WO2009071731A1 - Use of an ionic complex of gentamicin : aot for the treatment of brucellosis - Google Patents

Use of an ionic complex of gentamicin : aot for the treatment of brucellosis Download PDF

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Publication number
WO2009071731A1
WO2009071731A1 PCT/ES2008/070228 ES2008070228W WO2009071731A1 WO 2009071731 A1 WO2009071731 A1 WO 2009071731A1 ES 2008070228 W ES2008070228 W ES 2008070228W WO 2009071731 A1 WO2009071731 A1 WO 2009071731A1
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Prior art keywords
gentamicin
aot
use according
ionic complex
ionic
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PCT/ES2008/070228
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Spanish (es)
French (fr)
Inventor
Nora Ventosa Rull
Santiago Sala Verges
Jaume Veciana Miro
Elisa ELIZONDO SAEZ DE VICUÑA
Maria Jose Blanco Prieto
Carlos Gamazo De La Rasilla
David Gonzalez Fernandez
Edurne Imbuluzqueta Iturburua
Original Assignee
Instituto Cientifico Y Tecnologico De Navarra, S. A.
Consejo Superior De Investigaciones Cientificas
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Publication of WO2009071731A1 publication Critical patent/WO2009071731A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/541—Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention is framed in the pharmaceutical field, in particular in the treatment of Brucellosis, by the administration of an ionic complex of gentamicin and AOT.
  • Brucellosis is a zoonosis - infectious disease transmitted from animals to humans, caused by Brucella bacteria. It is a disease that affects both domestic animals, wild animals and cattle (cattle, goats, sheep, swine), as well as humans, with a worldwide distribution, especially in developing countries. There is a certain, not absolute, speciation, for example: B. melitensis affects sheep and goats, and is the most prevalent in man; B. suis affects pigs; B. abortus to cattle; B. ovis to sheep; B. you can mainly dogs.
  • the infection manifests itself by inducing among other pathologies, premature abortion of the fetus, the birth of unviable animals, and alterations in the genital apparatus of the males.
  • bacteria are excreted in large quantities during abortion or childbirth; They are found abundantly in colostrum and milk, in vaginal exudate and in the organs of the aborted fetus.
  • Bacteria can be transmitted to man by contact or ingestion of products derived from infected animals.
  • Human brucellosis is usually characterized by sweating and acute fever or intermittent with several clinical manifestations, such as adenopathies, hepato and splenomegaly, as well as osteoarticular, genital, and cardiac complications, with endocarditis being the main cause of the few deaths it causes.
  • Effective antibiotics against Brucella include tetracyclines, rifampin, and the aminoglycosides streptomycin and gentamicin.
  • the purpose of treatments for brucellosis is to improve the symptomatology of the disease, reduce complications and prevent relapse.
  • Brucella spp. It is very sensitive to most of the antibiotics studied in vitro, the clinical efficacy of these is reduced, and failures and relapses are frequent.
  • the treatments are long and combine different antimicrobial agents, so it is often the patient's abandonment that is responsible for the reduced therapeutic efficacy (Solera et al., 1997).
  • Second, the intracellular location of Brucella makes its treatment difficult, since antibiotics of proven efficacy in vitro are unable to cross membranes or inactivate intracellularly due to phagolysosomal pH.
  • Gentamicin is a brucelicidal antibiotic that exerts its action by binding to the 3OS subunit of the bacterial ribosome, disrupting protein synthesis. Like all aminoglycosides, gentamicin administered orally is inactive because it is not absorbed in any appreciable degree in the small intestine. Therefore, gentamicin is usually administered intravenously, intramuscularly, or topically to treat different infections. Even so, in the case of using this antibiotic as monotherapy, the required doses They exceed the toxic concentration mines.
  • An object of the present invention is the provision of an alternative treatment of Brucellosis.
  • Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which compliance with the treatment is improved to prevent the abandonment of said treatment.
  • Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which the accessibility of the active ingredient inside the host cell is improved.
  • Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which the dose of the active ingredient is decreased with respect to prior art therapies.
  • Another object of the present invention is the provision of an alternative treatment of Brucellosis, which is more effective at less concentration of the active ingredient in vivo.
  • Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which toxicity is reduced with respect to classical therapies.
  • PCA compressed antisolvent
  • WO1997038698 provides methods for administering drugs to the middle or inner ear of a mammal, whose methods comprise the insertion of a composition comprising a biocompatible polymer and at least one active pharmacological agent.
  • the invention relates to a method of treating Meniere's disease using a composition of hyaluronic acid and gentamicin.
  • the active pharmacological agent may be present in the form of an ionic complex with an unfriendly material.
  • Preferred unfriendly materials for Forming an ionic complex with gentamicin are sodium dodecyl sulfate (SDS) and sodium bis (2-ethylhexyl) sulphosuccinate (AOT).
  • SDS sodium dodecyl sulfate
  • AOT (2-ethylhexyl) sulphosuccinate
  • the present invention relates to the use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT), in a molar ratio of 1: 5 (gentamicin: AOT), for the manufacture of a medicament intended for treatment of a disease caused by a bacterium of the genus Brucella.
  • AOT sodium bis- (2-ethylhexyl) sulfosuccinate
  • the present invention relates to the use of the preceding paragraph, wherein the ionic complex is further processed by: a) dissolution of the gentamicin: AOT ionic complex in an organic solvent; b) spraying the solution resulting from step a) into a compressed fluid miscible with the organic solvent, which acts as an anti-solvent and causes the precipitation of a solid; c) the separation of the solid resulting from step b).
  • the present invention relates to an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), processed according to steps a), b ), and c) above.
  • the present invention relates to a pharmaceutical formulation comprising the processed ionic complex of gentamicin: AOT, mentioned in the previous paragraph, and at least one acceptable excipient in pharmacy.
  • the present invention relates to the use of an ionic complex of gentamicin and sodium bis- (2- ethylhexyl) sulphosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), for fluid processing tablets
  • Figure 1 is a representation of the molecular structure of the ionic complex of Gentamicin: AOT
  • Figure 2 depicts the IR curve of the ionic complex of gentamicin and AOT (GmAOT) with a 1: 5 gentamicin composition: AOT
  • FIG. 3 is a schematic representation of an apparatus for the preparation of the ionic complex processed gentamicin: AOT where each element represents: 1. CO2 cylinder 2, 4, 11. Stop valves
  • the present invention relates to the use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT), in a molar ratio of 1: 5 (gentamicin: AOT), for the manufacture of a medicament intended for treatment of a disease caused by Brucella spp. bacteria
  • Gentamicin (2- [4,6-diamino-3- [3-amino-6- (1- methylaminoethyl) tetrahydropyran-2-yl] oxy-2-hydroxycyclohexoxy] -5-methyl-4-methylamino-tetrahydropyran -3, 5- diol) is a broad-spectrum hydrophilic aminoglycoside antibiotic effective against various kinds of bacterial infections, particularly those caused by infections with gram-negative bacteria.
  • Gentamicin can be obtained by fermentation, or by chemical synthesis (Lek, part of the Sandoz group).
  • gentamicin sulfate can be used as raw material.
  • Gentamicin sulfate (CAS No. 1405-41-0) is commercially available and can be obtained for example from Sigma-Aldrich or Molekula.
  • AOT Sodium bis- (2-ethylhexyl) sulfosuccinate
  • the ionic complex of the present invention refers to the compound formed by gentamicin and AOT, where gentamicin and AOT are linked by ionic bonds.
  • This ionic complex can be prepared according to the method of "Hydrophobic Ion
  • Pairing "(HIP) which includes techniques such as” precipitation ion pairing "," monophase processing "and "two-phase emulsion”.
  • the technique for complexing gentamicin in the present invention is the "two-phase emulsion", described in WO01 / 32218 and
  • the ionic complex of the present invention can be prepared by dissolving gentamicin sulfate in a solvent that exposes the electrical charges of gentamicin, for example by using a buffer solution at a slightly acidic pH (4- 7). To this solution is added a similar volume of a solution of the AOT in an organic solvent not miscible with water, for example dichloromethane.
  • the complex can be isolated by centrifugation and separation of the organic and aqueous phases, followed by drying of the organic phase, and evaporation in vacuo.
  • the molar ratio of 1: 5 (gentamicin: AOT) in the ionic complex of the present invention refers to a molar concentration of AOT that is 5 times greater than that of gentamicin, as it equals the number of protonated amino groups of the Gentamicin at working pH. See Figure 1.
  • the present invention relates to the use of an ionic complex of gentamicin and bis- (2-ethylhexyl) Sodium sulphosuccinate (AOT) in a 1: 5 molar ratio (gentamicin: AOT), for processing with compressed fluids.
  • the present invention also relates to the use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT), in a molar ratio of 1: 5 (gentamicin: AOT), for the manufacture of a medicine intended for the treatment of a disease caused by the bacterium Brucella spp.
  • AOT sodium bis- (2-ethylhexyl) sulfosuccinate
  • the ionic complex is further processed by: a) dissolution of the gentamicin ionic complex: AOT in an organic solvent; b) spraying the solution resulting from step a) into a compressed fluid miscible with the organic solvent, which acts as an anti-solvent and causes the precipitation of a solid; c) the separation of the solid resulting from step b).
  • the term "gentamicin ion complex: processed AOT" or similar designations refers to the ionic complex obtained after steps a), b), and e), and optionally according to one or more of the embodiments related to these steps and exposed in the following passages.
  • the apparatus has a container containing the solution of the gentamicin and AOT ionic complex, in an organic solvent (12).
  • This vessel is connected, by means of a pipe, to a pump (10), thanks to which the solution can be supplied to the vessel precipitation (6), provided that the valve (11) is open.
  • the container containing the compressed fluid that acts as an antisolvent (1) is also connected to a pump (3), by means of which said compressed fluid is introduced into said vessel (6), provided that the valves (2 and 4) be open.
  • the reactor pressure (6) is controlled by the pressure regulating valve (8).
  • the reactor (6) is pressurized at a working pressure of 10 to 200 bar, at a working temperature of -50 to 200 0 C, and contains a CO2 molar fraction of 0.3 to 1.
  • the compressed fluid is It enters the reactor (6) through a nozzle (5), keeping the desired reactor pressure (6) constant with the help of the pressure regulating valve (8).
  • the molar fraction of CO2 is constantly maintained, initially pumping a pure organic solvent, such as acetone, until a steady state is achieved. In another preferred embodiment, it is during the steady state when the solution in the same organic solvent of the gentamicin ionic complex: AOT (12) is introduced into the reactor (6) through the nozzle (5).
  • the precipitate formed as a result of the anti-solvent effect of the compressed fluid on the spray solution falls on a filter (7), which separates the particulate material as a function of the light of the same filter. Particulate material must be separated at the same working conditions as spraying.
  • the filter may be external with respect to the reactor (6).
  • the particulate material is finally dried. Drying can be carried out inside the reactor (6), for example by means of a stream of compressed fluid. In the case of a drying inside the reactor (6), this is preferably followed by a depressurization of the system and the consequent collection of the solid.
  • the dissolution stage a) is carried out at an atmospheric working pressure.
  • the working conditions of the reactor are of a pressure of 50 to 150 bar, a temperature of 5 to 60 0 C, and a molar fraction of the compressed fluid of 0.7 to 1.
  • the pressure is about 100 bar
  • the temperature is about 25 0 C
  • the working pressures during stages (b) and (c) are the same.
  • the diameter of the nozzle can be from 10 to 500 ⁇ m. As is commonly known, a variation in the diameter of the nozzle entails a variation in the size of the particulate material obtained.
  • the spray nozzle is of the Hollow Cone type.
  • the filter light can vary from 0.05 to 100 ⁇ m, preferably the filter light varies between 0.2 to 30 ⁇ m.
  • a batch process can be achieved by discontinuous (one-time) and controlled feeding of the compressed fluid in the precipitation vessel; a discontinuous and controlled feeding of the organic solvent in the reactor until a steady state is achieved to keep the molar fraction of the compressed fluid constant; a spray discontinuous and controlled organic solution of the ionic complex of gentamicin and AOT; a separation of the precipitate obtained in a discontinuous and controlled manner within the same reactor.
  • a semi-continuous process can be achieved by continuous and controlled feeding of the compressed fluid in the precipitation vessel; a continuous and controlled feeding of the organic solvent in the reactor until a steady state is achieved to keep the molar fraction of the compressed fluid constant; a continuous and controlled spraying of the organic solution of the ionic complex of gentamicin and AOT; and a separation of the precipitate obtained by using a battery of filters external to the reactor that are replaced as they become saturated.
  • the organic solvent of step a) of the above-mentioned process is selected from monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-hexanol, 1- octanol , and trifluoroethanol; polyhydric alcohols such as propylene glycol, PEG 400, and 1,3-propanediol; ethers such as tetrahydrofuran (THF), and diethyl ether; alkanes such as decalin, isooctane, and mineral oil; aromatics such as benzene, toluene, chlorobenzene, and pyridine; amides such as n-methyl pyrrolidone (NMP), and N, N-dimethylformamide (DMF); esters such as ethyl acetate, propyl acetate, and methyl acetate; chlorocarbons such as dichlorome
  • monohydric alcohols
  • the organic solvent of step a) is acetone.
  • Low volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used.
  • Solvent mixtures such as 50% methanol and 50% acetone, can also be used, as well as mixtures with water, as long as the ionic complex is sufficiently soluble and the compressed fluid is miscible with said solvent mixture. . In any case, whatever the nature of the organic solvent, it must necessarily be miscible with the compressed fluid.
  • the composite material precipitates, and the organic solvent dissolves in the compressed fluid.
  • the solvent must have a relatively low toxicity and can be removed from the dispersion at a level that is acceptable according to the international committee on harmonization guidelines (ICH). Solvent removal at the levels required by the ICH may require subsequent handling such as "tray-drying" or tray drying.
  • the concentration of the ionic complex solution in the organic solvent is 0.001 to 0.3 g / ml, preferably 0.01 to 0.1 g / ml.
  • the concentration of the solution prepared in step a) of the present invention should be as high as possible, to reduce the amount of solvent to be removed in later stages, provided that this does not undesirably affect the characteristics of the final material.
