WO2011145914A1 - Lidocaine as a transformer and producer of transformed complexes of drugs delivered in nano-dosages using injection implants as prolonged release devices - Google Patents

Lidocaine as a transformer and producer of transformed complexes of drugs delivered in nano-dosages using injection implants as prolonged release devices Download PDF

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WO2011145914A1
WO2011145914A1 PCT/MX2011/000059 MX2011000059W WO2011145914A1 WO 2011145914 A1 WO2011145914 A1 WO 2011145914A1 MX 2011000059 W MX2011000059 W MX 2011000059W WO 2011145914 A1 WO2011145914 A1 WO 2011145914A1
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lidocaine
drug
drugs
injection
complexes
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PCT/MX2011/000059
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Spanish (es)
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WO2011145914A4 (en
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Alejandra Zepeda Flores
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Alejandra Zepeda Flores
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol

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  • the present invention is directed to methods for transforming pharmaceutical products approved by FDA (Food and Drug Administration) and COFEPRIS (Federal Commission for Protection against Health Risks) with lidocaine. example; Phosphomysin and Lincomysin, Neurobion (group B vitamins), Non-Steroidal and Steroidal Desinflammatory Analgesics (Dexamethasone).
  • the transformation process comprises the fusion of lidocaine molecules with one or more substances composed of drugs; and that is summarized in a final product where the functional groups of the drugs and lidocaine that give therapeutic identity to the transformed drugs are preserved.
  • This invention is a specific procedure that is based on the gnosis of adequate amounts of lidocaine for drug transformation, which are in liquid or lyophilized presentation and that result in nanodose that do not lose the efficacy or therapeutic effects of the drug becoming lidocaine-drug complexes;
  • the anesthetic function of lidocaine is annulled because the amide and the amine group sede their groups to function as anion and cation respectively, providing the necessary energy that is required in nucleophilic substitution, the result of this Chemical reaction produces major drug complexes and. better bioavailability that can be implanted through injection therapy near the specific receptors with the intention of avoiding physiological barriers that obstruct their performance.
  • This process has a sustained release that lasts 8 to 10 days.
  • Lidocaine was synthesized in 1943 by the Swedish chemist Nils Lófgren and is one of the most commonly used local anesthetic drugs in surgery and dentistry due to its short latency (1.5 to 2 hrs.) Wide diffusion, hypoallergenic properties, Tolerance, stability and low toxicity.
  • the therapeutic efficacy of some drugs is difficult to achieve when in their performance they disregard mechanisms that avoid metabolizing each time they cross physiological barriers to reach their site or receptors of action without degrading, so it requires high concentrations of active principle to achieve a significant therapeutic effect, but which ultimately affect other organs; Prolonged use of these drugs can cause adverse effects in chronic diseases, which require prolonged use of them, such as in bacterial recurrent respiratory infections where bacterial resistance is frequently generated and thus the non-elimination of bacteria, in peripheral neuropathies and diseases where chronic pain is suffered, medications take time to take effect and sometimes the non-elimination of the condition.
  • the characteristic of this invention is composed of elements that improve the production processes of complexes for the development and innovation of new drugs, fundamentally in the transformation and reformulation the necessary quantities of both reagents are known, where a reagent can be drugs as specific antibiotics for upper respiratory infections, complex B and Steroidal and non-steroidal analgesics, among others approved by the FDA and COFEPRIS, and the other reagent is lidocaine, which, when transformed, becomes lidocaine-drug complexes where the dose obtained is in a manometric scale preserving the therapeutic action and efficacy of the Transformed drug and adverse or toxic effects disappear allowing these new drugs to be used for long periods without presenting adverse effects or damage to organs, in the case of reformulated antibiotics they have a better therapeutic response, observing that the bacteria that affect the airways offer lower bacterial resistance and total elimination of these, in the neuropathies these new drugs offer a regeneration of the peripheral nerve and with it the disappearance of pain, in the case of chronic pain the steroidal and non-steroidal
  • lidocaine molecules with the molecules of one or more drugs approved by the FDA and COFEPRIS, being these antibiotics to treat upper respiratory infections, complex B as antineuritic and non-steroidal and spheroid disinflammatory drugs causing new formulas.
  • generation where the lidocaine molecule is used as a reagent capable of fusing with the molecules of the aforementioned drugs likewise, this performance leads to complex formation through a chain reaction that results in a macromolecule of the reformulated drug where The active substance of the drug is conserved (be it antibiotic, vitamins of group B, non-steroidal analgesic and steroidal) and the anesthetic function of lidocaine is lost.
  • the complexes are dispersed in the liquid solution, provided by the same presentation of lidocaine, other advantages of these transformed drugs are: the increase in bioavailability, the use of a much lower concentration of the drug, which allows it to be used for prolonged times , these lidocaine-drug complexes are applied by injection implants near the specific receptors thus avoiding physiological barriers, using the entire drug, this application is not invasive or painful, the drug when entering the body has a prolonged release that It lasts from 8 to 10 days which represents well-being in the treatment. DESCRIPTION
  • Lidocaine has a chemical structure that can be divided into four subunits, which have very interesting characteristics and have to do with the process of transformation described below.
  • Subunit 1 It is an aromatic nucleus, it is primarily responsible for the liposolubility of the molecule, it is formed by a substituted benzene ring, the addition of more groups at this level will increase the liposolubility, it should be mentioned that the benzene rings have more substitution reactions In addition, the reactions that can occur are nitration if it is with nitrogen, sulfation if it is with sulfide and halogenation if it is with bromide, in these it replaces an atom or group with a hydrogen of benzene, this indicates that it maintains its characteristic properties, As well as its structure and in acid reactions it serves as an electronic source, these characteristics are presented independently of the other functional groups contained in the molecule.
  • Subunit 2 Amide Union. This joins the aromatic nucleus with the hydrocarbon chain, is resistant to thermal variations, the amides have high boiling points due to the ability to establish firm hydrogen bonds, when the temperature increases in aqueous bases they hydrolyze, here the group is replaced -NH2 by -OH, in acidic conditions hydrolysis involves the attack of water on the protonated amine, that is; Hydrolysis of amines is one of the typical reactions of carboxylic acid derivatives. It is the part of the molecule that functions as an anion.
  • Subunit 3 Carbonated chain. It is usually an alcohol with 2 carbon atoms. This influences the liposolubility of the molecule, when the chain size increases the time of action of the drug increases and the liposolubility increases.
  • Subunit 4 Amine group, this determines the water solubility of the molecule and its binding to plasma proteins, the amines contain nitrogen that has a pair of non-shared electrons, the tendency of nitrogen to Sharing that pair of electrons is the basis of all its chemical behavior, which gives it the property of being the cationic zone that receives a positive H and gives two negative protons; the presence of an aqueous hydroxide ion easily converts them into free amines, amines are a typical ionic compound, when heated they generally decompose, amines have hydrogens replaced by organic groups, nitrite synthesis has the characteristic of increasing the length of a carbonated chain.
  • Lidocaine has a known local anesthetic action that prevents the spread of the nerve impulse by decreasing the permeability of the Na channel, blocking the initial phase of the action potential; To do this, it must cross the nerve membrane since its pharmacological action is essentially carried out by joining the receptor from the cytoplasmic side of it.
  • Another factor that influences its action is the fact that it quickly binds and dissociates from the sodium channel; the -NH2 and -OH groups and their derivatives act as powerful activators in the aromatic electrophilic substitution by exerting an inductive effect of electron attraction; the nitrogen of the group -NH2 is basic and tends to share its last pair of electrons to acquire a positive charge owned by the methyl group, this dispersion of the charge stabilizes the carbocation, the inductive effect stabilizes in the same way the positive charge that develops in the transition state accelerating the reaction.
  • Figure 2 Corresponds to the IR of lidocaine. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made at the Autonomous University of Querétaro.
  • Figure 3 Corresponds to the phosphomycin IR. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made at the Autonomous University of Querétaro.
  • Figure 4 Corresponds to the lincomycin IR. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the ARJ laboratory.
  • Figure 5 Corresponds to the dexamethasone IR. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the Autonomous University of Querétaro. Figure 6. Corresponds to the IR of the lidocaine-fosfomycin complex. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the Autonomous University of Querétaro.
  • Figure 7 Corresponds to the IR of the lidocaine-lincomycin complex. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the ARJ laboratory.
