
• the concentration of the lipid component for obtaining the L 3 -phase is of up to 10 mM, preferentially, of up to 5 mM.
• the concentration of the cosolvent is such that the molar ratio between the lipid and the cosolvent varies between 1 : 12 and 0.001 : 1.
• the temperature T L3 for heating the mixture for the formation of the L 3 - phase depends on the lipid used or, in other words, depends on its T m .
• the temperature T L3 should be in the range between 5 and 20° C above T m .
• T L3 should be in the range between
• the heating temperature is 65° C.
• compositions comprising one or more active principles.
• Such compositions may be pharmaceutical compositions, herbicide compositions, insecticide compositions, cosmetic compositions and the similar.
• the system of the invention is particularly usable in the preparation of a vehicle for pharmaceutical compositions or compositions for agricultural use, such as herbicide compositions, insecticide compositions or nematocidal compositions and the similar.
• the comparative seen in Figure 7 shows, through the spectrums of the UV absorption range, the profiles for amphotericin B (30 ⁇ l) in water, control (A); amphotericin B in pentanol, control (B); amphotericin B in its most appropriate solvent (sulphoxide dimethyl :methanol, for 20 ⁇ l (C) and 40 ⁇ l (D); amphotericin B in the system of the invention, and in one of its preferred forms DODAB/n-pentanol/water, at successive additions of 20 ⁇ l, 40 ⁇ l, 60 ⁇ l and 80 ⁇ l of amphotericin B (E).
• Figure 7 shows the accord between the spectrums of amphotericin B (Figures 7C and 7D) in its best solvent and in the carrier system of the invention ( Figure 7E).
• the mixture is then cooled to room temperature for sufficient time until equilibrium is attained and a transparent L 3 -phase is formed.
• Stable DODAB/alcohol/water systems may also be obtained at much lower concentrations than DODAB, such as, for example, 1.5 mM.
• the system thus formed is stable and appropriate for use as a vehicle for compositions containing active substances weakly soluble in water.
• the system may be used as a template for depositing inorganic particles, for example, of particles, preferentially nano-particles.
• Example 2 Use of the System of the DODAB/alcohol/water invention for the preparation of amphotericin B compositions
• Example 3 Use of the System of the DODAB/alcohol/water invention in the preparation of compositions for agricultural use
• an active substance such as, for example, citronella, lemon grass extract, neem oil and the similar is incorporated to the DODAB/alcohol/water system with a DODAB concentration of up to 1OmM.
• Example 5 DOBAB Bromide Titering and Assessment of alcohol content of dialyzed phase from Example 4.
• Bromide Titering About 2.9 to 3.0 g of mercuric nitrate are dissolved in a few hundred milliliters of water with the addition of 20 ml 2 N HN03. The solution is completed with water to 1000 ml.
• Indicator 100 mg of diphenylcarbazone are dissolved in 100 ml of 95% alcohol and stored in the dark, preferably in the refrigerator.
• Standard chloride Sodium chloride is dried at 120 0 C and 584.5 mg are dissolved in water and completed up to 1000 ml. The solution contains 10 milliequivalents per liter of chloride. It is used for the standardization of each new batch of mercuric nitrate solution.
• the bromide is available in 0.1 ml volume, and after the break (with ethanol) its volume goes to 0.6 ml.
• dialyzed sponge phase of example 4 must be damaged to make bromide available for titration.
• Alcohol content The concentration of alcohol within the bag is very small after the dialysis of example 4. For ethanol, measurements of refractometry were made, and the result is that about of ⁇ 0.1 % ethanol remains at the phase (compared with 15% in the sponge phase, i.e., the phase dialyzed retains ⁇ 1 % of the initial value). It is important to note that refractometry measures can be made without damaging the phase.
• the pentanol was determined by headspace chromatography, FID detector.

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