  • the dissolution of the ionic complex in the solvent will generally have a concentration of the ionic complex of at least about 0.001 g / ml, preferably at least about 0.01 g / ml, and more preferably at least about 0.1 g / ml.
  • concentrations of the ionic complex are also suitable for forming solid dispersions.
  • the concentration of the solution resulting from step a) is approximately 0.01 g / ml to 0.3 g / ml.
  • the compressed fluid miscible with the organic solvent which acts as an anti-solvent and causes the precipitation of a solid in step b), is selected from CO2, ethane, propane, hydrochlorofluorocarbons, and hydrofluorocarbons.
  • the fluid compressed in step b) is CO2, considered as an ecological solvent, since it is not toxic, it is not flammable, it is not corrosive, it is not harmful to the environment, and it is also very abundant in nature.
  • the ratio between the amount of compressed fluid and organic solvent corresponds to an approximate molar fraction of 0.3 to 1, preferably 0.5 to 1.
  • the separation of step c) of the process presented herein can be performed by filtration.
  • the separation of step c) is performed with a filter with a pore size of 0.05 to 100 ⁇ m, 0.05 to 50 ⁇ m, 0.05 to 25 ⁇ m, 0.1 to 10 ⁇ m , from 0.1 to 1 ⁇ m, approximately 0.22 ⁇ m.
  • the solid resulting from step c) of the process presented here is subsequently dried.
  • Said drying can be carried out using a stream of CO2 or other gases, a stove, or vacuum.
  • the gas stream for drying can be of a different nature, but to minimize the risk of fire or explosion due to ignition of flammable vapors, and also to minimize undesirable oxidation of the active ingredients, or others Materials present in the micro- and nanoparticles, it is preferable to use an inert gas such as nitrogen, nitrogen enriched air, or argon.
  • CO2 as a drying gas, is also a preferable embodiment of the present invention.
  • the temperature of the drying gas at the entrance to the device normally ranges from about -50 ° to about 200 0 C.
  • the present invention relates to an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1: 5
  • the present invention relates to the product obtainable according to steps a), b), and e).
  • gentamicin sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), processed according to steps a), b), and c), or the product obtainable according to with stages a), b), and c), it appears as a particulate material.
  • This "particulate material” is defined in the present invention as a material comprising discrete particles, or aggregates of said particles, or a mixture of both. In most cases, a mixture of separate particles and aggregates of particles appears. In all cases, the approximate size of said material particulate can range from 0.05 to 100 ⁇ m, sizes determined by scanning electron microscopy (SEM).
  • the present invention relates to a pharmaceutical formulation comprising the processed ionic gentamicin complex: AOT according to any of the previously described embodiments, and at least one pharmaceutically acceptable excipient.
  • the formulation of the ionic complexes of the present invention will depend on the nature of the clinical conditions associated with Brucellosis, on the severity of these conditions, on the patient to be treated, of the doctor's judgment, as well as the route of administration.
  • the ionic complex, processed or unprocessed, of the present invention can be conveniently administered in various pharmaceutical forms such as tablets, capsules, suppositories, suspensions, suspension powders, creams, transdermal patches, deposits, and the like.
  • excipients such as solubilizers or solvents, surfactants, pH modifiers, diluents, matrix systems, complexing agents, disintegrants, binders, glidants, non-sticks, lubricants, viscosifiers, flocculants, dispersants or deflocculants, redispersants, humectants, colorants , flavorings, preservatives, and so on, can be used for customary purposes and in typical amounts without affecting the characteristics of the compositions of the present invention. See for example, Remington's Pharmaceutical Sciences (1995).
  • Solubilizing agents or solvents include ethanol, propylene glycol, or polyethylene glycol.
  • a very useful class of excipients are surfactants. These surfactants do not refer to the AOT that forms an anionic complex with gentamicin, but to additional surfactants that can be advantageously used to increase the dissolution rate of gentamicin, facilitating the wetting or hydration of gentamicin, or increasing the speed of release of gentamicin from the dosage form. These surfactants are preferably present in the final pharmaceutical form in a percentage of up to 10% by weight.
  • surfactants preferably include fatty acid and alkyl sulfonates; commercial surfactants such as benzalkonium chloride (Hyamione® 1622); esters of sorbitan polyoxyethylene fatty acid (Tween®, Liposorb® O-20, Capmul® POE-O); and natural surfactants such as sodium taurocolic acid, l-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine, lecithin, and other phospholipids and mono-and diglycerides.
  • Such materials can be used advantageously to increase the dissolution rate, for example, by facilitating the wettability of the medicament, or alternatively increasing the release rate of gentamicin from its dosage form or pharmaceutical form.
  • pH modifiers such as acids, bases, or buffer solutions may be beneficial for retard the dissolution of the ionic complex (eg acids such as citric acid or succinic acid) or, alternatively, to enhance the dissolution rate of the ionic complex (for example bases such as sodium acetate or amines).
  • acids such as citric acid or succinic acid
  • bases such as sodium acetate or amines
  • diluents include lactose, mannitol, chilitol, microcrystalline cellulose, dibasic calcium phosphate (anhydrous and dihydrate), and starch.
  • matrix materials or matrix systems include hydrophilic matrices obtained by granulating gentamicin with hydrophilic cellulose derivatives of high digestible viscosity such as carboxymethyl cellulose or hydroxypropyl methylcellulose; hydrophobic or lipid matrices with mono, di, and triglyceride supports, fatty acids, waxes and mixed glycerides of synthetic origin; inert matrices such as laminar systems, floating systems, or bioadhesive systems.
  • hydrophilic matrices obtained by granulating gentamicin with hydrophilic cellulose derivatives of high digestible viscosity such as carboxymethyl cellulose or hydroxypropyl methylcellulose
  • inert matrices such as laminar systems, floating systems, or bioadhesive systems.
  • disintegrants include potato or corn starch, sodium carboxymethylaminopectin, sodium starch glycolate, formaldehydegelatin, formaldehyde casein, gelatin, calcium alginate, sodium alginate, cellulose derivatives such as sodium carboxymethyl cellulose, methyl cellulose, croscarmellose sodium, sodium bicarbonate, magnesium peroxide, saponins and synthetic foaming agents, and cross-linked forms of polyvinylpyrrolidone such as those sold under the trade name Crospovidone.
  • binders include cellulose derivatives such as methyl cellulose, microcrystalline cellulose, starch, starch mucilage, gelatin solution, hydrolyzed gelatin, derivatives of algic acid, polyvinylpyrrolidone, and gums such as guar gum, and tragacanth.
  • sliding, non-stick, or lubricating agents include derivatives of silica, magnesium stearate, calcium stearate, talc, or stearic acid.
  • viscosifying agents examples include natural polysaccharides such as alginates, gum arabic, carragaen, guar gum, and tragacanth; synthetic polymers such as carbomer, PVP, poloxamers; hydrophilic colloids such as methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose; and colloidal clays such as bentonite, or magnesium aluminum silicate
  • flocculating agents include electrolytes or anionic surfactants, due to the positive charge of gentamicin; alternatively they also include polyols such as sorbitol; hydrophilic polymers; or colloidal clays such as bentonite. Examples of dispersing or deflocculating agents include lecithins.
  • Redispersant agents include EDTA, potassium phosphate, citric acid, sodium citrate and aerosol.
  • humectants include surfactants with an HLB between 7 and 10, or hydrophilic polymers, glycerin, propylene glycol, or ethanol.
  • preservatives examples include sulphites (an antioxidant), benzalkonium chloride, methylparaben, propylparaben, benzyl alcohol, and sodium benzoate.
  • compositions of this invention may be employed in the compositions of this invention, including those excipients well known in the state of the art.
  • excipients such as colorants, flavorings, and the like can be used for customary purposes and in the usual amounts without affecting the properties of the compositions.
  • the ionic complex of the present invention can be administered through a wide variety of routes, including, but not limited to, the oral, nasal, rectal, vaginal, subcutaneous, and pulmonary routes. Generally, the oral route is preferred.
  • the ionic complex of the present invention can also be administered through suppositories or other transmucosal vehicles.
  • suppositories or other transmucosal vehicles will include excipients that facilitate the passage of the complex through the mucosa such as pharmaceutically acceptable surfactants.
  • the ionic complex can also be administered topically, or in a formulation designed to penetrate the skin.
  • formulations include lotions, creams, ointments, and the like that can be formulated according to methods commonly known in the state of the art.
  • the complexes can also be administered by injection, including intravenous, intramuscular, subcutaneous or intraperitoneal Common formulations for such use are liquid formulations in isotonic vehicles such as Hank or Ringer's solution. Alternative formulations include nasal sprays, liposomial formulations, delayed-release formulations, and the like, commonly known in the state of the art.
  • the ionic complexes of the present invention can also be used in a wide variety of dosage forms or pharmaceutical forms for the administration of gentamicin.
  • dosage forms are powders or granules that can be taken dry or reconstituted with the addition of water or other liquids to form a mixture, a suspension, or a solution; tablets capsules; And the pills.
  • excipients may be mixed, pulverized, or granulated with the compositions of this invention to form a suitable material for the above dosage forms.
  • the ionic complexes of the invention can be formulated as a suspension.
  • Such suspension can be formulated as a liquid or paste at the time of its manufacture, or it can be formulated as dry powder with a liquid, usually water, added later but before oral administration.
  • Such powders that then form a suspension are often referred to as sachets or powders.
  • Such dosage forms can be formulated and reconstituted by any known procedure. The simplest method would be the formulation of the dosage form as dry powder which is then reconstituted simply by adding the water and stirring the mixture. Alternatively, the dosage form can be formulated as a liquid and dry powder that combine and stir to form the oral suspension. In another embodiment, the dosage form can be formulated as two powders that are reconstituted by a first addition of water to a powder to form a solution to which the second powder is combined with stirring to form the suspension.
  • controlled or sustained release forms usually include matrix systems such as those described above, ion exchange resins, or film barriers that control the spread of gentamicin.
  • a treatment method comprising the systemic administration of an effective amount of ionic complex of gentamicin and AOT, processed in accordance with the present invention, or unprocessed, to treat, combat, or prevent , a disease caused by the bacterium Brucella spp.
  • the ionic gentamicin: AOT complexes of the present invention can be used in the manufacture of a medicament for the treatment of a disease caused by the bacterium Brucella spp.
  • the present invention provides the gentamicin ionic complex: AOT, processed or unprocessed, for use in the treatment of a disease caused by the bacterium Brucella spp.
  • the ionic complexes of the present invention are useful in the treatment of individuals infected with Brucella spp and for the prophylaxis of these individuals.
  • the ionic complexes of the present invention may be useful in the treatment of mammalian animals infected with Brucella spp.
  • Conditions that can be prevented or treated with the ionic complexes of the present invention, especially conditions that are associated with Brucella spp, include brucellosis, and symptoms or sequelae associated or produced by Brucella genus bacteria, such as abortion.
  • the mammal is a human person.
  • the gentamicin: AOT ion complexes of the present invention can be used in the manufacture of a medicament for the treatment of a disease caused by a bacterium selected from the group of B. melitensis, B. suis, B Abortus, B. ovis, B. canis, and B. neotomae.
  • a daily effective antibacterial amount of the ionic complexes of the present invention would be from 0.01 mg / kg to 100 mg / kg of weight. body weight, preferably 1 mg / kg to 50 mg / kg body weight, more preferably 1 mg / kg to 25 mg / kg body weight. It may also be appropriate to administer the required dose in two, three, four, or more sub-doses at the appropriate intervals during the day.
  • the aforementioned sub-doses may be formulated as unit dosage forms, for example, comprising 1 to 20 mg, and in particular 1 to 10 mg of the active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depend on the particular condition to be treated, the severity of the condition to be treated, age, weight, sex, the extent of the disease, and the general physical condition of the condition. patient, as well as the other medication that the individual can take, as is well known by those skilled in the art. Furthermore, it is evident that the above-mentioned daily effective amount can be decreased or increased depending on how the patient reacts to said medication, and / or depending on the evaluation performed by the physician prescribing the medicament of the present invention. Thus, the effective daily amounts mentioned above must be considered as guidelines or recommendations.
  • the ionic complexes of the present invention can be administered alone or in conjunction with other therapeutic agents.
  • examples of other therapeutic agents useful for combination with the ionic complexes of the present invention include tetracyclines, rifampin, and streptomycin.
  • the combination of one of the ionic complexes of the present invention and another therapeutic agent can be used as Medicine in a combination therapy.
  • the term "combination therapy" refers to a product that necessarily contains (a) a ionic complex of the present invention, and (b) another anti-brucellosis compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of Brucella sp infections, particularly for the treatment of infections caused by B. melitensis .
  • one of the ionic complexes of this invention can be co-administered in conjunction with, for example, tetracyclines, rifampicin, or streptomycin.
  • the present invention relates to the use of an ionic complex, processed or unprocessed, for the manufacture of a medicament useful for inhibiting the activity of Brucella spp in a mammal infected with the bacterium of Brucella spp, wherein said medicament is used in a combination therapy, which preferably comprises an ionic complex of the present invention and a tetracycline, rifampin, or streptomycin.
  • Example 1 Preparation of the ionic gentamicin complex with sodium Bis (2-ethylhexyl) sulphosuccinate (AOT) A solution of 4 mg / ml concentration of gentamicin sulfate was prepared in a buffer solution at pH 5 (10 mM sodium acetate, 10 mM KCl, 10 mM CaCl2). While stirring the solution an equal volume of dichloromethane was added with a concentration of the anionic surfactant Bis (2-ethylhexyl) sulfosuccinate (AOT) of 12.55 mg / ml.
  • AOT anionic surfactant Bis (2-ethylhexyl) sulfosuccinate
  • the molar concentration of the surfactant was 5 times higher than that of the active substance and was equivalent to the number of protonated amino groups of gentamicin at working pH After the addition, the mixture was stirred for approximately three hours and then centrifuged at 5000 rev./min for 5 minutes. The organic phase was separated from the aqueous one and after drying with anhydrous MgSO 4 it was evaporated in vacuo.
  • gentamicin and AOT An ionic complex of gentamicin and AOT (GmAOT) was obtained with a 1: 5 gentamicin: AOT composition that was analyzed by IR, NMR, DSC and elemental analysis (see IR curve in Figure 2).