  • Figure 8 Corresponds to the IR of the lidocaine-dexamethasone complex. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the Autonomous University of Querétaro.
  • the finding of this invention consists in procedures where it is possible to link the molecules of lidocaine with the molecules of one or more drugs, as well as the gnosis of the dilution of drugs to effective levels where the therapeutic effects of this drug are not lost.
  • an effective nanodose is obtained: specifically a procedure for lyophilized drugs, and another procedure for liquid drugs preferably drugs approved by the FDA and COFEPRIS, where the substrate of the chemical reaction is complexes of transformed drugs (lidocaine-drug complexes) that are They may be implanted by oral, intra-articular, intradermal, intramuscular, intrarectal injection, preferably near the specific receptors of the therapeutic principle of the transformed drugs, where their release is constant, effective and lasts 8-10 days.
  • the method for chemical change, or; transformation and complex formation of lyophilized drugs comprises two elementary phases:
  • Second phase ⁇ Requires lidocaine, an amount of 30 to 60mg. diluted from 4 to 6 mi.
  • Lidocaine is introduced into a tightly sealed glass container and the drug is subsequently introduced through an injection-suction and stirring mechanism to mix the two reagents; Through this methodology and the chemical process caused, substrates are obtained which, due to the effect of an energy factor, are transformed into new compounds.
  • the product obtained in phase one is mixed with an equivalent amount of 10 to 40 ml of 1 or 2% lidocaine (where lidocaine 1 % contains 10mg of lidocaine diluted in 1 ml of water and 2% lidocaine contains 20 mg of lidocaine diluted in 1 ml of water), this reaction lasts 2.5 minutes in which the temperature drops 2 to 3 °, the next 20 -25 minutes temperature variations from 1 to 1.5 ° C are recorded, during this reaction there is an effective collision between the particles that because they are dissolved have a close contact, for this reason requires a minimum kinetics that is changed to energy potential at the moment of impact.
  • the reaction is started with the mixture of the two reagents comprising one or more drugs that can be antibiotics, complex B and disinflammatenosis, steroids and non-steroids, in an adult dose, the following drugs were used as an example: linconcin 600 mg (lincomycin made by PFIZER), 8 mg Alin Depot (dexamethasone made by Chinoin), Neurobion (confine thiamine hydrochloride 100mg, pridoxine hydrochloride 100mg and linocobalamin lOOOmcg manufactured by Merck) each mixed with lidocaine (Pisaca) per PISA) in an equivalent amount of 10 to 40 ml of 1 or 2% lidocaine (where 1% lidocaine contains 10 mg of lidocaine diluted in 1 ml of water and 2% lidocaine contains 20 mg of diluted lidocaine in 1 ml of water), to carry out the reaction, it is mixed in a tightly closed glass container, and through an injection and suction
  • the present invention is based on the finding of gnosis of adequate amounts of lidocaine and the drug for the preparation of effective nanodoses;
  • the function of the water in which the lidocaine is diluted maintains an elementary role, since it provides the necessary space for the appropriate growth of the molecules, on the other hand its function in addition to being a solvent of the drug is intimately involved in the chemical change of the same, because its structure fosters bonds that are hydrogen bonds and it is the formation of these bonds that provides the energy needed to break the bonds that hold together the particles of the drug molecule and those of the lidocaine producing the formation of Lidocaine-Drug complexes.
  • Amines are a typical ionic compound that when heated decompose, amines have hydrogens replaced by organic groups, the synthesis of nitriles has the characteristic of increasing the length of a carbonated chain. This property of the amines benefits when merging the Lidocaine with drugs.
  • IR infrared
  • the drugs processed as an example in this invention were phosphomycin, lincomycin and dexamethasone, IR identities of the three IR drugs of lidocaine and the IR identities of the lidocaine-phosphomycin, lidocaine-lincomycin and lidocaine-dexamethasone complexes were performed.
  • the amide bond that joins the aromatic nucleus with the hydrocarbon chain is resistant to thermal variations, the amides have high boiling points due to the ability to establish firm hydrogen bonds, when the temperature increases in aqueous bases they hydrolyze, here they replaces the -NH2 group with -OH, in acidic conditions hydrolysis involves the attack of water on the protonated amide, that is; Hydrolysis of amides is one of the typical reactions of carboxylic acid derivatives.
  • the lidocaine molecule was fused with the drug giving it an improved bioavailability and an increase in the duration of therapeutic action.
  • Another finding of the invention was to take advantage of the reactive nature of the cations and anions of the same lidocaine molecule that causes the formation of complexes by chain reaction where a chemical reaction occurred, and where each of the molecules consumed a reactive particle and It produced a similar one, so each individual reaction depended on the previous one, thus joining the macromolecules to give rise to macromolecules that retain secondary bonds such as Van der Waals forces, dipole-dipole bonds, ion-dipole bonds and hydrogen bonds, These links are relatively weak but acting at the same time as a team are strong and their formation can provide enough energy to break a covalent bond. These secondary links exist between different parts of the macromolecule, thus having a key function in determining their forms, which in turn determine their properties.
  • FIGs 9,10 and 11 show the growth of the molecules of the lidocaine-drug complexes transforming into macromolecules, which outlines the complexes of the products.
  • Figure 9 shows the growth of the lidocaine-fosfomycin complex, where it is seen that first nuclei are formed that measure from 10 to 30 microns being observed at 30 minutes, then elongated flat crystals are formed in growth that leave the nucleus this is seen between 12 to 24 hrs. The crystals are divided into many splinter-shaped crystals. This is observed between 24 and 36 hours.
  • FIG. 10 the growth of the lidocaine-neurobion complex is observed, here after making the reaction macromolecule clusters are observed, reaching a stability in growth in 24 hours, where amorphous macromolecule clusters are already observed occupying a large part of space .
  • Figure 11 shows the growth of the lidocaine complex. dexamethasone, here after making the reaction you can see clusters of macromolecules, reaching a stability in growth in 24 hours, where you can already see clusters of amorphous macromolecules occupying a large part of space
  • the finding of the present invention is based on the gnosis of the dilution of the drug at effective nanometric levels where effective therapeutic effects are preserved and having managed to fuse lidocaine with drugs that may be antibiotics preferably for respiratory tract infections, complex B and Steroidal and non-steroidal disinflammatory analgesics, and thus finding a way to develop a new range of transformed drugs where the amount of active ingredient required to treat pathologies is significantly reduced, since the final substrate obtained contains a nanometric amount of the principle active but with an increase in potency so that it retains the efficacy and therapeutic effect of the drug that was taken to form the complex together with lidocaine, likewise this product can be implanted every eight days since it is the time it lasts its release and therapeutic function through injection It is close to the specific receptors, that is, close to the affected organs thus skipping the physiological barriers and with this the loss of the active principle that remains in these barriers. All this provides the following advantages compared to traditional drugs.
  • lidocaine-drug complexes for prolonged times without presenting toxic, adverse or collateral effects, it does not damage organs, in the case of antibiotics the fact of applying them for long periods allows us to eliminate the bacteria and thus avoid relapses or recurrent respiratory infections.
  • the product obtained is a transformed drug that has an improved bioavailability, since its ability to transfer the membrane is greater because it is more liposoluble because The aromatic nucleus of lidocaine is added and as the hydrocarbon chain increases in size this makes the drug more potent and with longer duration in its action.
  • the macromolecules that are formed are complex, where their particles are joined by forces of Van der Waals, which when entering the body these by physiological conditions are separated leaving free small particles of the drug, which bind to specific receptors by performing Its therapeutic action. This condition gives us a continuous and prolonged release of the drug, which lasts 8 to 10 days, which translates into an improvement in bioavailability.
  • the treatment carried out lasted 12 weeks and consisted of a weekly applied nanodose of the lidocaine-fosfomycin or lidocaine-lincomycin complex depending on the pathogenic bacteria, to combat chronic tonsillitis in the individual.
  • lidocaine-dexamethasone or lidocaine-diclofenac complexes 100 patients were studied per year who received nanodosis of lidocaine-dexamethasone or lidocaine-diclofenac complexes; who were grouped as follows: a) 25 patients with rheumatoid arthritis.
  • the selection criteria were the following: a) Patients with pain of more than one month.
  • the treatment lasted 6 to 8 weeks and consisted of a nanodose implantation every week of the lidocaine-dexamethasone or lidocaine-diclofenac complex, developed to combat chronic pain in the individual.