  • Example 2 Preparation of microparticles of the gentamicin ionic complex: processed AOT
  • the reactor (6) of 300 ml capacity was pressurized with CO2. Carbon dioxide was introduced at a flow rate of 36.67 ml / min and the pressure (P w ) was kept constant at 100 bar by a pressure regulating valve (8) located at the outlet of the reactor. The working temperature (T w ) was 25 0 C.
  • pure acetone was first pumped at a flow rate of 2 ml / min and for 20 min until a steady state is achieved. At this time, 10 ml of a solution of concentration 0.3 g / ml of the ionic gentamicin complex: AOT in acetone was introduced at the same flow rate.
  • Both the solvent and the solution were introduced to the reactor through a nozzle (5) with a diameter of 100 ⁇ m.
  • the precipitate formed as a result of the anti-solvent effect of CO2 was collected in a 0.2 ⁇ m pore filter (7) placed in the bottom of the reactor.
  • the drying of the microparticles is carried out by means of a stream of CO2 at 36.67 ml / min and 100 bar for one hour.
  • the system was depressurized and the solid was collected.
  • the precipitate obtained was a white solid.
  • the particle size obtained was determined by scanning electron microscopy (SEM) and was 3 to 5 ⁇ m approximately .
  • Example 3 Pharmacological activity of the gentamicin ionic complex: AOT processed and unprocessed The bacterial species chosen as a model to study the pharmacological activity of the ionic complex GmAOT for the treatment of brucellosis, was Brucella melitensis.
  • the minimum inhibitory concentrations were determined following the protocol standardized by the CLSI (Clinical and Laboratory Standards Institute).
  • the bacterial inoculum (Brucella melitensis) previously prepared was added to each well.
  • a colony forming unit (ufe) count was made and the MIC was defined as the minimum amount of the antibiotic that inhibits bacterial growth.
  • gentamicin ionic complexes AOT, processed and unprocessed, did not reduce the activity of gentamicin when compared to gentamicin sulfate.
  • MIC minimum inhibitory activity

Abstract

The invention relates to an ionic complex of gentamicin and sodium bis(2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1:5 (gentamicin : AOT) for the production of a drug intended for the treatment of a disease caused by a bacterium of the genus Brucella. In one embodiment of the invention, the therapeutic ionic complex is also treated by: (a) dissolving the gentamicin : AOT ionic complex in an organic solvent; (b) spraying the solution resulting from step (a) into a compressed fluid miscible with the organic solvent, which acts as an antisolvent and causes the precipitation of a solid; and (c) separating the solid resulting from step (b).

Description

USO DEL COMPLEJO IÓNICO DE GENTAMICINA : AOT PARA EL TRATAMIENTO DE LA BRÚCELOSIS USE OF THE IONIC GENTAMYCIN COMPLEX: AOT FOR THE TREATMENT OF BRÚCELOSIS
La presente invención se enmarca en el campo farmacéutico, en particular en el tratamiento de la Brucelosis, mediante la administración de un complejo iónico de gentamicina y AOT.The present invention is framed in the pharmaceutical field, in particular in the treatment of Brucellosis, by the administration of an ionic complex of gentamicin and AOT.
La brucelosis es una zoonosis -enfermedad infecciosa transmitida de animales a los seres humanos, causada por las bacterias del género Brucella. Es una enfermedad que afecta tanto a animales domésticos, salvajes y al ganado (vacuno, caprino, ovino, suido) , asi como a los seres humanos, con una distribución mundial, especialmente en los países en vías de desarrollo. Existe una cierta, que no absoluta, especiación, así por ejemplo: B. melitensis afecta al ganado ovino y caprino, y es la más prevalente en el hombre; B. suis afecta a cerdos; B. abortus al ganado vacuno; B. ovis al ovino; B. canis principalmente a perros .Brucellosis is a zoonosis - infectious disease transmitted from animals to humans, caused by Brucella bacteria. It is a disease that affects both domestic animals, wild animals and cattle (cattle, goats, sheep, swine), as well as humans, with a worldwide distribution, especially in developing countries. There is a certain, not absolute, speciation, for example: B. melitensis affects sheep and goats, and is the most prevalent in man; B. suis affects pigs; B. abortus to cattle; B. ovis to sheep; B. you can mainly dogs.
En el reservorio natural, los animales, la infección se manifiesta induciendo entre otras patologías, el aborto prematuro del feto, el nacimiento de animales inviables, y las alteraciones en el aparato genital de los machos. En estos animales infectados, las bacterias son excretadas en grandes cantidades durante el aborto o parto; se encuentran abundantemente en el calostro y leche, en el exudado vaginal y en los órganos del feto abortado.In the natural reservoir, animals, the infection manifests itself by inducing among other pathologies, premature abortion of the fetus, the birth of unviable animals, and alterations in the genital apparatus of the males. In these infected animals, bacteria are excreted in large quantities during abortion or childbirth; They are found abundantly in colostrum and milk, in vaginal exudate and in the organs of the aborted fetus.
Las bacterias se pueden transmitir al hombre por el contacto o ingestión de productos derivados de los animales infectados. La brucelosis humana suele caracterizarse por sudoración y fiebre aguda o intermitente con varias manifestaciones clínicas, como adenopatías, hepato y esplenomegalia, así como complicaciones osteoarticulares, genitales, y cardíacas, siendo la endocarditis la principal causa de los escasos fallecimientos que provoca.Bacteria can be transmitted to man by contact or ingestion of products derived from infected animals. Human brucellosis is usually characterized by sweating and acute fever or intermittent with several clinical manifestations, such as adenopathies, hepato and splenomegaly, as well as osteoarticular, genital, and cardiac complications, with endocarditis being the main cause of the few deaths it causes.
Antibióticos efectivos contra Brucella incluyen a las tetraciclinas, rifampicina, y los aminoglicósidos streptomicina y gentamicina. El propósito de los tratamientos para la brucelosis es mejorar la sintomatología de la enfermedad, reducir las complicaciones y prevenir las recaídas. Pese a que Brucella spp. es muy sensible a la mayoría de los antibióticos estudiados in vitro, la eficacia clínica de éstos es reducida, y son frecuentes los fracasos y las recaídas. En primer lugar, los tratamientos son largos y combinan diferentes agentes antimicrobianos, por lo que, a menudo, es el abandono por parte del paciente el responsable de la reducida eficacia terapéutica (Solera et al., 1997) . En segundo lugar, la localización intracelular de Brucella dificulta su tratamiento, ya que los antibióticos de probada eficacia in vitro, son incapaces de atravesar membranas o se inactivan intracelularmente debido al pH fagolisosomal .Effective antibiotics against Brucella include tetracyclines, rifampin, and the aminoglycosides streptomycin and gentamicin. The purpose of treatments for brucellosis is to improve the symptomatology of the disease, reduce complications and prevent relapse. Although Brucella spp. It is very sensitive to most of the antibiotics studied in vitro, the clinical efficacy of these is reduced, and failures and relapses are frequent. First, the treatments are long and combine different antimicrobial agents, so it is often the patient's abandonment that is responsible for the reduced therapeutic efficacy (Solera et al., 1997). Second, the intracellular location of Brucella makes its treatment difficult, since antibiotics of proven efficacy in vitro are unable to cross membranes or inactivate intracellularly due to phagolysosomal pH.
La gentamicina es un antibiótico brucelicida que ejerce su acción mediante su unión a la subunidad 3OS del ribosoma bacteriano, interrumpiendo la síntesis de proteínas. Como todos los aminoglicósidos, la gentamicina administrada por vía oral es inactiva debido a que no se absorbe en ningún grado apreciable en el intestino delgado. Por consiguiente, la gentamicina se administra habitualmente por vía intravenosa, intramuscular, o tópica para tratar diferentes infecciones. Aun así, en el caso de utilizar este antibiótico como monoterapia, las dosis requeridas sobrepasan la mímina concentración tóxica.Gentamicin is a brucelicidal antibiotic that exerts its action by binding to the 3OS subunit of the bacterial ribosome, disrupting protein synthesis. Like all aminoglycosides, gentamicin administered orally is inactive because it is not absorbed in any appreciable degree in the small intestine. Therefore, gentamicin is usually administered intravenously, intramuscularly, or topically to treat different infections. Even so, in the case of using this antibiotic as monotherapy, the required doses They exceed the toxic concentration mines.
Un objeto de la presente invención es la provisión de un tratamiento alternativo de la Brucelosis.An object of the present invention is the provision of an alternative treatment of Brucellosis.
Otro objeto de la presente invención es la provisión de un tratamiento alternativo de la Brucelosis, en el cual se mejore el cumplimiento del tratamiento para prevenir el abandono de dicho tratamiento.Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which compliance with the treatment is improved to prevent the abandonment of said treatment.
Otro objeto de la presente invención es la provisión de un tratamiento alternativo de la Brucelosis, en el cual se mejore la accesibilidad del principio activo al interior de la célula huésped.Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which the accessibility of the active ingredient inside the host cell is improved.
Otro objeto de la presente invención es la provisión de un tratamiento alternativo de la Brucelosis, en el cual se disminuya la dosis del principio activo respecto a las terapias del estado de la técnica.Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which the dose of the active ingredient is decreased with respect to prior art therapies.
Otro objeto de la presente invención es la provisión de un tratamiento alternativo de la Brucelosis, que sea más efectivo a menos concentración del principio activo in vivo .Another object of the present invention is the provision of an alternative treatment of Brucellosis, which is more effective at less concentration of the active ingredient in vivo.
Otro objeto de la presente invención es la provisión de un tratamiento alternativo de la Brucelosis, en el cual se reduzca la toxicidad respecto a las terapias clásicas.Another object of the present invention is the provision of an alternative treatment of Brucellosis, in which toxicity is reduced with respect to classical therapies.
Asi, subsiste la necesidad de tratamientos contra la brucelosis que puedan superar al menos una de la desventajas de las terapias actuales tales como los efectos secundarios, su limitada eficacia, la aparición de resistencias, escasa accesibilidad del principio activo al interior de la célula bacteriana, toxicidad, o bajo cumplimiento por parte de los pacientes.Thus, there remains a need for treatments against brucellosis that can overcome at least one of the disadvantages of current therapies such as side effects, their limited efficacy, the appearance of resistance, poor accessibility of the active substance inside the bacterial cell, toxicity, or low compliance by patients.
Journal of Pharmaceutical Sciences, 1998, 87(9), 1149- 1154; y Journal of Controlled Reléase, 1997, 44, 77-85, describen la preparación del complejo iónico de gentamicina con bis- (2-etilhexil) sulfosuccinato sódico (AOT) mediante la técnica denominada "Hydrophobic Ion Pairing" (HIP) .Journal of Pharmaceutical Sciences, 1998, 87 (9), 1149-1154; and Journal of Controlled Relay, 1997, 44, 77-85, describe the preparation of the ionic gentamicin complex with sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) using the technique called "Hydrophobic Ion Pairing" (HIP).
"Precipitation with a compressed antisolvent" (PCA) (Industrial Engineering Chemical Research, 2003, 42, 6476- 6493; Industrial Engineering Chemical Research, 2003, 42, 6375-6383) describe un método para la obtención de micro o nanoparticulas de un principio activo en el cual el fluido comprimido actúa como anti-solvente sobre una disolución del principio activo a precipitar. Mediante este método, el principio activo es disuelto en un disolvente orgánico y después pulverizado a través de una boquilla en el seno de un fluido comprimido que es miscible con el disolvente pero que actúa como antisolvente sobre el principio activo. El fluido comprimido invade rápidamente las gotas de disolvente, causando la precipitación del fármaco en forma de pequeñas partículas de tamaño micro- y/o nanoscópico ."Precipitation with a compressed antisolvent" (PCA) (Industrial Engineering Chemical Research, 2003, 42, 6476-6493; Industrial Engineering Chemical Research, 2003, 42, 6375-6383) describes a method for obtaining micro or nanoparticles of a principle active in which the compressed fluid acts as an anti-solvent on a solution of the active substance to precipitate. By this method, the active principle is dissolved in an organic solvent and then sprayed through a nozzle into a compressed fluid that is miscible with the solvent but acts as an anti-solvent on the active principle. The compressed fluid quickly invades the drops of solvent, causing the precipitation of the drug in the form of small particles of micro- and / or nanoscopic size.
WO1997038698 proporciona métodos para administrar medicamentos al oído medio o interno de un mamífero, cuyos métodos comprenden la inserción de una composición que comprende un polímero biocompatible y por lo menos un agente farmacológico activo. En particular, la invención se refiere a un método para tratar la enfermedad de Meniere usando una composición de ácido hialurónico y gentamicina. El agente farmacológico activo puede estar presente en la forma de un complejo iónico con un material antipático . Los materiales antipáticos preferidos para formar un complejo iónico con gentamicina son el dodecil sulfato sódico (SDS) y el bis (2-etilhexil) sulfosuccinato sódico (AOT) . Este complejo iónico se puede preparar según los procedimientos conocidos en el arte, como lo recogido en WO 94/08599 y la solicitud de patente americana s/n 08/473,008.WO1997038698 provides methods for administering drugs to the middle or inner ear of a mammal, whose methods comprise the insertion of a composition comprising a biocompatible polymer and at least one active pharmacological agent. In particular, the invention relates to a method of treating Meniere's disease using a composition of hyaluronic acid and gentamicin. The active pharmacological agent may be present in the form of an ionic complex with an unfriendly material. Preferred unfriendly materials for Forming an ionic complex with gentamicin are sodium dodecyl sulfate (SDS) and sodium bis (2-ethylhexyl) sulphosuccinate (AOT). This ionic complex can be prepared according to the procedures known in the art, as set out in WO 94/08599 and the American patent application s / n 08 / 473,008.
Descripción resumida de la invenciónSummary Description of the Invention
La presente invención se refiere a la utilización de un complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT), en una relación molar de 1:5 (gentamicina : AOT) , para la fabricación de un medicamento destinado al tratamiento de una enfermedad causada por una bacteria del género Brucella.The present invention relates to the use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT), in a molar ratio of 1: 5 (gentamicin: AOT), for the manufacture of a medicament intended for treatment of a disease caused by a bacterium of the genus Brucella.