  • peripheral diabetic neuropathy a sample of 100 adult patients per year was observed. They were administered nanodosis of the lidocaine-neurobion complex, through implants through one injection per week.
  • the selection criteria were: a) Patients with diabetes more than 10 years old
  • the diagnosis was only clinical, the treatment consisted of a weekly application of nanodosis of the lidocaine-neurobion complex developed to combat peripheral diabetic neuropathy in the individual.
  • the application of the complex was carried out as follows; a weekly application for 12 weeks, enough time for nerve terminals to regenerate. There was a clear improvement since the second application with a total remission of symptoms at week 12. It should be noted that the pathology of neuropathy if not controlled again will return to injuring the nerve terminals, the patient was informed, it is recommended to receive treatment every 6 months.

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Abstract

The invention relates to a specific method based on suitable quantities of lidocaine for the transformation of drugs approved by the FDA and COFEPRIS, either in liquid or lyopilised form, producing nano-dosages that do not reduce the effectiveness or the therapeutic effects of the drug, converting same into lidocaine-drug complexes. The transformation method, which results in an end product comprising the fusion of molecules of lidocaine with one or more substances comprising drugs, the prior art and the different methods, techniques and instruments result in the formation of intelligent transformed complexes which can be implanted by means of injection close to the specific receptors, characterised by a release that lasts between 8 and 10 days.

Description

LA LIDOCAÍNA COMO TRANSFORMADORA Y PRODUCTORA DE COMPLEJOS DE FÁRMACOS TRASFORMADOS APLICADOS EN NANODOSIS MEDIANTE IMPLANTES POR INYECCIÓN COMO DISPOSITIVOS DE LIBERACIÓN PROLONGADA  LIDOCAINE AS TRANSFORMER AND PRODUCER OF TRANSFORMED DRUG COMPLEXES APPLIED IN NANODOSIS BY IMPLANTS BY INJECTION AS PROLONGED RELEASE DEVICES
BREVE DESCRIPCION DE LA INVENCION La presente invención está dirigida a procedimientos para transformar con lidocaína productos farmacéuticos aprobados por la FDA (Administración de Alimentos y Fármacos, por sus siglas en inglés) y la COFEPRIS (Comisión Federal para la Protección contra Riesgos Sanitarios), por ejemplo; Fosfomisina y Lincomisina, Neurobión (vitaminas del grupo B), Analgésicos Desinflamatorios no Esteroideos y Esteroideos (Dexametasona). BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to methods for transforming pharmaceutical products approved by FDA (Food and Drug Administration) and COFEPRIS (Federal Commission for Protection against Health Risks) with lidocaine. example; Phosphomysin and Lincomysin, Neurobion (group B vitamins), Non-Steroidal and Steroidal Desinflammatory Analgesics (Dexamethasone).
El proceso de transformación comprende la fusión de moléculas de la lidocaína con una o más sustancias compuestas de fármacos; y que se resume en un producto final donde se conservan los grupos funcionales de los fármacos y de la lidocaína que dan identidad terapéutica a los fármacos transformados. Esta invención es un procedimiento especifico que se basa en la gnosis de las cantidades adecuadas de lidocaína para la transformación de fármacos, que están en presentación liquida o liofilizada y que dan como resultado nanodosis que no pierden la eficacia ni los efectos terapéuticos del fármaco convirtiéndose en complejos lidocaína-fármaco; En el proceso de transformación se anula la función anestésica de la lidocaína debido a que la unión amida y el grupo amina seden su grupos para funcionar como anión y catión respectivamente, proporcionando la energía necesaria que se requiere en la sustitución nucleófila, el resultado de esta reacción química produce complejos de fármacos de mayor y. mejor biodisponibilidad que se podrán implantar a través de un terapia por inyección cerca de los receptores específicos con la intención de evitar barreras fisiológicas que obstruyen su desempeño. Este proceso tiene una liberación sostenida que dura de 8 a 10 días. The transformation process comprises the fusion of lidocaine molecules with one or more substances composed of drugs; and that is summarized in a final product where the functional groups of the drugs and lidocaine that give therapeutic identity to the transformed drugs are preserved. This invention is a specific procedure that is based on the gnosis of adequate amounts of lidocaine for drug transformation, which are in liquid or lyophilized presentation and that result in nanodose that do not lose the efficacy or therapeutic effects of the drug becoming lidocaine-drug complexes; In the process of transformation the anesthetic function of lidocaine is annulled because the amide and the amine group sede their groups to function as anion and cation respectively, providing the necessary energy that is required in nucleophilic substitution, the result of this Chemical reaction produces major drug complexes and. better bioavailability that can be implanted through injection therapy near the specific receptors with the intention of avoiding physiological barriers that obstruct their performance. This process has a sustained release that lasts 8 to 10 days.
ANTECEDENTES BACKGROUND
La lidocaína fue sintetizada en 1943 por el químico sueco Nils Lófgren y es uno de los fármacos anestésicos locales más utilizados en cirugía y odontología debido a sus propiedades de corto periodo de latencia (1.5 a 2 hrs.) amplia difusión, hipoalergénica, tolerancia, estabilidad y baja toxicidad. Hasta hace pocos años sus principales indicaciones terapéuticas eran anestesia infiltrativa y conductiva, anestésico local, en el bloqueo nervioso del dolor utilizado en odontología, anestesia local espinal, epidural y caudal, para infiltraciones articulares y musculares, como antiarrítmico controlando arritmias ventnculares, extrasístoles, taquicardia y fibrilación, anticonvulsivante por depresión de las neuronas corticales, como diluyente, como vehículo, como aditivo y en la formación de algunos liposomas. En el 2001 se utilizo en la preparación de dispersiones solidas especialmente productos farmacéuticos; estos procedimientos suponen la disolución de una o más sustancias insolubles o relativamente insolubles, preferentemente sustancias activas farmacéuticamente y/o una o más sustancias solubles en agua, preferentemente vehículos, en fluidos supercríticos y la posterior eliminación de disolvente mediante expansión rápida, invención correspondiente al documento WO0166091 ( A1). Posteriormente y de acuerdo al documento WO/2008/033497 se utiliza la lidocaína, con hidrogel de pluronic, alginate y chitosan para la elaboración de nanopartículas de gel inteligentes para la liberación de fármacos, sola o en combinación mediante un método termorreversible. Lidocaine was synthesized in 1943 by the Swedish chemist Nils Lófgren and is one of the most commonly used local anesthetic drugs in surgery and dentistry due to its short latency (1.5 to 2 hrs.) Wide diffusion, hypoallergenic properties, Tolerance, stability and low toxicity. Until a few years ago its main therapeutic indications were infiltrative and conductive anesthesia, local anesthetic, in the nerve block of pain used in dentistry, spinal, epidural and caudal local anesthesia, for joint and muscular infiltrations, as an antiarrhythmic controlling ventnular arrhythmias, extrasystoles, tachycardia and fibrillation, anticonvulsant due to depression of cortical neurons, as a diluent, as a vehicle, as an additive and in the formation of some liposomes. In 2001 it was used in the preparation of solid dispersions, especially pharmaceutical products; These procedures involve the dissolution of one or more insoluble or relatively insoluble substances, preferably pharmaceutically active substances and / or one or more water soluble substances, preferably vehicles, in supercritical fluids and subsequent solvent removal by rapid expansion, invention corresponding to the document WO0166091 (A1). Subsequently, and according to WO / 2008/033497, lidocaine is used, with hydrogel of pluronic, alginate and chitosan for the elaboration of intelligent gel nanoparticles for drug release, alone or in combination by a thermo-reversible method.
En la actualidad, la eficacia terapéutica de algunos fármacos resulta difícil de lograr cuando en su desempeño prescinde de mecanismos que eviten metabolizarse cada vez que atraviesen barreras fisiológicas para llegar a su sitio o receptores de acción sin degradarse, así es que requiere de concentraciones elevadas de principio activo para lograr un efecto terapéutico significativo, pero que finalmente afectan otros órganos; el uso prolongado de esos fármacos puede ocasionar efectos adversos en enfermedades crónicas, que requieren el uso prolongados de los mismos, como en infecciones de vías respiratorias recurrentes bacterianas donde se genera frecuentemente resistencia bacteriana y con ello la no eliminación de las bacterias, en neuropatías periféricas y enfermedades donde se padecen dolores crónicos, los medicamentos tardan en hacer efecto y en ocasiones la no eliminación del padecimiento. At present, the therapeutic efficacy of some drugs is difficult to achieve when in their performance they disregard mechanisms that avoid metabolizing each time they cross physiological barriers to reach their site or receptors of action without degrading, so it requires high concentrations of active principle to achieve a significant therapeutic effect, but which ultimately affect other organs; Prolonged use of these drugs can cause adverse effects in chronic diseases, which require prolonged use of them, such as in bacterial recurrent respiratory infections where bacterial resistance is frequently generated and thus the non-elimination of bacteria, in peripheral neuropathies and diseases where chronic pain is suffered, medications take time to take effect and sometimes the non-elimination of the condition.