En una realización, la presente invención se refiere a la utilización del párrafo anterior, en donde el complejo iónico está adicionalmente procesado mediante: a) la disolución del complejo iónico gentamicina : AOT en un disolvente orgánico; b) el pulverizado de la disolución resultante de la etapa a) en un fluido comprimido miscible con el disolvente orgánico, que actúa como antisolvente y causa la precipitación de un sólido; c) la separación del sólido resultante de la etapa b) .In one embodiment, the present invention relates to the use of the preceding paragraph, wherein the ionic complex is further processed by: a) dissolution of the gentamicin: AOT ionic complex in an organic solvent; b) spraying the solution resulting from step a) into a compressed fluid miscible with the organic solvent, which acts as an anti-solvent and causes the precipitation of a solid; c) the separation of the solid resulting from step b).
En otra realización, la presente invención se refiere a un complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT) en una relación molar de 1:5 (gentamicina : AOT) , procesado según las etapas a) , b) , y c) arriba mencionadas.In another embodiment, the present invention relates to an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), processed according to steps a), b ), and c) above.
En otra realización, la presente invención se refiere a una formulación farmacéutica que comprende el complejo iónico procesado de gentamicina : AOT, mencionado en el párrafo anterior, y al menos un excipiente aceptable en farmacia .In another embodiment, the present invention relates to a pharmaceutical formulation comprising the processed ionic complex of gentamicin: AOT, mentioned in the previous paragraph, and at least one acceptable excipient in pharmacy.
En otra realización, la presente invención se refiere a la utilización de un complejo iónico de gentamicina y bis- (2- ethylhexyl) sulfosuccinato sódico (AOT) en una relación molar de 1:5 (gentamicina : AOT), para su procesamiento con fluidos comprimidos.In another embodiment, the present invention relates to the use of an ionic complex of gentamicin and sodium bis- (2- ethylhexyl) sulphosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), for fluid processing tablets
Descripción de las figurasDescription of the figures
Figura 1 es una representación de la estructura molecular del complejo iónico de Gentamicina : AOTFigure 1 is a representation of the molecular structure of the ionic complex of Gentamicin: AOT
Figura 2 representa la curva IR del complejo iónico de gentamicina y AOT (GmAOT) con una composición 1:5 gentamicina : AOTFigure 2 depicts the IR curve of the ionic complex of gentamicin and AOT (GmAOT) with a 1: 5 gentamicin composition: AOT
Figura 3 es una representación esquemática de un aparato para la preparación del complejo iónico procesado gentamicina : AOT donde cada elemento representa: 1. Bombona de CO2 2, 4, 11. Válvulas de pasoFigure 3 is a schematic representation of an apparatus for the preparation of the ionic complex processed gentamicin: AOT where each element represents: 1. CO2 cylinder 2, 4, 11. Stop valves
3. Bomba de inyección de CO23. CO2 injection pump
5. Boquilla o tobera5. Nozzle or nozzle
6. Reactor o vasija de precipitación6. Reactor or precipitation vessel
7. Filtro 8. Válvula reguladora de presión7. Filter 8. Pressure regulating valve
9. Colector9. Collector
10. Bomba de introducción de líquidos10. Liquid introduction pump
12. Disolución orgánica del material a precipitar12. Organic dissolution of the material to precipitate
Descripción de la invenciónDescription of the invention
La presente invención se refiere a la utilización de un complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT), en una relación molar de 1:5 (gentamicina : AOT) , para la fabricación de un medicamento destinado al tratamiento de una enfermedad causada por la bacteria Brucella spp .The present invention relates to the use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT), in a molar ratio of 1: 5 (gentamicin: AOT), for the manufacture of a medicament intended for treatment of a disease caused by Brucella spp. bacteria
La gentamicina (2- [ 4, 6-diamino-3- [3-amino-6- ( 1- metilaminoetil) tetrahidropiran-2-il] oxi-2-hidroxi- ciclohexoxi] -5-metil- 4-metilamino-tetrahidropiran-3, 5- diol) es un antibiótico aminoglicósido hidrofílico de amplio espectro efectivo frente a diversas clases de infecciones bacterianas, particularmente las causadas por infecciones con bacterias gram-negativo .Gentamicin (2- [4,6-diamino-3- [3-amino-6- (1- methylaminoethyl) tetrahydropyran-2-yl] oxy-2-hydroxycyclohexoxy] -5-methyl-4-methylamino-tetrahydropyran -3, 5- diol) is a broad-spectrum hydrophilic aminoglycoside antibiotic effective against various kinds of bacterial infections, particularly those caused by infections with gram-negative bacteria.
Figure imgf000008_0001
Figure imgf000008_0001
La gentamicina se puede obtener por fermentación, o por síntesis química (Lek, parte del grupo Sandoz) . Para la preparación del complejo iónico de gentamicina y un surfactante aniónico aceptable en farmacia, se puede partir de la gentamicina sulfato como materia prima. La gentamicina sulfato (n° CAS 1405-41-0) es disponible en el mercado y puede obtenerse por ejemplo de Sigma-Aldrich o Molekula .Gentamicin can be obtained by fermentation, or by chemical synthesis (Lek, part of the Sandoz group). For the preparation of the ionic complex of gentamicin and an anionic surfactant acceptable in pharmacy, gentamicin sulfate can be used as raw material. Gentamicin sulfate (CAS No. 1405-41-0) is commercially available and can be obtained for example from Sigma-Aldrich or Molekula.
El bis- ( 2-etilhexil ) sulfosuccinato sódico (AOT) es un surfactante de naturaleza aniónico y puede obtenerse comercialmente de Sigma-Aldrich.Sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) is a surfactant of an anionic nature and can be obtained commercially from Sigma-Aldrich.
El complejo iónico de la presente invención, o compuesto iónico sin procesar, alude al compuesto formado por la gentamicina y el AOT, en donde la gentamicina y el AOT están unidos por enlaces iónicos. Éste complejo iónico puede prepararse según el método de "Hydrophobic IonThe ionic complex of the present invention, or unprocessed ionic compound, refers to the compound formed by gentamicin and AOT, where gentamicin and AOT are linked by ionic bonds. This ionic complex can be prepared according to the method of "Hydrophobic Ion
Pairing" (HIP) , el cual incluye las técnicas como el "precipitation ion pairing", "monophase processing" y "two-phase emulsión". Preferiblemente, la técnica para la complejación de la gentamicina en la presente invención es la "two-phase emulsión", descrita en WO01/32218 yPairing "(HIP), which includes techniques such as" precipitation ion pairing "," monophase processing "and "two-phase emulsion". Preferably, the technique for complexing gentamicin in the present invention is the "two-phase emulsion", described in WO01 / 32218 and
US5981474, cuyas referencias son incorporadas en la presente invención.US5981474, whose references are incorporated in the present invention.
En una realización particular, el complejo iónico de la presente invención puede prepararse mediante la disolución del sulfato de gentamicina en un disolvente que exponga las cargas eléctricas de la gentamicina, por ejemplo mediante la utilización de una disolución tampón a un pH ligeramente ácido (4-7) . A esta disolución se añade un volumen similar de una disolución del AOT en un disolvente orgánico no miscible con agua, por ejemplo el diclorometano . El complejo puede aislarse por centrifugación y separación de las fases orgánica y acuosa, seguido del secado de la fase orgánica, y evaporación al vacio.In a particular embodiment, the ionic complex of the present invention can be prepared by dissolving gentamicin sulfate in a solvent that exposes the electrical charges of gentamicin, for example by using a buffer solution at a slightly acidic pH (4- 7). To this solution is added a similar volume of a solution of the AOT in an organic solvent not miscible with water, for example dichloromethane. The complex can be isolated by centrifugation and separation of the organic and aqueous phases, followed by drying of the organic phase, and evaporation in vacuo.
La relación molar de 1:5 (gentamicina : AOT) en el complejo iónico de la presente invención alude a una concentración molar del AOT que es 5 veces mayor que la de la gentamicina, en tanto que equivale al número de grupos amino protonados de la gentamicina al pH de trabajo. Véase Figura 1.The molar ratio of 1: 5 (gentamicin: AOT) in the ionic complex of the present invention refers to a molar concentration of AOT that is 5 times greater than that of gentamicin, as it equals the number of protonated amino groups of the Gentamicin at working pH. See Figure 1.
Aparte de sus aplicaciones terapéuticas, se ha descubierto que el complejo iónico de gentamicina y AOT preparado mediante el método "Hydrophobic Ion Pairing" (véase la patente US5981474), en ser soluble en disolventes orgánicos, es de utilidad para la preparación de micro o nanoparticulas de gentamicina mediante el arriba mencionado proceso PCA. Asi, en una realización, la presente invención se refiere a la utilización de un complejo iónico de gentamicina y bis- (2-ethylhexyl) sulfosuccinato sódico (AOT) en una relación molar de 1:5 (gentamicina : AOT) , para su procesamiento con fluidos comprimidos .Apart from its therapeutic applications, it has been discovered that the ionic complex of gentamicin and AOT prepared by the "Hydrophobic Ion Pairing" method (see US5981474), being soluble in organic solvents, is useful for the preparation of micro or nanoparticles of gentamicin by the above-mentioned PCA process. Thus, in one embodiment, the present invention relates to the use of an ionic complex of gentamicin and bis- (2-ethylhexyl) Sodium sulphosuccinate (AOT) in a 1: 5 molar ratio (gentamicin: AOT), for processing with compressed fluids.
Por consiguiente, la presente invención también se refiere a la utilización de un complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT), en una relación molar de 1:5 (gentamicina : AOT), para la fabricación de un medicamento destinado al tratamiento de una enfermedad causada por la bacteria Brucella spp . , en donde el complejo iónico está adicionalmente procesado mediante : a) la disolución del complejo iónico gentamicina : AOT en un disolvente orgánico; b) el pulverizado de la disolución resultante de la etapa a) en un fluido comprimido miscible con el disolvente orgánico, que actúa como antisolvente y causa la precipitación de un sólido; c) la separación del sólido resultante de la etapa b) .Accordingly, the present invention also relates to the use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT), in a molar ratio of 1: 5 (gentamicin: AOT), for the manufacture of a medicine intended for the treatment of a disease caused by the bacterium Brucella spp. , wherein the ionic complex is further processed by: a) dissolution of the gentamicin ionic complex: AOT in an organic solvent; b) spraying the solution resulting from step a) into a compressed fluid miscible with the organic solvent, which acts as an anti-solvent and causes the precipitation of a solid; c) the separation of the solid resulting from step b).
En la presente invención, el término "complejo iónico gentamicina : AOT procesado" o similares denominaciones, alude al complejo iónico obtenido después de las etapas a) , b) , y e), y opcionalmente según una o varias de la realizaciones relacionadas con estas etapas y expuestas en los siguientes pasajes.In the present invention, the term "gentamicin ion complex: processed AOT" or similar designations refers to the ionic complex obtained after steps a), b), and e), and optionally according to one or more of the embodiments related to these steps and exposed in the following passages.
En una realización, el procesado adicional del complejo iónico gentamicina : AOT se lleva a cabo en un aparato como el reproducido esquemáticamente en la Figura 3. En particular, el aparato presenta un recipiente que contiene la disolución del complejo iónico de gentamicina y AOT, en un disolvente orgánico (12) . Este recipiente está conectado, mediante una tubería, a una bomba (10), gracias a la cual puede suministrarse la disolución a la vasija de precipitación (6), siempre que la válvula (11) está abierta. Asimismo, el recipiente que contiene el fluido comprimido que actúa como antisolvente (1) se encuentra también conectado a una bomba (3), mediante la cual se introduce dicho fluido comprimido a la mencionada vasija (6), siempre y cuando las válvulas (2 y 4) estén abiertas. La presión del reactor (6) se controla mediante la válvula reguladora de presión (8) . El reactor (6) se encuentra presurizado a una presión de trabajo de 10 a 200 bar, a una temperatura de trabajo de -50 a 200 0C, y contiene una fracción molar de CO2 de 0,3 a 1. El fluido comprimido se introduce en el reactor (6) a través de una boquilla (5), manteniendo la presión deseada del reactor (6) constante con la ayuda de la válvula reguladora de presión (8) . En una realización preferible, la fracción molar de CO2 se mantiene de forma constante, bombeándose inicialmente un disolvente orgánico puro, como la acetona, hasta conseguir un estado estacionario. En otra realización preferible, es durante el estado estacionario cuando se introduce, en el reactor (6) a través de una boquilla (5), la disolución en el mismo disolvente orgánico del complejo iónico gentamicina : AOT (12) . El precipitado formado como consecuencia del efecto antisolvente del fluido comprimido sobre la disolución pulverizada, cae sobre un filtro (7), el cual separa el material particulado en función de la luz del mismo filtro. La separación del material particulado se ha de realizar a las mismas condiciones de trabajo que la pulverización. Alternativamente, el filtro puede ser externo respecto al reactor (6) . El material particulado es finalmente secado. El secado puede realizarse dentro del reactor (6), mediante por ejemplo una corriente del fluido comprimido. En el caso de un secado en el interior del reactor (6), éste es preferiblemente seguido de una despresurización del sistema y la consiguiente recolección del sólido. En una realización preferible de la presente invención, la etapa a) de disolución se realiza a una presión de trabajo atmosférica .In one embodiment, further processing of the gentamicin: AOT ionic complex is carried out in an apparatus such as that schematically reproduced in Figure 3. In particular, the apparatus has a container containing the solution of the gentamicin and AOT ionic complex, in an organic solvent (12). This vessel is connected, by means of a pipe, to a pump (10), thanks to which the solution can be supplied to the vessel precipitation (6), provided that the valve (11) is open. Likewise, the container containing the compressed fluid that acts as an antisolvent (1) is also connected to a pump (3), by means of which said compressed fluid is introduced into said vessel (6), provided that the valves (2 and 4) be open. The reactor pressure (6) is controlled by the pressure regulating valve (8). The reactor (6) is pressurized at a working pressure of 10 to 200 bar, at a working temperature of -50 to 200 0 C, and contains a CO2 molar fraction of 0.3 to 1. The compressed fluid is It enters the reactor (6) through a nozzle (5), keeping the desired reactor pressure (6) constant with the help of the pressure regulating valve (8). In a preferable embodiment, the molar fraction of CO2 is constantly maintained, initially pumping a pure organic solvent, such as acetone, until a steady state is achieved. In another preferred embodiment, it is during the steady state when the solution in the same organic solvent of the gentamicin ionic complex: AOT (12) is introduced into the reactor (6) through the nozzle (5). The precipitate formed as a result of the anti-solvent effect of the compressed fluid on the spray solution falls on a filter (7), which separates the particulate material as a function of the light of the same filter. Particulate material must be separated at the same working conditions as spraying. Alternatively, the filter may be external with respect to the reactor (6). The particulate material is finally dried. Drying can be carried out inside the reactor (6), for example by means of a stream of compressed fluid. In the case of a drying inside the reactor (6), this is preferably followed by a depressurization of the system and the consequent collection of the solid. In a preferable embodiment of the present invention, the dissolution stage a) is carried out at an atmospheric working pressure.
En otra realización preferible de la presente invención, las condiciones de trabajo del reactor son de una presión de 50 a 150 bar, una temperatura de 5 a 60 0C, y una fracción molar del fluido comprimido de 0,7 a 1. En una realización incluso más preferible de la presente invención, la presión de trabajo es aproximadamente de 100 bar, la temperatura es aproximadamente de 25 0C, y la fracción molar del fluido comprimido de 0,95. Las presiones de trabajo durante las etapas (b) y (c) son iguales.In another preferable embodiment of the present invention, the working conditions of the reactor are of a pressure of 50 to 150 bar, a temperature of 5 to 60 0 C, and a molar fraction of the compressed fluid of 0.7 to 1. In a even more preferably the present invention embodiment, the pressure is about 100 bar, the temperature is about 25 0 C, and the mole fraction of the compressed fluid 0.95. The working pressures during stages (b) and (c) are the same.
El diámetro de la boquilla puede ser de 10 a 500 μm. Como es comúnmente sabido, una variación en el diámetro de la boquilla conlleva una variación del tamaño del material particulado obtenido.The diameter of the nozzle can be from 10 to 500 μm. As is commonly known, a variation in the diameter of the nozzle entails a variation in the size of the particulate material obtained.
En una realización preferente de la presente invención, la boquilla para pulverizar es del tipo Hollow Cone .In a preferred embodiment of the present invention, the spray nozzle is of the Hollow Cone type.
La luz del filtro puede variar de 0,05 a 100 μm, preferiblemente la luz del filtro varia entre 0,2 a 30 μm.The filter light can vary from 0.05 to 100 μm, preferably the filter light varies between 0.2 to 30 μm.
El proceso de la presente invención puede realizarse por lotes o de forma semicontinuada . Un proceso por lotes se puede conseguir mediante la alimentación discontinua (de una sola vez) y controlada del fluido comprimido en la vasija de precipitación; una alimentación discontinua y controlada del disolvente orgánico en el reactor hasta conseguir un estado estacionario para mantener constante la fracción molar del fluido comprimido; un pulverizado discontinuo y controlado de la disolución orgánica del complejo iónico de gentamicina y AOT; una separación del precipitado obtenido de forma discontinua y controlada dentro del mismo reactor. Un proceso semicontinuado se puede conseguir mediante la alimentación continua y controlada del fluido comprimido en la vasija de precipitación; una alimentación continua y controlada del disolvente orgánico en el reactor hasta conseguir un estado estacionario para mantener constante la fracción molar del fluido comprimido; un pulverizado continuo y controlado de la disolución orgánica del complejo iónico de gentamicina y AOT; y una separación del precipitado obtenido mediante el uso de una batería de filtros externos al reactor que van reemplazándose en la medida en que se saturen.The process of the present invention can be carried out in batches or semi-continuously. A batch process can be achieved by discontinuous (one-time) and controlled feeding of the compressed fluid in the precipitation vessel; a discontinuous and controlled feeding of the organic solvent in the reactor until a steady state is achieved to keep the molar fraction of the compressed fluid constant; a spray discontinuous and controlled organic solution of the ionic complex of gentamicin and AOT; a separation of the precipitate obtained in a discontinuous and controlled manner within the same reactor. A semi-continuous process can be achieved by continuous and controlled feeding of the compressed fluid in the precipitation vessel; a continuous and controlled feeding of the organic solvent in the reactor until a steady state is achieved to keep the molar fraction of the compressed fluid constant; a continuous and controlled spraying of the organic solution of the ionic complex of gentamicin and AOT; and a separation of the precipitate obtained by using a battery of filters external to the reactor that are replaced as they become saturated.
En una realización de la presente invención, el disolvente orgánico de la etapa a) del proceso mencionado arriba es seleccionado entre alcoholes monohídricos como el metanol, etanol, 1-propanol, 2-propanol, 1-butanol, 1-hexanol, 1- octanol, y trifluoroetanol; alcoholes polihídricos como el propilenglicol, PEG 400, y 1, 3-propanediol; éteres como el tetrahidrofurano (THF) , y dietiléter; alcanos como la decalina, isooctano, y aceite mineral; aromáticos como el benceno, tolueno, clorobenceno, y piridina; amidas como la n-metil pirrolidona (NMP), y N, N-dimetilformamida (DMF); esteres como el acetato de etilo, acetato de propilo, y acetato de metilo; clorocarbonos como el diclorometano, cloroformo, tetraclorometano, 1, 2-dicloroetano, y 1,1,1- tricloroetano; cetonas como la acetona, cetona etil metílica, y cetona isobutílica metílica; otros disolventes como etilenodiamina, acetonitrilo, y trimetilfosfato . En una realización preferible de la presente invención, el disolvente orgánico de la etapa a) es la acetona. Disolventes de baja volatilidad tales como dimetilacetamida o dimetilsulfóxido pueden también ser utilizados. Las mezclas de disolventes, tales como metanol al 50% y acetona al 50%, pueden también ser utilizadas, al igual que las mezclas con agua, siempre y cuando el complejo iónico sea suficientemente soluble y el fluido comprimido sea miscible con dicha mezcla de disolventes. En cualquier caso, sea cual sea la naturaleza del disolvente orgánico, éste ha de ser necesariamente miscible con el fluido comprimido.In one embodiment of the present invention, the organic solvent of step a) of the above-mentioned process is selected from monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-hexanol, 1- octanol , and trifluoroethanol; polyhydric alcohols such as propylene glycol, PEG 400, and 1,3-propanediol; ethers such as tetrahydrofuran (THF), and diethyl ether; alkanes such as decalin, isooctane, and mineral oil; aromatics such as benzene, toluene, chlorobenzene, and pyridine; amides such as n-methyl pyrrolidone (NMP), and N, N-dimethylformamide (DMF); esters such as ethyl acetate, propyl acetate, and methyl acetate; chlorocarbons such as dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane, and 1,1,1-trichloroethane; ketones such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; other solvents such as ethylenediamine, acetonitrile, and trimethyl phosphate. In a preferable embodiment of the present invention, the organic solvent of step a) is acetone. Low volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used. Solvent mixtures, such as 50% methanol and 50% acetone, can also be used, as well as mixtures with water, as long as the ionic complex is sufficiently soluble and the compressed fluid is miscible with said solvent mixture. . In any case, whatever the nature of the organic solvent, it must necessarily be miscible with the compressed fluid.
Durante el pulverizado de la disolución del complejo iónico de gentamicina y AOT en la etapa b) , precipita el material compuesto, y el disolvente orgánico se disuelve en el fluido comprimido. Además, el disolvente debe tener una toxicidad relativamente baja y que se pueda eliminar de la dispersión a un nivel que sea aceptable según el comité internacional sobre pautas de la armonización (ICH) . La eliminación del disolvente a los niveles exigidos por la ICH puede requerir una manipulación posterior como el "tray-drying" o secado con bandejas.During the spraying of the solution of the ionic complex of gentamicin and AOT in step b), the composite material precipitates, and the organic solvent dissolves in the compressed fluid. In addition, the solvent must have a relatively low toxicity and can be removed from the dispersion at a level that is acceptable according to the international committee on harmonization guidelines (ICH). Solvent removal at the levels required by the ICH may require subsequent handling such as "tray-drying" or tray drying.
En una realización de la presente invención, la concentración de la disolución del complejo iónico en el disolvente orgánico es de 0,001 a 0,3 g/ml, preferiblemente, de 0,01 a 0,1 g/ml.In one embodiment of the present invention, the concentration of the ionic complex solution in the organic solvent is 0.001 to 0.3 g / ml, preferably 0.01 to 0.1 g / ml.
La concentración de la disolución preparada en la etapa a) de la presente invención, conviene que sea lo más alta posible, para reducir la cantidad de disolvente a eliminar en etapas posteriores, siempre que ello no afecte de manera indeseada las características del material final. Así, la disolución del complejo iónico en el disolvente tendrá generalmente una concentración del complejo iónico de por lo menos de cerca de 0,001 g/ml, preferiblemente por lo menos de cerca de 0,01 g/ml, y más preferiblemente por lo menos de cerca de 0,1 g/ml . Sin embargo, concentraciones del complejo iónico más bajas son también adecuadas para formar dispersiones sólidas. En una realización de la presente invención, la concentración de la disolución resultante de la etapa a) es aproximadamente de 0,01 g/ml a 0,3 g/ml.The concentration of the solution prepared in step a) of the present invention, should be as high as possible, to reduce the amount of solvent to be removed in later stages, provided that this does not undesirably affect the characteristics of the final material. Thus, the dissolution of the ionic complex in the solvent will generally have a concentration of the ionic complex of at least about 0.001 g / ml, preferably at least about 0.01 g / ml, and more preferably at least about 0.1 g / ml. However, lower concentrations of the ionic complex are also suitable for forming solid dispersions. In one embodiment of the present invention, the concentration of the solution resulting from step a) is approximately 0.01 g / ml to 0.3 g / ml.
En una realización de la presente invención, el fluido comprimido miscible con el disolvente orgánico, que actúa como antisolvente y causa la precipitación de un sólido en la etapa b) , es seleccionado entre CO2, etano, propano, hidroclorofluorocarbonos, y hidrofluorocarbonos . Preferiblemente, el fluido comprimido en la etapa b) es el CO2, considerado como un disolvente ecológico, ya que no es tóxico, no es inflamable, no es corrosivo, no es dañino para el medio ambiente, y además es muy abundante en la naturaleza. También preferiblemente, la relación entre la cantidad de fluido comprimido y de disolvente orgánico corresponde a una fracción molar aproximada de 0,3 a 1, preferiblemente de 0,5 a 1.In one embodiment of the present invention, the compressed fluid miscible with the organic solvent, which acts as an anti-solvent and causes the precipitation of a solid in step b), is selected from CO2, ethane, propane, hydrochlorofluorocarbons, and hydrofluorocarbons. Preferably, the fluid compressed in step b) is CO2, considered as an ecological solvent, since it is not toxic, it is not flammable, it is not corrosive, it is not harmful to the environment, and it is also very abundant in nature. . Also preferably, the ratio between the amount of compressed fluid and organic solvent corresponds to an approximate molar fraction of 0.3 to 1, preferably 0.5 to 1.
En una realización de la presente invención, la separación de la etapa c) del proceso aquí presentado se puede realizar mediante filtración. Preferiblemente, la separación de la etapa c) se realiza con un filtro con un tamaño de poro de 0,05 a 100 μm, de 0,05 a 50 μm, de 0,05 a 25 μm, de 0,1 a 10 μm, de 0,1 a 1 μm, de aproximadamente 0, 22μm.In an embodiment of the present invention, the separation of step c) of the process presented herein can be performed by filtration. Preferably, the separation of step c) is performed with a filter with a pore size of 0.05 to 100 μm, 0.05 to 50 μm, 0.05 to 25 μm, 0.1 to 10 μm , from 0.1 to 1 μm, approximately 0.22μm.
En otra realización de la presente invención, el sólido resultante de la etapa c) del proceso aquí presentado es posteriormente secado. Dicho secado puede llevarse a cabo usando una corriente de CO2 u otros gases, una estufa, o al vacio. La corriente de gas para realizar el secado puede ser de diferente naturaleza, pero para reducir al mínimo el riesgo de fuego o de explosión debido a la ignición de vapores inflamables, y también para reducir al mínimo la oxidación indeseable de los principios activos, u otros materiales presentes en las micro- y nanopartículas, es preferible utilizar un gas inerte como el nitrógeno, aire enriquecido con nitrógeno, o argón. El CO2, como gas de secado, también es una realización preferible de la presente invención. La temperatura del gas de secado en la entrada al aparato oscila normalmente de unos -50° a unos 2000C.In another embodiment of the present invention, the solid resulting from step c) of the process presented here is subsequently dried. Said drying can be carried out using a stream of CO2 or other gases, a stove, or vacuum. The gas stream for drying can be of a different nature, but to minimize the risk of fire or explosion due to ignition of flammable vapors, and also to minimize undesirable oxidation of the active ingredients, or others Materials present in the micro- and nanoparticles, it is preferable to use an inert gas such as nitrogen, nitrogen enriched air, or argon. CO2, as a drying gas, is also a preferable embodiment of the present invention. The temperature of the drying gas at the entrance to the device normally ranges from about -50 ° to about 200 0 C.
En otra realización, la presente invención se refiere a un complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT) en una relación molar de 1:5In another embodiment, the present invention relates to an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1: 5
(gentamicina : AOT) , procesado según las etapas a) , b) , y c) anteriormente descritas, y opcionalmente según cualesquiera de las realizaciones anteriormente descritas y relacionadas con las etapas a) , b) , y c) . Así, la presente invención se refiere al producto obtenible según con las etapas a) , b) , y e) .(gentamicin: AOT), processed according to steps a), b), and c) described above, and optionally according to any of the embodiments described above and related to steps a), b), and c). Thus, the present invention relates to the product obtainable according to steps a), b), and e).
El complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT) en una relación molar de 1:5 (gentamicina : AOT) , procesado según las etapas a) , b) , y c) , o el producto obtenible según con las etapas a) , b) , y c) , aparece como un material particulado.The ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), processed according to steps a), b), and c), or the product obtainable according to with stages a), b), and c), it appears as a particulate material.