VENTAJAS DE LA PATENTE ADVANTAGES OF THE PATENT
La característica de esta invención se compone de elementos que mejoran los procesos de producción de complejos para el desarrollo e innovación de nuevos fármacos, fundamentalmente en la transformación y reformulación se conocen las cantidades necesarias de ambos reactivos, donde un reactivo pueden ser fármacos como antibióticos específicos para infecciones de vías respiratorias altas, complejo B y analgésicos esteroideos y no esteroideos entre otros aprobados por la FDA y la COFEPRIS y el otro reactivo es la lidocaína, que al ser transformados se convierten en complejos lidocaína-fármacos donde la dosis que se obtiene es en escala manométrica conservando la acción y eficacia terapéutica del fármaco transformado y los efectos adversos o tóxicos desaparecen permitiendo que estos nuevos fármacos puedan ser utilizados por tiempos prolongados sin presentar efectos adversos ni daño a órganos, para el caso de los antibióticos reformulados estos presentan una mejor respuesta terapéutica, observándose que las bacterias que afectan las vías respiratorias ofrecen menor resistencia bacteriana y eliminación total de las mismas, en las neuropatías estos nuevos fármacos ofrecen una regeneración del nervio periférico y con ello la desaparición del dolor, en el caso del dolor crónico los analgésicos desinflamatorios esteroideos y no esteroideos, el dolor cede o desaparece, no se presentan efectos colaterales ni adversos con el uso prolongado de estos fármacos transformados. The characteristic of this invention is composed of elements that improve the production processes of complexes for the development and innovation of new drugs, fundamentally in the transformation and reformulation the necessary quantities of both reagents are known, where a reagent can be drugs as specific antibiotics for upper respiratory infections, complex B and Steroidal and non-steroidal analgesics, among others approved by the FDA and COFEPRIS, and the other reagent is lidocaine, which, when transformed, becomes lidocaine-drug complexes where the dose obtained is in a manometric scale preserving the therapeutic action and efficacy of the Transformed drug and adverse or toxic effects disappear allowing these new drugs to be used for long periods without presenting adverse effects or damage to organs, in the case of reformulated antibiotics they have a better therapeutic response, observing that the bacteria that affect the airways offer lower bacterial resistance and total elimination of these, in the neuropathies these new drugs offer a regeneration of the peripheral nerve and with it the disappearance of pain, in the case of chronic pain the steroidal and non-steroidal anti-inflammatory analgesics, the pain subsides or disappears There are no side or adverse effects with prolonged use of these transformed drugs.
Estos procedimientos suponen la fusión de las moléculas de la lidocaína con las moléculas de uno o más fármacos aprobados por la FDA y la COFEPRIS, siendo estos antibióticos para tratar infecciones respiratorias altas, complejo B como antineurítico y desinflamatorios no esteroideos y esferoides originando formulas de nueva generación donde a la molécula de la lidocaína se usa como un reactivo capaz de fusionarse con las moléculas de los fármacos antes mencionados, así mismo, este desempeño propicia formación de complejos mediante una reacción en cadena que da como resultado una macromolécula del fármaco reformulado en donde se conserva el principio activo del fármaco ( ya sea antibiótico, vitaminas del grupo B, analgésico no esteroideo y esteroideo) y se pierde la función anestésica de la lidocaína. Los complejos están dispersos en la solución liquida, proporcionada por la misma presentación de la lidocaína, otras ventajas de estos fármacos transformados son: el aumento en la biodisponibilidad, el uso de una concentración mucho menor del fármaco, lo que permite' utilizarlo por tiempos prolongados, estos complejos lidocaína- fármacos son aplicados mediante implantes por inyección cerca de los receptores específicos evitando de esta manera las barreras fisiológicas, utiliza la totalidad del fármaco, esta aplicación no es invasiva ni dolorosa, el fármaco al entrar al cuerpo tiene una liberación prolongada que dura de 8 a 10 días lo que representa bienestar en el tratamiento. DESCRIPCIÓN These procedures involve the fusion of lidocaine molecules with the molecules of one or more drugs approved by the FDA and COFEPRIS, being these antibiotics to treat upper respiratory infections, complex B as antineuritic and non-steroidal and spheroid disinflammatory drugs causing new formulas. generation where the lidocaine molecule is used as a reagent capable of fusing with the molecules of the aforementioned drugs, likewise, this performance leads to complex formation through a chain reaction that results in a macromolecule of the reformulated drug where The active substance of the drug is conserved (be it antibiotic, vitamins of group B, non-steroidal analgesic and steroidal) and the anesthetic function of lidocaine is lost. The complexes are dispersed in the liquid solution, provided by the same presentation of lidocaine, other advantages of these transformed drugs are: the increase in bioavailability, the use of a much lower concentration of the drug, which allows it to be used for prolonged times , these lidocaine-drug complexes are applied by injection implants near the specific receptors thus avoiding physiological barriers, using the entire drug, this application is not invasive or painful, the drug when entering the body has a prolonged release that It lasts from 8 to 10 days which represents well-being in the treatment. DESCRIPTION
Para comprender las propiedades reactivas de la molécula de la lidocaína, se muestra el esquema representado en la figura 1. La lidocaína tiene una estructura química que se puede dividir en cuatro subunidades, mismas que presentan características muy interesantes y que tienen que ver con el proceso de transformación que a continuación se describe. To understand the reactive properties of the lidocaine molecule, the scheme shown in Figure 1 is shown. Lidocaine has a chemical structure that can be divided into four subunits, which have very interesting characteristics and have to do with the process of transformation described below.
Subunidad 1 : Es un núcleo aromático, es el principal responsable de la liposolubilidad de la molécula, está formado por un anillo bencénico sustituido, la adición de más grupos a este nivel aumentara la liposolubilidad, cabe mencionar que los anillos bencénicos presentan reacciones de sustitución más que de adición, las reacciones que puede presentar son de nitración si es con nitrógeno, sulfatación si es con sulfuro y halogenación si es con bromuro, en estas sustituye un átomo o grupo por un hidrogeno del benceno, esto indica que mantiene sus propiedades características, así como su estructura y en reacciones acidas sirve de fuente electrónica, estas características se presentan independientemente de los otros grupos funcionales que contenga la molécula. Subunit 1: It is an aromatic nucleus, it is primarily responsible for the liposolubility of the molecule, it is formed by a substituted benzene ring, the addition of more groups at this level will increase the liposolubility, it should be mentioned that the benzene rings have more substitution reactions In addition, the reactions that can occur are nitration if it is with nitrogen, sulfation if it is with sulfide and halogenation if it is with bromide, in these it replaces an atom or group with a hydrogen of benzene, this indicates that it maintains its characteristic properties, As well as its structure and in acid reactions it serves as an electronic source, these characteristics are presented independently of the other functional groups contained in the molecule.
Subunidad 2: Unión amida. Esta une al núcleo aromático con la cadena hidrocarbonatada, es resistente a las variaciones térmicas, las amidas presentan puntos de ebullición elevados debido a la capacidad para establecer puentes de hidrogeno firmes, cuando aumenta la temperatura en bases acuosas se hidrolizan, aquí se reemplaza el grupo -NH2 por -OH, en condiciones acidas la hidrólisis implica el ataque del agua sobre la amina protonada, es decir; la hidrólisis de aminas es una de las reacciones típicas de los derivados de ácidos carboxílicos. Es la parte de la molécula que funciona como anión. Subunit 2: Amide Union. This joins the aromatic nucleus with the hydrocarbon chain, is resistant to thermal variations, the amides have high boiling points due to the ability to establish firm hydrogen bonds, when the temperature increases in aqueous bases they hydrolyze, here the group is replaced -NH2 by -OH, in acidic conditions hydrolysis involves the attack of water on the protonated amine, that is; Hydrolysis of amines is one of the typical reactions of carboxylic acid derivatives. It is the part of the molecule that functions as an anion.