Este "material particulado" se define en la presente invención como un material que comprende partículas discretas, o bien a agregados de dichas partículas, o una mezcla de ambas. En la mayoría de los casos, aparece una mezcla de partículas separadas y agregados de partículas. En todos los casos, el tamaño aproximado de dicho material particulado puede oscilar de 0,05 a 100 μm, tamaños determinados por microscopía electrónica de barrido (SEM) .This "particulate material" is defined in the present invention as a material comprising discrete particles, or aggregates of said particles, or a mixture of both. In most cases, a mixture of separate particles and aggregates of particles appears. In all cases, the approximate size of said material particulate can range from 0.05 to 100 μm, sizes determined by scanning electron microscopy (SEM).
En una realización, la presente invención se refiere a una formulación farmacéutica que comprende el complejo iónico procesado de gentamicina : AOT según cualesquiera de las realizaciones anteriormente descritas, y al menos un excipiente aceptable en farmacia.In one embodiment, the present invention relates to a pharmaceutical formulation comprising the processed ionic gentamicin complex: AOT according to any of the previously described embodiments, and at least one pharmaceutically acceptable excipient.
La formulación de los complejos iónicos de la presente invención, ya sea el complejo iónico gentamicina : AOT procesado, o sin procesar, dependerá de la naturaleza de la condiciones clínicas asociadas a la Brucelosis, de la severidad de estas condiciones, del paciente a tratar, del juicio del médico, así como de la ruta de administración. El complejo iónico, procesado o no procesado, de la presente invención puede ser administrado convenientemente en varias formas farmacéuticas como son los comprimidos, cápsulas, supositorios, suspensiones, polvos para suspensión, cremas, parches transdérmicos, depósitos, y similares .The formulation of the ionic complexes of the present invention, whether the ionic gentamicin complex: processed, or unprocessed AOT, will depend on the nature of the clinical conditions associated with Brucellosis, on the severity of these conditions, on the patient to be treated, of the doctor's judgment, as well as the route of administration. The ionic complex, processed or unprocessed, of the present invention can be conveniently administered in various pharmaceutical forms such as tablets, capsules, suppositories, suspensions, suspension powders, creams, transdermal patches, deposits, and the like.
Generalmente, los excipientes tales como los solubilizadores o disolventes, surfactantes, modificadores del pH, diluyentes, sistemas matrices, agentes formadores de complejos, disgregantes, aglutinantes, deslizantes, antiadherentes, lubrificantes, viscosizantes, floculantes, dispersantes o defloculantes, redispersantes, humectantes, colorantes, aromatizantes, conservantes, y así sucesivamente, se pueden utilizar para los propósitos acostumbrados y en cantidades típicas sin afectar las características de las composiciones de la presente invención. Véase por ejemplo, Remington's Pharmaceutical Sciences (1995) . Los sistemas matriz convencionales, los agentes comple jadores, los solubilizadores, los diluyentes, los disgregantes, o los aglutinantes pueden también añadirse como parte de la composición inicial o añadirse mediante la granulación por vía húmeda, por compresión, u otras. Estos materiales pueden abarcar hasta 90 % en peso de la composición.Generally, excipients such as solubilizers or solvents, surfactants, pH modifiers, diluents, matrix systems, complexing agents, disintegrants, binders, glidants, non-sticks, lubricants, viscosifiers, flocculants, dispersants or deflocculants, redispersants, humectants, colorants , flavorings, preservatives, and so on, can be used for customary purposes and in typical amounts without affecting the characteristics of the compositions of the present invention. See for example, Remington's Pharmaceutical Sciences (1995). Conventional matrix systems, complexing agents, solubilizers, diluents, disintegrants, or binders may also be added as part of the initial composition or added by wet granulation, compression, or others. These materials can cover up to 90% by weight of the composition.
Entre los agentes solubilizadores o disolventes, se incluyen el etanol, propilenglicol, o polietilenglicol .Solubilizing agents or solvents include ethanol, propylene glycol, or polyethylene glycol.
Una clase muy útil de excipientes son los surfactantes . Estos surfactantes no se refieren al AOT que forma un complejo aniónico con la gentamicina, sino a surfactantes adicionales que se pueden emplear de manera ventajosa para aumentar la velocidad de disolución de la gentamicina, facilitando el mojado o hidratación de la gentamicina, o aumentando la velocidad de liberación de la gentamicina de la forma de dosificación. Estos surfactantes están preferiblemente presentes en la forma farmacéutica final en un porcentaje de hasta 10 % en peso. Ejemplos de surfactantes incluyes preferiblemente los sulfonatos de ácidos grasos y de alkiles; surfactantes comerciales tales como el cloruro del benzalconio (Hyamione® 1622); esteres del ácido graso del polioxietileno de sorbitano (Tween®, Liposorb® O-20, Capmul® POE-O); y surfactantes naturales tales como el ácido taurocólico de sodio, l-palmitoil-2- oleoil-sn-glicero-3-fosfocolina, lecitina, y otros fosfolipidos y mono-y diglicéridos . Tales materiales se pueden emplear de forma ventajosa para aumentar la velocidad de disolución, por ejemplo, facilitando la humectabilidad del medicamento, o alternativamente aumentando la velocidad de liberación de la gentamicina a partir de su forma de dosificación o forma farmacéutica.A very useful class of excipients are surfactants. These surfactants do not refer to the AOT that forms an anionic complex with gentamicin, but to additional surfactants that can be advantageously used to increase the dissolution rate of gentamicin, facilitating the wetting or hydration of gentamicin, or increasing the speed of release of gentamicin from the dosage form. These surfactants are preferably present in the final pharmaceutical form in a percentage of up to 10% by weight. Examples of surfactants preferably include fatty acid and alkyl sulfonates; commercial surfactants such as benzalkonium chloride (Hyamione® 1622); esters of sorbitan polyoxyethylene fatty acid (Tween®, Liposorb® O-20, Capmul® POE-O); and natural surfactants such as sodium taurocolic acid, l-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine, lecithin, and other phospholipids and mono-and diglycerides. Such materials can be used advantageously to increase the dissolution rate, for example, by facilitating the wettability of the medicament, or alternatively increasing the release rate of gentamicin from its dosage form or pharmaceutical form.
La adición de modificadores del pH tales como ácidos, bases, o soluciones tampón puede ser beneficiosa para retardar la disolución del complejo iónico (por e j . ácidos tales como el ácido cítrico o ácido succínico) o, alternativamente, para realzar la velocidad de disolución del complejo iónico (por ejemplo bases tales como el acetato sódico o aminas) .The addition of pH modifiers such as acids, bases, or buffer solutions may be beneficial for retard the dissolution of the ionic complex (eg acids such as citric acid or succinic acid) or, alternatively, to enhance the dissolution rate of the ionic complex (for example bases such as sodium acetate or amines).
Ejemplos de diluyentes incluyen la lactosa, el manitol, el chilitol, la celulosa microcristalina, el fosfato de calcio dibásico (anhidro y dihidratado) , y el almidón.Examples of diluents include lactose, mannitol, chilitol, microcrystalline cellulose, dibasic calcium phosphate (anhydrous and dihydrate), and starch.
Los ejemplos de los materiales matriciales o sistemas matriz incluyen las matrices hidrófilas obtenidas por granulación de la gentamicina con derivados celulósicos hidrófilos de elevada viscosidad no digeribles tales como la carboximetilcelulosa o hidroxipropilmetilcelulosa; las matrices hidrófobas o lipídicas con soportes de mono, di, y triglicéridos, ácidos grasos, ceras y glicéridos mixtos de origen sintético; las matrices inertes tales como los sistemas laminares, sistemas flotantes, o sistemas bioadhesivos .Examples of matrix materials or matrix systems include hydrophilic matrices obtained by granulating gentamicin with hydrophilic cellulose derivatives of high digestible viscosity such as carboxymethyl cellulose or hydroxypropyl methylcellulose; hydrophobic or lipid matrices with mono, di, and triglyceride supports, fatty acids, waxes and mixed glycerides of synthetic origin; inert matrices such as laminar systems, floating systems, or bioadhesive systems.
Los ejemplos de disgregantes incluyen el almidón de patata o maíz, la sodio-carboximetilaminopectina, glicolato sódico de almidón, la formaldehidogelatina, formaldehidocaseína, gelatina, el alginato de calcio, el alginato de sodio, derivados de la celulosa tales como la carboximetilcelulosa sódica, la celulosa metílica, la croscarmelosa sódica, el bicarbonato sódico, el peróxido de magnesio, las saponinas y espumantes sintéticos, y las formas reticuladas de polivinilpirrolidona tales como aquellas vendidas bajo el nombre comercial Crospovidona .Examples of disintegrants include potato or corn starch, sodium carboxymethylaminopectin, sodium starch glycolate, formaldehydegelatin, formaldehyde casein, gelatin, calcium alginate, sodium alginate, cellulose derivatives such as sodium carboxymethyl cellulose, methyl cellulose, croscarmellose sodium, sodium bicarbonate, magnesium peroxide, saponins and synthetic foaming agents, and cross-linked forms of polyvinylpyrrolidone such as those sold under the trade name Crospovidone.
Los ejemplos de aglutinantes incluyen a derivados de la celulosa tales como la celulosa metílica, celulosa microcristalina, el almidón, el mucílago de almidón, la solución de gelatina, la gelatina hidrolizada, derivados del ácido alginico, la polivinilpirrolidona, y las gomas tales como la goma guar, y el tragacanto.Examples of binders include cellulose derivatives such as methyl cellulose, microcrystalline cellulose, starch, starch mucilage, gelatin solution, hydrolyzed gelatin, derivatives of algic acid, polyvinylpyrrolidone, and gums such as guar gum, and tragacanth.
Los ejemplos de agentes deslizantes, antiadherentes, o lubrificantes incluyen a derivados del sílice, estearato magnésico, estearato calcico, talco, o ácido esteáricoExamples of sliding, non-stick, or lubricating agents include derivatives of silica, magnesium stearate, calcium stearate, talc, or stearic acid.
Los ejemplos de agentes viscosizantes incluyen a polisacáridos naturales como los alginatos, goma arábiga, carragaen, goma guar, y tragacanto; polímeros sintéticos como el carbómero, PVP, poloxámeros; coloides hidrófilos como la metilcelulosa, carboximetilcelulosa sódica, hidroxipropilcelulosa, hidroxipropilmetilcelulosa, celulosa microcristalina; y las arcillas coloidales como la bentonita, o el silicato de aluminio y magnesioExamples of viscosifying agents include natural polysaccharides such as alginates, gum arabic, carragaen, guar gum, and tragacanth; synthetic polymers such as carbomer, PVP, poloxamers; hydrophilic colloids such as methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose; and colloidal clays such as bentonite, or magnesium aluminum silicate
(Veegum®) .(Veegum®).
Los ejemplos de agentes floculantes incluyen a los electrolitos o tensioactivos aniónicos, debido a la carga positiva de la gentamicina; alternativamente incluyen también a polioles como el sorbitol; polímeros hidrófilos; o arcillas coloidales tales como la bentonita. Los ejemplos de agentes dispersantes o defloculantes incluyen a las lecitinas.Examples of flocculating agents include electrolytes or anionic surfactants, due to the positive charge of gentamicin; alternatively they also include polyols such as sorbitol; hydrophilic polymers; or colloidal clays such as bentonite. Examples of dispersing or deflocculating agents include lecithins.
Entre los agentes redispersantes, destacan el EDTA, fosfato potásico, acido cítrico, citrato sódico y aerosil.Redispersant agents include EDTA, potassium phosphate, citric acid, sodium citrate and aerosol.
Los ejemplos de humectantes incluyen a los tensioactivos con un HLB entre 7 y 10, o polímeros hidrófilos, glicerina, propilenglicol, o etanol.Examples of humectants include surfactants with an HLB between 7 and 10, or hydrophilic polymers, glycerin, propylene glycol, or ethanol.
Los ejemplos de conservantes incluyen los sulfitos (un antioxidante) , el cloruro del benzalconio, el metilparabeno, el propilparabeno, el alcohol benzílico, y el benzoato sódico.Examples of preservatives include sulphites (an antioxidant), benzalkonium chloride, methylparaben, propylparaben, benzyl alcohol, and sodium benzoate.
Otros excipientes convencionales se pueden emplear en las composiciones de esta invención, incluyendo aquellos excipientes bien conocidos en el estado de la técnica.Other conventional excipients may be employed in the compositions of this invention, including those excipients well known in the state of the art.
Generalmente, los excipientes tales como los colorantes, aromatizantes, y similares pueden utilizarse para los propósitos acostumbrados y en las cantidades habituales sin afectar las propiedades de las composiciones.Generally, excipients such as colorants, flavorings, and the like can be used for customary purposes and in the usual amounts without affecting the properties of the compositions.
El complejo iónico de la presente invención, ya sea procesado o sin procesar, puede administrarse a través de una variedad amplia de vías, incluyendo, pero sin limitarse a, las vías oral, nasal, rectal, vaginal, subcutánea, y pulmonar. Generalmente, se prefiere la vía oral .The ionic complex of the present invention, whether processed or unprocessed, can be administered through a wide variety of routes, including, but not limited to, the oral, nasal, rectal, vaginal, subcutaneous, and pulmonary routes. Generally, the oral route is preferred.
El complejo iónico de la presente invención, ya sea procesado o sin procesar, puede también administrarse a través de supositorios o de otros vehículos transmucosales . Típicamente, tales formulaciones incluirán los excipientes que facilitan el paso del complejo a través de la mucosa tales como los surfactantes aceptables en farmacia.The ionic complex of the present invention, whether processed or unprocessed, can also be administered through suppositories or other transmucosal vehicles. Typically, such formulations will include excipients that facilitate the passage of the complex through the mucosa such as pharmaceutically acceptable surfactants.
El complejo iónico, ya sea procesado o sin procesar, se puede también administrar por la vía tópica, o en una formulación diseñada para penetrar la piel. Éstas formulaciones incluyen lociones, cremas, los ungüentos, y similares que se pueden formular de acuerdo a los métodos comúnmente conocidos en el estado de la técnica.The ionic complex, whether processed or unprocessed, can also be administered topically, or in a formulation designed to penetrate the skin. These formulations include lotions, creams, ointments, and the like that can be formulated according to methods commonly known in the state of the art.