Subunidad 3: Cadena carbonatada. Generalmente es un alcohol con 2 átomos de carbono. Esta influye en la liposolubilidad de la molécula, cuando aumenta el tamaño de la cadena aumenta el tiempo de acción del fármaco y aumenta la liposolubilidad. Subunidad 4: Grupo amina, esta determina la hidrosolubilidad de la molécula y su unión a proteínas plasmáticas, las aminas contienen nitrógeno que posee un par de electrones no compartidos, la tendencia del nitrógeno a compartir ese par de electrones es la base de todo su comportamiento químico, lo cual le da la propiedad de ser la zona catión ica que recibe un H positivo y da dos protones negativos; la presencia de un ion hidróxido acuoso las convierte con facilidad en aminas libres, las aminas son un compuesto iónico típico, al ser calentadas por lo general se descomponen, las aminas tienen hidrógenos reemplazados por grupos orgánicos, la síntesis de nitritos tiene la característica de aumentar la longitud de una cadena carbonatada. Subunit 3: Carbonated chain. It is usually an alcohol with 2 carbon atoms. This influences the liposolubility of the molecule, when the chain size increases the time of action of the drug increases and the liposolubility increases. Subunit 4: Amine group, this determines the water solubility of the molecule and its binding to plasma proteins, the amines contain nitrogen that has a pair of non-shared electrons, the tendency of nitrogen to Sharing that pair of electrons is the basis of all its chemical behavior, which gives it the property of being the cationic zone that receives a positive H and gives two negative protons; the presence of an aqueous hydroxide ion easily converts them into free amines, amines are a typical ionic compound, when heated they generally decompose, amines have hydrogens replaced by organic groups, nitrite synthesis has the characteristic of increasing the length of a carbonated chain.
La lidocaína tiene una acción conocida de anestésico local que impide la propagación del impulso nervioso disminuyendo la permeabilidad del canal del Na, bloqueando la fase inicial del potencial de acción; para ello debe atravesar la membrana nerviosa puesto que su acción farmacológica fundamentalmente la lleva acabo uniéndose al receptor desde el lado citoplasmático de la misma. Otro factor que influye en su acción es el hecho de que esta se une y disocia rápidamente del canal del sodio; los grupos -NH2 y -OH y sus derivados actúan como activantes poderosos en la sustitución electrofilica aromática ejerciendo un efecto inductivo de atracción de electrones; el nitrógeno del grupo -NH2 es básico y tiende a compartir su último par de electrones para adquirir una carga positiva propiedad del grupo metilo, esta dispersión de la carga estabiliza el carbocatión, el efecto inductivo estabiliza de la mismo forma la carga positiva que se desarrolla en el estado de transición acelerando la reacción. Lidocaine has a known local anesthetic action that prevents the spread of the nerve impulse by decreasing the permeability of the Na channel, blocking the initial phase of the action potential; To do this, it must cross the nerve membrane since its pharmacological action is essentially carried out by joining the receptor from the cytoplasmic side of it. Another factor that influences its action is the fact that it quickly binds and dissociates from the sodium channel; the -NH2 and -OH groups and their derivatives act as powerful activators in the aromatic electrophilic substitution by exerting an inductive effect of electron attraction; the nitrogen of the group -NH2 is basic and tends to share its last pair of electrons to acquire a positive charge owned by the methyl group, this dispersion of the charge stabilizes the carbocation, the inductive effect stabilizes in the same way the positive charge that develops in the transition state accelerating the reaction.
RELACION DE LAS FIGURAS Figura 1. Corresponde a la molécula de la lidocaína. RELATIONSHIP OF THE FIGURES Figure 1. Corresponds to the lidocaine molecule.
Figura 2. Corresponde al IR de la lidocaína. Espectro obtenido en un equipo infrarrojo, marca Perkin Elmer modelo Spectrum 100. Realizado en la Universidad Autónoma de Querétaro. Figure 2. Corresponds to the IR of lidocaine. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made at the Autonomous University of Querétaro.
Figura 3. Corresponde al IR del fosfomicina. Espectro obtenido en un equipo infrarrojo, marca Perkin Elmer modelo Spectrum 100. Realizado en la Universidad Autónoma de Querétaro.  Figure 3. Corresponds to the phosphomycin IR. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made at the Autonomous University of Querétaro.
Figura 4. Corresponde al IR del lincomicina. Espectro obtenido en un equipo infrarrojo, marca Perkin Elmer modelo Spectrum 100. Realizado por el laboratorio ARJ. Figure 4. Corresponds to the lincomycin IR. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the ARJ laboratory.
Figura 5. Corresponde al IR del dexametasona. Espectro obtenido en un equipo infrarrojo, marca Perkin Elmer modelo Spectrum 100. Realizado por la Universidad Autónoma de Querétaro. Figura 6. Corresponde al IR del complejo lidocaína-fosfomicina. Espectro obtenido en un equipo infrarrojo, marca Perkin Elmer modelo Spectrum 100. Realizado por la Universidad Autónoma de Querétaro. Figure 5. Corresponds to the dexamethasone IR. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the Autonomous University of Querétaro. Figure 6. Corresponds to the IR of the lidocaine-fosfomycin complex. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the Autonomous University of Querétaro.
Figura 7. Corresponde al IR del complejo lidocaína-lincomicina. Espectro obtenido en un equipo infrarrojo, marca Perkin Elmer modelo Spectrum 100. Realizado por el laboratorio ARJ. Figure 7. Corresponds to the IR of the lidocaine-lincomycin complex. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the ARJ laboratory.
Figura 8. Corresponde al IR del complejo lidocaína-dexametasona. Espectro obtenido en un equipo infrarrojo, marca Perkin Elmer modelo Spectrum 100. Realizado por la Universidad Autónoma de Querétaro. Figure 8. Corresponds to the IR of the lidocaine-dexamethasone complex. Spectrum obtained in an infrared device, Perkin Elmer brand Spectrum 100 model. Made by the Autonomous University of Querétaro.
Figura 9. Corresponde al crecimiento del complejo lidocaína-fosfomicina visto en un microscopio óptico del grupo ICB a 100 Figure 9. Corresponds to the growth of the lidocaine-fosfomycin complex seen in an optical microscope of the ICB group at 100
Figura 10. Corresponde al crecimiento del complejo lidocaína-neurobion visto en un microscopio óptico del grupo ICB a 100 Figure 10. Corresponds to the growth of the lidocaine-neurobion complex seen in an optical microscope of the ICB group at 100
Figura 11. Corresponde al crecimiento del complejo lidocaína-dexametasona visto en un microscopio óptico del grupo ICB a 100 DESCRIPCIÓN DETALLADA DE LA INVENCIÓN Figure 11. Corresponds to the growth of the lidocaine-dexamethasone complex seen in an optical microscope of the ICB group at 100 DETAILED DESCRIPTION OF THE INVENTION
El hallazgo de esta invención, consiste en procedimientos donde se permite unir las moléculas de la lidocaína con las moléculas de uno o más fármacos, así como la gnosis de la dilución de los fármacos a niveles efectivos donde no se pierden los efectos terapéuticos, de esta manera se obtiene una nanodosis eficaz: específicamente un procedimiento para fármacos liofilizados, y otro procedimiento para fármacos líquidos preferentemente fármacos aprobados por la FDA y la COFEPRIS, donde el sustrato de la reacción química son complejos de fármacos transformados (complejos lidocaína-fármaco) que se podrán implantar por inyección vía bucal, intraarticular, intradérmica, intramuscular, intrarectal preferentemente cerca de los receptores específicos del principio terapéutico de los fármacos transformados, donde su liberación es constante, efectiva y dura 8 - 10 días. The finding of this invention consists in procedures where it is possible to link the molecules of lidocaine with the molecules of one or more drugs, as well as the gnosis of the dilution of drugs to effective levels where the therapeutic effects of this drug are not lost. an effective nanodose is obtained: specifically a procedure for lyophilized drugs, and another procedure for liquid drugs preferably drugs approved by the FDA and COFEPRIS, where the substrate of the chemical reaction is complexes of transformed drugs (lidocaine-drug complexes) that are They may be implanted by oral, intra-articular, intradermal, intramuscular, intrarectal injection, preferably near the specific receptors of the therapeutic principle of the transformed drugs, where their release is constant, effective and lasts 8-10 days.