Los complejos pueden también administrarse por inyección, incluyendo la vía intravenosa, intramuscular, subcutánea o intraperitoneal . Las formulaciones comunes para tal uso son formulaciones liquidas en vehículos isotónicos tales como solución de Hank o Ringer. Formulaciones alternativas incluyen a los aerosoles nasales, formulaciones liposomiales, formulaciones de liberación retardada, y similares, comúnmente conocidas en el estado de la técnica.The complexes can also be administered by injection, including intravenous, intramuscular, subcutaneous or intraperitoneal Common formulations for such use are liquid formulations in isotonic vehicles such as Hank or Ringer's solution. Alternative formulations include nasal sprays, liposomial formulations, delayed-release formulations, and the like, commonly known in the state of the art.
Cualquier formulación conveniente puede ser utilizada. Un compendio de formulaciones conocidas en el estado de la técnica se encuentra en Remington's Pharmaceutical Sciences, última edición, Mack Publishing Company, USA. La referencia a este manual es rutinaria en la profesión farmacéutica .Any convenient formulation can be used. A compendium of formulations known in the state of the art is found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, USA. The reference to this manual is routine in the pharmaceutical profession.
Los complejos iónicos de la presente invención se pueden también utilizar en una variedad amplia de formas de dosificación o formas farmacéuticas para la administración de la gentamicina. Ejemplos de formas de dosificación son los polvos o los granulos que se pueden tomar secos o reconstituidos con la adición de agua u otros líquidos para formar una mezcla, una suspensión, o una solución; comprimidos; cápsulas; y las pildoras. Diversos excipientes pueden mezclarse, pulverizar, o granular con las composiciones de esta invención para formar un material conveniente para las formas de dosificación antedichas .The ionic complexes of the present invention can also be used in a wide variety of dosage forms or pharmaceutical forms for the administration of gentamicin. Examples of dosage forms are powders or granules that can be taken dry or reconstituted with the addition of water or other liquids to form a mixture, a suspension, or a solution; tablets capsules; And the pills. Various excipients may be mixed, pulverized, or granulated with the compositions of this invention to form a suitable material for the above dosage forms.
Los complejos iónicos de la invención se pueden formular como suspensión. Tal suspensión se puede formular como un liquido o pasta a la hora de su fabricación, o puede ser formulada como polvo seco con un liquido, habitualmente el agua, añadida posteriormente pero antes de la administración oral. Tales polvos que luego forman una suspensión se refieren a menudo como bolsitas o polvos orales para reconstitución. Tales formas de dosificación se pueden formular y reconstituir mediante cualquier procedimiento ya conocido. El método más simple seria la formulación de la forma de dosificación como polvo seco que luego es reconstituido simplemente agregando el agua y agitando la mezcla. Alternativamente, la forma de dosificación se puede formular como un liquido y polvo seco que se combinan y agitan para formar la suspensión oral. En otra realización, la forma de dosificación puede formularse como dos polvos que se reconstituyen mediante una primera adición de agua a un polvo para formar una solución a la cual el segundo polvo se combina con agitación para formar la suspensión.The ionic complexes of the invention can be formulated as a suspension. Such suspension can be formulated as a liquid or paste at the time of its manufacture, or it can be formulated as dry powder with a liquid, usually water, added later but before oral administration. Such powders that then form a suspension are often referred to as sachets or powders. Oral for reconstitution. Such dosage forms can be formulated and reconstituted by any known procedure. The simplest method would be the formulation of the dosage form as dry powder which is then reconstituted simply by adding the water and stirring the mixture. Alternatively, the dosage form can be formulated as a liquid and dry powder that combine and stir to form the oral suspension. In another embodiment, the dosage form can be formulated as two powders that are reconstituted by a first addition of water to a powder to form a solution to which the second powder is combined with stirring to form the suspension.
Alternativamente, el complejo iónico de la presente invención puede presentarse como una forma de liberación controlada o sostenida. Las formas de liberación controlada o sostenida incluyen habitualmente sistemas matriz como los descritos anteriormente, resinas de intercambio iónico, o barreras peliculares que controlan la difusión de la gentamicina.Alternatively, the ionic complex of the present invention can be presented as a controlled or sustained release form. Controlled or sustained release forms usually include matrix systems such as those described above, ion exchange resins, or film barriers that control the spread of gentamicin.
En una realización de la presente invención, se contempla un método de tratamiento que comprende la administración sistémica de una cantidad eficaz de complejo iónico de gentamicina y AOT, procesado de acuerdo con la presente invención, o sin procesar, para tratar, combatir, o prevenir, una enfermedad causada por la bacteria Brucella spp . Por lo tanto, los complejos iónicos de gentamicina : AOT de la presente invención se pueden utilizar en la fabricación de un medicamento destinado al tratamiento de una enfermedad causada por la bacteria Brucella spp. En otras palabras, la presente invención proporciona el complejo iónico gentamicina : AOT, procesado o sin procesar, para su utilización en el tratamiento de una enfermedad causada por la bacteria Brucella spp.In one embodiment of the present invention, a treatment method is contemplated which comprises the systemic administration of an effective amount of ionic complex of gentamicin and AOT, processed in accordance with the present invention, or unprocessed, to treat, combat, or prevent , a disease caused by the bacterium Brucella spp. Therefore, the ionic gentamicin: AOT complexes of the present invention can be used in the manufacture of a medicament for the treatment of a disease caused by the bacterium Brucella spp. In other words, the present invention provides the gentamicin ionic complex: AOT, processed or unprocessed, for use in the treatment of a disease caused by the bacterium Brucella spp.
Debido a sus propiedades antibacterianas favorables, como se hará evidente de los ejemplos que siguen, los complejo iónico de la presente invención son útiles en el tratamiento de los individuos infectados por Brucella spp y para la profilaxis de estos individuos. En general, los complejo iónicos de la presente invención pueden ser útiles en el tratamiento de animales mamíferos infectados con Brucella spp. Las condiciones que se pueden prevenir o tratar con los complejos iónicos de la presente invención, especialmente las condiciones que se asocian a la Brucella spp, incluyen la brucelosis, y síntomas o secuelas asociadas o producidas por las bacterias del género Brucella, tales como el aborto prematuro del feto, fiebres inconstantes, sudor, debilidad, anemia, dolores de cabeza, depresión, y dolor muscular y corporal, hepatitis granulomatosa, artritis, espondilitis, anemia, leucopenia, trombocitopenia, meningitis, uveitis, neuritis óptica, fiebre reumática, y endocarditis, entre otras.Due to their favorable antibacterial properties, as will be apparent from the examples that follow, the ionic complexes of the present invention are useful in the treatment of individuals infected with Brucella spp and for the prophylaxis of these individuals. In general, the ionic complexes of the present invention may be useful in the treatment of mammalian animals infected with Brucella spp. Conditions that can be prevented or treated with the ionic complexes of the present invention, especially conditions that are associated with Brucella spp, include brucellosis, and symptoms or sequelae associated or produced by Brucella genus bacteria, such as abortion. premature fetus, inconstant fevers, sweat, weakness, anemia, headaches, depression, and muscle and body aches, granulomatous hepatitis, arthritis, spondylitis, anemia, leukopenia, thrombocytopenia, meningitis, uveitis, optic neuritis, rheumatic fever, and endocarditis , among other.
En una realización preferente de la presente invención, el mamífero es una persona humana.In a preferred embodiment of the present invention, the mammal is a human person.
En otra realización de la presente invención, los complejos iónicos gentamicina : AOT de la presente invención se pueden utilizar en la fabricación de un medicamento destinado al tratamiento de una enfermedad causada por una bacteria seleccionada del grupo de B. melitensis, B. suis, B. abortus, B. ovis, B. canis, y B. neotomae .In another embodiment of the present invention, the gentamicin: AOT ion complexes of the present invention can be used in the manufacture of a medicament for the treatment of a disease caused by a bacterium selected from the group of B. melitensis, B. suis, B Abortus, B. ovis, B. canis, and B. neotomae.
En general, se contempla que una cantidad antibacteriana eficaz diaria de los complejos iónicos de la presente invención, sería de 0,01 mg/kg a 100 mg/kg de peso corporal, preferiblemente de 1 mg/kg a 50 mg/kg de peso corporal, más preferiblemente de 1 mg/kg a 25 mg/kg de peso corporal. Puede ser también apropiado administrar la dosis requerida en dos, tres, cuatro, o más subdosis en los intervalos apropiados durante el día. Las subdosis antedichas se pueden formular como formas unitarias de dosificación, por ejemplo, comprendiendo de 1 a 20 mg, y en particular de 1 a 10 mg del ingrediente activo por forma unitaria de dosificación.In general, it is contemplated that a daily effective antibacterial amount of the ionic complexes of the present invention would be from 0.01 mg / kg to 100 mg / kg of weight. body weight, preferably 1 mg / kg to 50 mg / kg body weight, more preferably 1 mg / kg to 25 mg / kg body weight. It may also be appropriate to administer the required dose in two, three, four, or more sub-doses at the appropriate intervals during the day. The aforementioned sub-doses may be formulated as unit dosage forms, for example, comprising 1 to 20 mg, and in particular 1 to 10 mg of the active ingredient per unit dosage form.
La dosificación y la frecuencia exactas de la administración dependen de la condición particular a tratar, de la severidad de la condición a tratar, de la edad, del peso, del sexo, de la extensión de la enfermedad, y de la condición física general del paciente, así como de la otra medicación que el individuo pueda tomar, tal y como es bien sabido por los expertos en la materia. Además, es evidente que la cantidad eficaz diaria antedicha se puede disminuir o aumentar dependiendo de cómo reacciona el paciente a dicha medicación, y/o dependiendo de la evaluación realizada por el médico que prescribe el medicamento de la presente invención. Así, las cantidades eficaces diarias mencionadas más arriba se tienen que considerar como pautas o recomendaciones.The exact dosage and frequency of administration depend on the particular condition to be treated, the severity of the condition to be treated, age, weight, sex, the extent of the disease, and the general physical condition of the condition. patient, as well as the other medication that the individual can take, as is well known by those skilled in the art. Furthermore, it is evident that the above-mentioned daily effective amount can be decreased or increased depending on how the patient reacts to said medication, and / or depending on the evaluation performed by the physician prescribing the medicament of the present invention. Thus, the effective daily amounts mentioned above must be considered as guidelines or recommendations.
Los complejos iónicos de la presente invención pueden administrarse solo o conjuntamente con otros agentes terapéuticos. Ejemplos de otros agentes terapéuticos útiles para su combinación con los complejos iónicos de la presente invención incluyen a tetraciclinas, rifampicina, y la estreptomicina.. Así, la combinación de uno de los complejos iónicos de la presente invención y otro agente terapéutico se puede utilizar como medicina en una terapia de combinación. El término "terapia de la combinación" se refiere a un producto que contiene obligatoriamente (a) un complejo iónico de la presente invención, y (b) otro compuesto anti-brucelosis, como preparación combinada para el uso simultáneo, separado o secuencial en el tratamiento de las infecciones por Brucella sp, particularmente para el tratamiento de infecciones causadas por la B. melitensis . Asi, para combatir o para tratar infecciones por Brucella sp, uno de los complejos iónicos de esta invención se puede co-administrar conjuntamente con por ejemplo, tetraciclinas, rifampicina, o estreptomicina.The ionic complexes of the present invention can be administered alone or in conjunction with other therapeutic agents. Examples of other therapeutic agents useful for combination with the ionic complexes of the present invention include tetracyclines, rifampin, and streptomycin. Thus, the combination of one of the ionic complexes of the present invention and another therapeutic agent can be used as Medicine in a combination therapy. The term "combination therapy" refers to a product that necessarily contains (a) a ionic complex of the present invention, and (b) another anti-brucellosis compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of Brucella sp infections, particularly for the treatment of infections caused by B. melitensis . Thus, to combat or treat Brucella sp infections, one of the ionic complexes of this invention can be co-administered in conjunction with, for example, tetracyclines, rifampicin, or streptomycin.
Por consiguiente, la presente invención se refiere al uso de un complejo iónico, procesado o sin procesar, para la fabricación de un medicamento útil para inhibir la actividad de la Brucella spp en un mamífero infectado con la bacteria de la Brucella spp, en donde dicho medicamento se utiliza en una terapia de combinación, la cual comprende preferiblemente un complejo iónico de la presente invención y una tetraciclina, rifampicina, o estreptomicina .Accordingly, the present invention relates to the use of an ionic complex, processed or unprocessed, for the manufacture of a medicament useful for inhibiting the activity of Brucella spp in a mammal infected with the bacterium of Brucella spp, wherein said medicament is used in a combination therapy, which preferably comprises an ionic complex of the present invention and a tetracycline, rifampin, or streptomycin.
EjemplosExamples
La presente invención se ilustra mediante los siguientes ejemplos, que no deben interpretarse como limitantes.The present invention is illustrated by the following examples, which should not be construed as limiting.
Ejemplo 1: Preparación del complejo iónico de gentamicina con Bis (2-etilhexil) sulfosuccinato de sodio (AOT) Se preparó una disolución de concentración 4 mg/ml de sulfato de gentamicina en una disolución tampón a pH 5(10 mM acetato de sodio, 10 mM KCl, 10 mM CaCl2) . Mientras se agitaba la disolución se añadió un volumen igual de diclorometano con una concentración del surfactante aniónico Bis (2-etilhexil) sulfosuccinato de sodio (AOT) de 12,55 mg/ml. La concentración molar del surfactante era 5 veces mayor que la del principio activo y equivalía al número de grupos amino protonados de la gentamicina al pH de trabajo. Tras la adición se agitó la mezcla durante aproximadamente tres horas y luego se centrifugó a 5000 rev./min durante 5 minutos. Se separó la fase orgánica de la acuosa y tras secarla con MgSO4 anhidro se evaporó a vacio.Example 1: Preparation of the ionic gentamicin complex with sodium Bis (2-ethylhexyl) sulphosuccinate (AOT) A solution of 4 mg / ml concentration of gentamicin sulfate was prepared in a buffer solution at pH 5 (10 mM sodium acetate, 10 mM KCl, 10 mM CaCl2). While stirring the solution an equal volume of dichloromethane was added with a concentration of the anionic surfactant Bis (2-ethylhexyl) sulfosuccinate (AOT) of 12.55 mg / ml. The molar concentration of the surfactant was 5 times higher than that of the active substance and was equivalent to the number of protonated amino groups of gentamicin at working pH After the addition, the mixture was stirred for approximately three hours and then centrifuged at 5000 rev./min for 5 minutes. The organic phase was separated from the aqueous one and after drying with anhydrous MgSO 4 it was evaporated in vacuo.