El método para el cambio químico, o bien; transformación y formación de complejos de los fármacos liofilizados comprende dos fases elementales: The method for chemical change, or; transformation and complex formation of lyophilized drugs comprises two elementary phases:
Primera Fase: · Requiere lidocaína, una cantidad de 30 a 60mg. diluida de 4 a 6 mi. First phase: · Requires lidocaine, an amount of 30 to 60mg. diluted from 4 to 6 mi.
• Se requiere una dosis terapéutica, adulto; del fármaco en su presentación comercial (liofilizada) para esta prueba en especifico como ejemplo se utilizo un antibiótico (fosfocil 1g por Senosiain). • A therapeutic dose is required, adult; of the drug in its commercial presentation (lyophilized) for this specific test as an example an antibiotic was used (fosfocil 1g by Senosiain).
Dentro de un recipiente de vidrio cerrado herméticamente se introduce la lidocaína y posterior el fármaco a través de un mecanismo de inyección-succión y agitación para mezclar los dos reactivos; a través de esta metodología y del proceso químico provocado se obtiene sustratos que por efecto de un factor energético se transforman en nuevos compuestos. Lidocaine is introduced into a tightly sealed glass container and the drug is subsequently introduced through an injection-suction and stirring mechanism to mix the two reagents; Through this methodology and the chemical process caused, substrates are obtained which, due to the effect of an energy factor, are transformed into new compounds.
A través de procedimientos cuantitativos se determina el desempeño de la actividad química, quien da la identidad funcional del nuevo fármaco, la reacción de una onda expansiva provocada por el movimiento rápido de la moléculas de ambos reactivos provoca un aumento en la temperatura de entre 11 y 14 °C , lo que origina una gran cantidad de energía cinética que se convierte en energía potencial que domina las fuerzas de repulsión entre las nubes de electrones acercándose estrechamente y permitiendo después un reordenamiento de electrones, durante este proceso se rompen los enlaces existentes y se forman otros nuevos, dando lugar a un cambio químico neto. Esta reacción es exotérmica, en esta etapa la energía potencial de los productos es más baja que la de los reactivos, La energía liberada aparece como un aumento de la energía cinética de los productos por lo que la temperatura se eleva conforme progresa la reacción, esta reacción se sostiene durante 2.5 minutos al termino de ella la temperatura regresa a temperatura ambiente, se obtiene un liquido homogéneo donde no se observan partículas dispersas. Through quantitative procedures the performance of the chemical activity is determined, who gives the functional identity of the new drug, the reaction of an expansive wave caused by the rapid movement of the molecules of both reagents causes an increase in temperature between 11 and 14 ° C, which causes a large amount of kinetic energy that is converted into potential energy that dominates the repulsive forces between electron clouds, approaching closely and then allowing an electron rearrangement, during this process the existing bonds are broken and they form new ones, leading to a net chemical change. This reaction is exothermic, at this stage the potential energy of the products is lower than that of the reagents. The energy released appears as an increase in the kinetic energy of the products so the temperature rises as the reaction progresses, this reaction is held for 2.5 minutes at the end of it the temperature returns to room temperature, a homogeneous liquid is obtained where no dispersed particles are observed.
Segunda fase: Second stage:
Inmediatamente después a la primera fase y a través de un mecanismo de inyección- succión y agitación, se mezcla el producto obtenido en la fase uno con una cantidad equivalente de 10 a 40 mi de lidocaína al 1 o 2 % (en donde la lidocaína al 1% contiene 10mg de lidocaína diluida en 1 mi de agua y la lidocaína al 2 % contiene 20 mg de lidocaína diluida en 1 mi de agua) , esta reacción dura 2.5 minutos mismos en los que la temperatura baja 2 a 3°, los siguientes 20-25 minutos se registran variaciones de la temperatura de 1 a 1.5 °C, durante esta reacción se presenta una colisión efectiva entre las partículas que por estar disueltas tienen un contacto estrecho, por esta razón requiere una cinética mínima que es cambiada a energía potencial en el momento del impacto. Durante esta reacción el soluto posee una energía potencial mayor que los reactivos, el aumento neto en la energía potencial que tiene lugar conforme se forman los complejos ocurre a expensas de la energía cinética, es decir existe una disminución global neta en la energía cinética promedio conforme procede la reacción, motivo por el cual baja la temperatura de la mezcla, esta reacción es endotérmica pues la energía cinética es convertida a energía potencial, en este sentido el sistema absorbe o almacena energía, esto favorece a que exista una gran cantidad de energía disponible en la colisión para formar un complejo activado, resultando así una elevada energía de activación y por lo tanto se presenta una reacción lenta. Para el caso de los fármacos en presentación liquida con las partículas dispersas, no se requiere realizar el primer paso de la reacción que se lleva a cabo con los fármacos liofilizados, por lo que se suprime. Se inicia la reacción con la mezcla de los dos reactivos que comprenden uno o más fármacos que pueden ser antibióticos, complejo B y desinflámatenos, esteroideos y no esteroideos, en una dosis adulto, se utilizaron para este caso como ejemplo los siguientes fármacos : el linconcin de 600 mg (lincomicina elaborada por PFIZER), Alin Depot de 8 mg (dexametasona elaborada por Chinoin), Neurobion (confine clorhidrato de tiamina 100mg, clorhidrato de pridoxina 100mg y cinocobalamina lOOOmcg fabricada por Merck) mezclados cada uno con la lidocaína(Pisacaina elaborada por PISA) en una cantidad equivalente de entre 10 a 40 mi de lidocaína al 1 o 2 %,( donde la lidocaína al 1 % contiene 10mg de lidocaína diluida en 1 mi de agua y la lidocaína al 2 % contiene 20 mg de lidocaína diluida en 1 mi de agua), para llevar a cabo la reacción, se mezcla en un recipiente de vidrio cerrado herméticamente, y a través de un mecanismo de inyección y succión por un lapso de 1 a 1.5 minutos y la reacción dura de 2 a 4 minutos De la misma manera, y a través de procedimientos de medición se determina el desempeño de la actividad química, la temperatura baja de 1.5 a 3°, y en un lapso de 20 a 25 minutos se registran variaciones de la temperatura de 1 a 1.5 °C , la reacción dura en total desde el inicio hasta el final de 25 a 35 minutos, mientras tanto esta reacción provoca una colisión efectiva entre las partículas que por estar disueltas tienen un contacto estrecho, por esta razón requiere una cinética mínima que es reemplazada por energía potencial en el momento del impacto. Durante esta reacción el producto se encuentran a una energía potencial mayor que la de los reactivos, el aumento neto en la energía potencial que tiene lugar conforme se forman los productos ocurre a expensas de la energía cinética, es decir; existe una disminución global neta en la energía cinética promedio conforme procede la reacción, motivo por el cual baja la temperatura de la mezcla. Esta reacción es endotérmica pues la energía cinética es convertida a energía potencial, en este sentido el sistema absorbe o almacena energía, esto favorece a que exista una gran cantidad de energía disponible en la colisión para formar un complejo activado, resultando así una elevada energía de activación y por lo tanto se presenta una reacción lenta. Immediately after the first phase and through an injection-suction and stirring mechanism, the product obtained in phase one is mixed with an equivalent amount of 10 to 40 ml of 1 or 2% lidocaine (where lidocaine 1 % contains 10mg of lidocaine diluted in 1 ml of water and 2% lidocaine contains 20 mg of lidocaine diluted in 1 ml of water), this reaction lasts 2.5 minutes in which the temperature drops 2 to 3 °, the next 20 -25 minutes temperature variations from 1 to 1.5 ° C are recorded, during this reaction there is an effective collision between the particles that because they are dissolved have a close contact, for this reason requires a minimum kinetics that is changed to energy potential at the moment of impact. During this reaction the solute has a potential energy greater than the reactants, the net increase in potential energy that occurs as the complexes occur at the expense of kinetic energy, that is, there is a net overall decrease in the average kinetic energy as the reaction proceeds, which is why the temperature of the mixture falls, this reaction is endothermic because the kinetic energy is converted to potential energy, in this sense the system absorbs or stores energy, this favors a large amount of available energy in the collision to form an activated complex, resulting in a high activation energy and therefore a slow reaction occurs. In the case of drugs in liquid presentation with dispersed particles, it is not necessary to perform the first step of the reaction that is carried out with lyophilized drugs, so it is suppressed. The reaction is started with the mixture of the two reagents comprising one or more drugs that can be antibiotics, complex B and disinflammatenosis, steroids and non-steroids, in an adult dose, the following drugs were used as an example: linconcin 600 mg (lincomycin made by PFIZER), 8 mg Alin Depot (dexamethasone made by Chinoin), Neurobion (confine thiamine hydrochloride 100mg, pridoxine hydrochloride 100mg and linocobalamin lOOOmcg manufactured by Merck) each mixed with lidocaine (Pisaca) per PISA) in an equivalent amount of 10 to 40 ml of 1 or 2% lidocaine (where 1% lidocaine contains 10 mg of lidocaine diluted in 1 ml of water and 2% lidocaine contains 20 mg of diluted lidocaine in 1 ml of water), to carry out the reaction, it is mixed in a tightly closed glass container, and through an injection and suction mechanism for a period of 1 to 1.5 minutes and the reaction lasts from 2 to 4 minutes In the same way, and through measurement procedures the performance of the chemical activity is determined, the temperature drops from 1.5 to 3 °, and in a span of 20 to 25 minutes variations of the temperature of 1 to 1.5 ° C, the reaction lasts in total from the beginning to the end of 25 to 35 minutes, meanwhile this reaction causes an effective collision between the particles that because they are dissolved have a close contact, for this reason it requires a minimum kinetics that is replaced by potential energy at the moment of impact. During this reaction the product is at a potential energy greater than that of the reagents, the net increase in the potential energy that takes place as the products occur at the expense of kinetic energy, that is; There is a net overall decrease in average kinetic energy as the reaction proceeds, which is why the temperature of the mixture falls. This reaction is endothermic because the kinetic energy is converted to potential energy, in this sense the system absorbs or stores energy, this favors that there is a large amount of energy available in the collision to form an activated complex, resulting in a high energy of activation and therefore a slow reaction occurs.