Se obtuvo un complejo iónico de gentamicina y AOT (GmAOT) con una composición 1:5 gentamicina : AOT que fue analizado por IR, RMN, DSC y análisis elemental (véase la curva IR en la Figura 2 ) .An ionic complex of gentamicin and AOT (GmAOT) was obtained with a 1: 5 gentamicin: AOT composition that was analyzed by IR, NMR, DSC and elemental analysis (see IR curve in Figure 2).
Ejemplo 2: Preparación de microparticulas del complejo iónico gentamicina : AOT procesadoExample 2: Preparation of microparticles of the gentamicin ionic complex: processed AOT
Se presurizó el reactor (6) de 300 mi de capacidad con CO2. El dióxido de carbono fue introducido a un caudal de 36,67 ml/min y la presión (Pw) se mantuvo constante a 100 bar mediante una válvula reguladora de presión (8) situada a la salida del reactor. La temperatura de trabajo (Tw) fue de 25 0C. Para conseguir una fracción molar de CO2 constante de 0,95 (xw) en el interior del reactor, se bombeó primero acetona pura a un caudal de 2 ml/min y durante 20 min hasta conseguir un estado estacionario. En este momento se introdujeron al mismo caudal 10 mi de una disolución de concentración 0,3 g/ml del complejo iónico de gentamicina : AOT en acetona. Tanto el disolvente como la disolución se introdujeron al reactor a través de una boquilla (5) de diámetro de 100 μm. El precipitado formado como consecuencia del efecto antisolvente del CO2 se recogió en un filtro de 0,2 μm de poro (7) colocado en la parte inferior del reactor. El secado de las microparticulas se realiza mediante una corriente de CO2 a 36,67 ml/min y 100 bar durante una hora. Finalmente se despresurizó el sistema y se recogió el sólido. El precipitado obtenido fue un sólido blanco. El tamaño de las partículas obtenida fue determinado por microscopía electrónica de barrido (SEM) y era de 3 a 5 μm aproximadamente .The reactor (6) of 300 ml capacity was pressurized with CO2. Carbon dioxide was introduced at a flow rate of 36.67 ml / min and the pressure (P w ) was kept constant at 100 bar by a pressure regulating valve (8) located at the outlet of the reactor. The working temperature (T w ) was 25 0 C. To achieve a constant CO2 molar fraction of 0.95 (x w ) inside the reactor, pure acetone was first pumped at a flow rate of 2 ml / min and for 20 min until a steady state is achieved. At this time, 10 ml of a solution of concentration 0.3 g / ml of the ionic gentamicin complex: AOT in acetone was introduced at the same flow rate. Both the solvent and the solution were introduced to the reactor through a nozzle (5) with a diameter of 100 μm. The precipitate formed as a result of the anti-solvent effect of CO2 was collected in a 0.2 μm pore filter (7) placed in the bottom of the reactor. The drying of the microparticles is carried out by means of a stream of CO2 at 36.67 ml / min and 100 bar for one hour. Finally the system was depressurized and the solid was collected. The precipitate obtained was a white solid. The particle size obtained was determined by scanning electron microscopy (SEM) and was 3 to 5 μm approximately .
Ejemplo 3: Actividad farmacológica del complejo iónico gentamicina : AOT procesado y sin procesar La especie bacteriana escogida como modelo para estudiar la actividad farmacológica del complejo iónico GmAOT para el tratamiento de la brucelosis, fue la Brucella melitensis .Example 3: Pharmacological activity of the gentamicin ionic complex: AOT processed and unprocessed The bacterial species chosen as a model to study the pharmacological activity of the ionic complex GmAOT for the treatment of brucellosis, was Brucella melitensis.
Para el estudio de la actividad de las diferentes gentamicinas (Gm) se determinaron las concentraciones mínimas inhibitorias (CMI o MIC) siguiendo el protocolo normalizado por el CLSI (Clinical and Laboratory Standards Institute) .For the study of the activity of the different gentamicins (Gm), the minimum inhibitory concentrations (MIC or MIC) were determined following the protocol standardized by the CLSI (Clinical and Laboratory Standards Institute).
El estudio se llevó a cabo en placas de microtitulación estériles en las cuales se añadió el medio de cultivo autoclavado, en la primera columna 180μl y en los demás pocilios lOOμl. En cada pocilio se añadió el inoculo bacteriano (Brucella melitensis) previamente preparado. Una vez añadido el antibiótico en forma de sulfato de gentamicina, y en forma de complejo iónico, procesado y sin procesar de acuerdo con la presente invención, se hizo un recuento de la unidades formadoras de colonias (ufe) y se definió la CMI como la cantidad mínima del antibiótico que inhibe el crecimiento bacteriano.The study was carried out in sterile microtiter plates in which the autoclaved culture medium was added, in the first 180μl column and in the other lOOμl wells. The bacterial inoculum (Brucella melitensis) previously prepared was added to each well. Once the antibiotic was added in the form of gentamicin sulfate, and in the form of an ionic complex, processed and unprocessed in accordance with the present invention, a colony forming unit (ufe) count was made and the MIC was defined as the minimum amount of the antibiotic that inhibits bacterial growth.
De los estudios in vitro realizados frente a dichos inóculos bacterianos de Brucella melitensis, quedó demostrado que los complejos iónicos de gentamicina : AOT, procesado y sin procesar, no redujeron la actividad de la gentamicina cuando se compararon con el sulfato de gentamicina. Así, la actividad mínima inhibitoria (MIC) fue de 0,125 microgramos/mL en todos los casos. From in vitro studies conducted against these bacterial inoculums of Brucella melitensis, it was shown that the gentamicin ionic complexes: AOT, processed and unprocessed, did not reduce the activity of gentamicin when compared to gentamicin sulfate. Thus, the minimum inhibitory activity (MIC) was 0.125 micrograms / mL in all cases.

Claims

R E I V I N D I C A C I O N E S
1. Utilización de un complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT), en una relación molar de 1:5 (gentamicina : AOT), para la fabricación de un medicamento destinado al tratamiento de una enfermedad causada por una bacteria del género Brucella .1. Use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT), in a molar ratio of 1: 5 (gentamicin: AOT), for the manufacture of a medicament for the treatment of a disease caused by a bacterium of the genus Brucella.
2. Utilización según la reivindicación 1, en donde el complejo iónico está adicionalmente procesado mediante: a) la disolución del complejo iónico gentamicina : AOT en un disolvente orgánico; b) el pulverizado de la disolución resultante de la etapa a) en un fluido comprimido miscible con el disolvente orgánico, que actúa como antisolvente y causa la precipitación de un sólido; c) la separación del sólido resultante de la etapa b) .2. Use according to claim 1, wherein the ionic complex is further processed by: a) dissolution of the gentamicin ionic complex: AOT in an organic solvent; b) spraying the solution resulting from step a) into a compressed fluid miscible with the organic solvent, which acts as an anti-solvent and causes the precipitation of a solid; c) the separation of the solid resulting from step b).
3. Utilización según la reivindicación 2, en donde el disolvente orgánico de la etapa a) es seleccionado entre alcoholes monohídricos como el metanol, etanol, 1-propanol, 2-propanol, 1-butanol, 1-hexanol, 1- octanol, y trifluoroetanol; alcoholes polihidricos como el propilenglicol, PEG 400, y 1, 3-propanediol; éteres como el tetrahidrofurano (THF) , y dietiléter; alcanos como la decalina, isooctano, y aceite mineral; aromáticos como el benceno, tolueno, clorobenceno, y piridina; amidas como la n-metil pirrolidona (NMP) , y N, N-dimetilformamida (DMF); esteres como el acetato de etilo, y acetato de metilo; clorocarbonos como el diclorometano, cloroformo, tetraclorometano, y 1,2- dicloroetano; otros disolventes como acetona, etilenodiamina, acetonitrilo, trimetilfosfato, y dimetilsulfoxida; y mezclas de ellos. 3. Use according to claim 2, wherein the organic solvent of step a) is selected from monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-hexanol, 1- octanol, and trifluoroethanol; polyhydric alcohols such as propylene glycol, PEG 400, and 1,3-propanediol; ethers such as tetrahydrofuran (THF), and diethyl ether; alkanes such as decalin, isooctane, and mineral oil; aromatics such as benzene, toluene, chlorobenzene, and pyridine; amides such as n-methyl pyrrolidone (NMP), and N, N-dimethylformamide (DMF); esters such as ethyl acetate, and methyl acetate; chlorocarbons such as dichloromethane, chloroform, tetrachloromethane, and 1,2-dichloroethane; other solvents such as acetone, ethylenediamine, acetonitrile, trimethylphosphate, and dimethylsulfoxide; and mixtures of them.
4. Utilización según la reivindicación 2, en donde el disolvente orgánico de la etapa a) es la acetona.4. Use according to claim 2, wherein the organic solvent of step a) is acetone.
5. Utilización según cualesquiera de las reivindicaciones 2-4, en donde la concentración de la disolución resultante de la etapa a) es aproximadamente de 0,001 g/ml a 0,5 g/ml .5. Use according to any of claims 2-4, wherein the concentration of the solution resulting from step a) is approximately 0.001 g / ml to 0.5 g / ml.
6. Utilización según cualesquiera de las reivindicaciones 2-5, en donde el fluido comprimido de la etapa b) es seleccionado entre CO2, etano, propano, hidroclorofluorocarbonos, y hidrofluorocarbonos .6. Use according to any of claims 2-5, wherein the compressed fluid of step b) is selected from CO2, ethane, propane, hydrochlorofluorocarbons, and hydrofluorocarbons.
7. Utilización según cualesquiera de las reivindicaciones 2-5, en donde el fluido comprimido de la etapa b) es el CO2.7. Use according to any of claims 2-5, wherein the compressed fluid of step b) is CO 2 .
8. Utilización según cualesquiera de las reivindicaciones 2-7, en donde la relación entre la cantidad de fluido comprimido y de disolvente orgánico corresponde a una fracción molar aproximada de 0,3 a 1.8. Use according to any of claims 2-7, wherein the ratio between the amount of compressed fluid and organic solvent corresponds to an approximate molar fraction of 0.3 to 1.
9. Utilización según cualesquiera de las reivindicaciones 2-8, en donde el pulverizado de la etapa b) se realiza en un reactor a una presión aproximada de 10 a 200 bar, y a una temperatura aproximada de -50 a 200 0C.9. Use according to any of claims 2-8, wherein the spraying of step b) is carried out in a reactor at an approximate pressure of 10 to 200 bar, and at an approximate temperature of -50 to 200 0 C.
10. Utilización según cualesquiera de las reivindicaciones 2-9, en donde la separación de la etapa c) se realiza por filtración.10. Use according to any of claims 2-9, wherein the separation of step c) is carried out by filtration.
11. Utilización según cualesquiera de las reivindicaciones 2-10, en donde el sólido resultante de la etapa c) es posteriormente secado. 11. Use according to any of claims 2-10, wherein the solid resulting from step c) is subsequently dried.
12. Utilización según la reivindicación 11, en donde el secado se realiza usando una corriente de CO2 u otros gases, una estufa, o al vacio.12. Use according to claim 11, wherein drying is carried out using a stream of CO2 or other gases, a stove, or vacuum.
13. Utilización según cualesquiera de las reivindicaciones 1-12, en donde la bacteria es seleccionada del grupo de B. melitensis, B. suis, B. abortus, B. ovis, B. canis, y B. neotomae .13. Use according to any of claims 1-12, wherein the bacterium is selected from the group of B. melitensis, B. suis, B. abortus, B. ovis, B. canis, and B. neotomae.
14. Utilización según cualesquiera de las reivindicaciones 1-12, en donde la bacteria es B. melitensis,14. Use according to any of claims 1-12, wherein the bacterium is B. melitensis,
15. Utilización según cualesquiera de las reivindicaciones 1-14, en donde el paciente a tratar es un animal mamífero.15. Use according to any of claims 1-14, wherein the patient to be treated is a mammalian animal.
16. Utilización según cualesquiera de las reivindicaciones 1-14, en donde el paciente a tratar es el hombre.16. Use according to any of claims 1-14, wherein the patient to be treated is the man.
17. Utilización según cualesquiera de las reivindicaciones 1-16, en donde la enfermedad causada por una bacteria del género Brucella es la brucelosis.17. Use according to any of claims 1-16, wherein the disease caused by a bacterium of the genus Brucella is brucellosis.
18. Complejo iónico de gentamicina y bis- (2-etilhexil) sulfosuccinato sódico (AOT) en una relación molar de 1:5 (gentamicina : AOT), procesado según las etapas a), b) , y c) de cualesquiera de las reivindicaciones 2-12.18. Ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulfosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), processed according to steps a), b), and c) of any of the claims 2-12.
19. Formulación farmacéutica que comprende el complejo iónico procesado de gentamicina : AOT según la reivindicación 18, y al menos un excipiente aceptable en farmacia. 19. Pharmaceutical formulation comprising the processed ionic gentamicin complex: AOT according to claim 18, and at least one pharmaceutically acceptable excipient.
20. Utilización del complejo iónico procesado gentamicina : AOT según la reivindicación 18, como medicamento.20. Use of the gentamicin processed ionic complex: AOT according to claim 18, as a medicament.
21. Utilización de un complejo iónico de gentamicina y bis- (2-ethylhexyl) sulfosuccinato sódico (AOT) en una relación molar de 1:5 (gentamicina : AOT), para su procesamiento con fluidos comprimidos. 21. Use of an ionic complex of gentamicin and sodium bis- (2-ethylhexyl) sulphosuccinate (AOT) in a molar ratio of 1: 5 (gentamicin: AOT), for processing with compressed fluids.
PCT/ES2008/070228 2007-12-07 2008-12-05 Use of an ionic complex of gentamicin : aot for the treatment of brucellosis WO2009071731A1 (en)

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