La presente invención se basa en el hallazgo de la gnosis de las cantidades adecuadas de la lidocaína y del fármaco para la preparación de nanodosis eficaces; en estas nanodosis se conservan los efectos terapéuticos del fármaco, así como los grupos funcionales de la molécula de la lidocaína esenciales en el desempeño de la reacción de transformación y formación de nuevos complejos de fármacos de antibióticos, complejo B y analgésicos esteroideos y no esteroideos entre otros, así mismo; la función del agua en la que se encuentra diluida la lidocaína mantiene un papel elemental, ya que aporta el espacio necesario para el crecimiento apropiado de las moléculas, por otra parte su función además de ser disolvente del fármaco está íntimamente implicada en el cambio químico del mismo, pues su estructura propicia enlaces que son puentes de hidrogeno y es la formación de estos enlaces lo que proporciona la energía necesaria para que se rompan los enlaces que mantienen unidas a las partículas de la molécula del fármaco y las de la lidocaína produciendo la formación de complejos Lidocaína-Fármaco. En la figura 1 tenemos la estructura de la molécula de la lidocaína, esta estructura determina el comportamiento químico de la misma primero observemos que el grupo amina determina la hidrosolubilidad de la molécula y su unión a proteínas plasmáticas. Las aminas contienen nitrógeno que posee un par de electrones no compartidos, la tendencia del nitrógeno a compartir ese par de electrones es la base de todo su comportamiento químico lo que le da la propiedad de ser la zona catiónica, recibe un H positivo y da dos protones negativos. En el agua los cationes son atraídos al polo negativo de un disolvente polar solvatando los cationes en su polo negativo esencialmente en sus electrones no compartidos; la presencia de un ión hidróxido acuoso las convierte con facilidad en aminas libres. Las aminas son un compuesto iónico típico que al ser calentadas se descomponen, las aminas tienen hidrógenos reemplazados por grupos orgánicos, la síntesis de nitrilos tiene la característica de aumentar la longitud de una cadena carbonatada. Esta propiedad de las aminas beneficia a la hora de fusionarse la lidocaína con los fármacos. Para expresar y demostrar este resultado se anexa la identidad infrarroja (IR) de tres medicamentos que se tomaron como ejemplo para transformar. Las identidades IR que se exhiben en la presente invención se efectuaron en la Universidad Autónoma de Querétaro utilizando un equipo infrarrojo marca Perkin Elmer modelo Spectrum 100, y por el laboratorio ARJ, con un equipo infrarrojo de las mismas características. Los fármacos procesados como ejemplo en esta invención fueron la fosfomicina, lincomicina y dexametasona, se realizaron Identidades IR de los tres fármacos el IR de la lidocaína y las identidades IR de los complejos lidocaína- fosfomicina, lidocaína-lincomicina y lidocaína-dexametasona, la figura 2 corresponde al IR de la lidocaína, la figura 3 corresponde al IR de la fosfomicina, la figura 4 corresponde al IR de la lincomicina, la figura 5 al IR de la dexametasona, la figura 6 al IR del complejo lidocaína- fosfomicina, la figura 7 al IR del complejo lidocaína- lincomicina, la figura 8 al IR del complejo lidocaína-dexametasona, en todos los estudios IR se observa que por efecto del grupo amina la cadena hidrocarbonatada aumento su longitud mejorando de esta manera la liposolubilidad y aumentando la duración de acción del complejo lidocaína-fármaco, este grupo amina se transformo y por esta razón perdió su efecto anestésico ya que es este el que reacciona en el bloqueo del canal del sodio. La unión amida que une al núcleo aromático con la cadena hidrocarbonatada, es resistente a las variaciones térmicas, las amidas presentan puntos de ebullición elevados debido a la capacidad para establecer puentes de hidrogeno firmes, cuando aumenta la temperatura en bases acuosas se hidrolizan, aquí se reemplaza el grupo -NH2 por -OH, en condiciones acidas la hidrólisis implica el ataque del agua sobre la amida protonada, es decir; la hidrólisis de amidas es una de las reacciones típicas de los derivados de ácidos carboxílicos. Es la región de la molécula que actúa como un anión, los aniones son atraídos al polo positivo de una molécula polar como el agua, en donde los polos positivos se encuentran en los hidrógenos, los enlaces ión-dipolo sujetan los aniones por puentes de hidrogeno, en los IR de las figuras 6, 7 y 8 se observa que por las propiedades mencionadas los grupos -NH2 se reemplazaron por grupos OH unidos por puentes de hidrogeno, en cuanto al núcleo aromático, que es el principal responsable de la liposolubilidad de la molécula de la lidocaína se conserva y la cadena hidrocarbonatada aumenta en tamaño por lo que aumenta la liposolubilidad y duración de acción. Como se observa en los estudios IR con respecto a los grupos funcionales terapéuticos de los fármacos se conservaron en los complejos lidocaína-fármacos motivo por el cual no se pierde la función terapéutica, es decir; si se transforma un antibiótico el producto sigue teniendo un efecto antibiótico, en el caso del analgésico desinflamatorío esteroideo o no esteroideo, sigue teniendo efectos analgésicos desinflamatorios y así sucede con cualquier fármaco que se utilice, como ya se explico, la molécula de la lidocaína se fusiono con el fármaco otorgándole una biodisponibilidad mejorada y un aumento en la duración de acción terapéutica. Otro hallazgo de la invención fue aprovechar el carácter reactivo de los cationes y aniones de la molécula de la lidocaína mismas que origina la formación de complejos por reacción en cadena donde ocurrió una reacción química, y donde cada una de las moléculas consumió una partícula reactiva y produjo otra similar, por lo que cada reacción individual dependió de la anterior uniendo de esta manera las macromoléculas para dar origen a macromoléculas que conservan enlaces secundarios como fuerzas de Van der Waals, enlaces dipolo-dipolo, enlaces ión-dipolo y puentes de hidrogeno, estos enlaces son relativamente débiles pero al actuar al mismo tiempo como un equipo son fuertes y su formación puede proporcionar la energía suficiente para romper un enlace covalente. Estos enlaces secundarios existen entre distintas partes de la macromolécula, teniendo así una función clave en la determinación de sus formas, formas que a su vez determinan sus propiedades. Se requiere de un crecimiento adecuado para tener una excelente función terapéutica, para lo cual es necesario el espacio idóneo este espacio lo da el diluyente de la molécula de la lidocaína. En las figuras 9,10 y 11 se muestran los crecimientos de las moléculas de los complejos lidocaína-fármacos transformándose en macromoléculas que esboza de esta manera los complejos de los productos. En la figura 9 se observa el crecimiento del complejo lidocaína-fosfomicina, donde se ve que primero se forman núcleos que miden de 10 a 30 mieras observándose a los 30 minutos, después se forman cristales planos alargados en crecimiento que salen del núcleo esto se ve entre 12 a 24 hrs. los cristales se fraccionan en muchos cristales con forma de astillas se observa esto entre las 24 a 36 hrs. para completar la formación de los complejos entre las 36 a 48 horas cuando ya se obtienen complejos estables y tomando una forma de cúmulos de macromoléculas amorfas. En las figuras 10 se observa el crecimiento del complejo lidocaína-neurobion, aquí después de hacer la reacción se observan cúmulos de macromoléculas, alcanzando una estabilidad en el crecimiento en 24 horas, donde ya se observan cúmulos de macromoléculas amorfas ocupando una gran parte de espacio. En la Figura 11 se observa el crecimiento del complejo lidocaína- dexametasona, aquí después de hacer la reacción se observan cúmulos de macromoléculas, alcanzando una estabilidad en el crecimiento en 24 horas, donde ya se observan cúmulos de macromoléculas amorfas ocupando una gran parte de espacio The present invention is based on the finding of gnosis of adequate amounts of lidocaine and the drug for the preparation of effective nanodoses; The therapeutic effects of the drug, as well as the functional groups of the lidocaine molecule essential in the performance of the transformation reaction and formation of new complexes of antibiotic drugs, B-complex and steroidal and non-steroidal analgesic drugs between others, likewise; The function of the water in which the lidocaine is diluted maintains an elementary role, since it provides the necessary space for the appropriate growth of the molecules, on the other hand its function in addition to being a solvent of the drug is intimately involved in the chemical change of the same, because its structure fosters bonds that are hydrogen bonds and it is the formation of these bonds that provides the energy needed to break the bonds that hold together the particles of the drug molecule and those of the lidocaine producing the formation of Lidocaine-Drug complexes. In Figure 1 we have the structure of the lidocaine molecule, this structure determines the chemical behavior of it first let us observe that the amine group determines the water solubility of the molecule and its binding to plasma proteins. The amines contain nitrogen that has a pair of non-shared electrons, the tendency of nitrogen to share that pair of electrons is the basis of all its chemical behavior which gives it the property of being the cationic zone, receives a positive H and gives two negative protons In water the cations are attracted to the negative pole of a polar solvent by solvating the cations in their negative pole essentially in their non-shared electrons; The presence of an aqueous hydroxide ion easily converts them into free amines. Amines are a typical ionic compound that when heated decompose, amines have hydrogens replaced by organic groups, the synthesis of nitriles has the characteristic of increasing the length of a carbonated chain. This property of the amines benefits when merging the Lidocaine with drugs. To express and demonstrate this result, the infrared (IR) identity of three medications that were taken as an example to transform is attached. The IR identities that are exhibited in the present invention were carried out at the Autonomous University of Querétaro using a Perkin Elmer infrared equipment model Spectrum 100, and by the ARJ laboratory, with an infrared equipment of the same characteristics. The drugs processed as an example in this invention were phosphomycin, lincomycin and dexamethasone, IR identities of the three IR drugs of lidocaine and the IR identities of the lidocaine-phosphomycin, lidocaine-lincomycin and lidocaine-dexamethasone complexes were performed. 2 corresponds to the Lidocaine IR, Figure 3 corresponds to the phosphomycin IR, Figure 4 corresponds to the lincomycin IR, Figure 5 to the dexamethasone IR, Figure 6 to the lidocaine phosphomycin complex IR, Figure 6 7 at the IR of the lidocaine-lincomycin complex, Figure 8 at the IR of the lidocaine-dexamethasone complex, in all IR studies it is observed that by effect of the amine group the hydrocarbon chain increased its length thereby improving liposolubility and increasing the duration of action of the lidocaine-drug complex, this amine group was transformed and for this reason it lost its anesthetic effect since it is this that reacts in the blockade of the sodium channel. The amide bond that joins the aromatic nucleus with the hydrocarbon chain is resistant to thermal variations, the amides have high boiling points due to the ability to establish firm hydrogen bonds, when the temperature increases in aqueous bases they hydrolyze, here they replaces the -NH2 group with -OH, in acidic conditions hydrolysis involves the attack of water on the protonated amide, that is; Hydrolysis of amides is one of the typical reactions of carboxylic acid derivatives. It is the region of the molecule that acts as an anion, the anions are attracted to the positive pole of a polar molecule such as water, where the positive poles are in the hydrogen, the ion-dipole bonds hold the anions by hydrogen bonds , in the IR of Figures 6, 7 and 8 it can be seen that by the mentioned properties the -NH2 groups were replaced by OH groups linked by hydrogen bonds, as for the aromatic nucleus, which is the main responsible for the liposolubility of the Lidocaine molecule is conserved and the hydrocarbon chain increases in size so it increases liposolubility and duration of action. As observed in the IR studies with respect to the therapeutic functional groups of the drugs, they were conserved in the lidocaine-drug complexes, which is why the therapeutic function is not lost, that is; if a antibiotic the product continues to have an antibiotic effect, in the case of the steroidal or non-steroidal anti-inflammatory analgesic, it still has anti-inflammatory analgesic effects and this is the case with any drug that is used, as explained, the lidocaine molecule was fused with the drug giving it an improved bioavailability and an increase in the duration of therapeutic action. Another finding of the invention was to take advantage of the reactive nature of the cations and anions of the same lidocaine molecule that causes the formation of complexes by chain reaction where a chemical reaction occurred, and where each of the molecules consumed a reactive particle and It produced a similar one, so each individual reaction depended on the previous one, thus joining the macromolecules to give rise to macromolecules that retain secondary bonds such as Van der Waals forces, dipole-dipole bonds, ion-dipole bonds and hydrogen bonds, These links are relatively weak but acting at the same time as a team are strong and their formation can provide enough energy to break a covalent bond. These secondary links exist between different parts of the macromolecule, thus having a key function in determining their forms, which in turn determine their properties. Adequate growth is required to have an excellent therapeutic function, for which the ideal space is necessary this space is given by the diluent of the lidocaine molecule. Figures 9,10 and 11 show the growth of the molecules of the lidocaine-drug complexes transforming into macromolecules, which outlines the complexes of the products. Figure 9 shows the growth of the lidocaine-fosfomycin complex, where it is seen that first nuclei are formed that measure from 10 to 30 microns being observed at 30 minutes, then elongated flat crystals are formed in growth that leave the nucleus this is seen between 12 to 24 hrs. The crystals are divided into many splinter-shaped crystals. This is observed between 24 and 36 hours. to complete the formation of the complexes between 36 and 48 hours when stable complexes are already obtained and taking a form of clusters of amorphous macromolecules. In figures 10 the growth of the lidocaine-neurobion complex is observed, here after making the reaction macromolecule clusters are observed, reaching a stability in growth in 24 hours, where amorphous macromolecule clusters are already observed occupying a large part of space . Figure 11 shows the growth of the lidocaine complex. dexamethasone, here after making the reaction you can see clusters of macromolecules, reaching a stability in growth in 24 hours, where you can already see clusters of amorphous macromolecules occupying a large part of space
El hallazgo de la presente invención se basa en la gnosis de la dilución del fármaco a niveles efectivos nanometricos donde se conservan los efectos terapéuticos eficaces y haber logrado fusionar la lidocaína con fánnacos que pueden ser antibióticos preferentemente para infecciones de las vías respiratorias, complejo B y analgésicos desinflamatorios esteroideos y no esteroideo, y encontrando de esta manera una forma de elaborar una nueva gama de fármacos transformados en donde se reduce de manera importante la cantidad de principio activo requerido para tratar patologías, pues el sustrato final obtenido contiene una cantidad nanometríca del principio activo pero con un aumento en la potencia de manera que conserva la eficacia y el efecto terapéutico del fármaco que se tomo para formar el complejo junto con la lidocaína, así mismo este producto puede ser implantado cada ocho días ya que es el tiempo en que dura su liberación y función terapéutica a través de inyección cerca de los receptores específicos, es decir, cerca de los órganos afectados saltándose así las barreras fisiológicas y con esto la pérdida del principio activo que se va quedando en dichas barreras. Todo esto proporciona las siguientes ventajas en comparación con los fármacos tradicionales. The finding of the present invention is based on the gnosis of the dilution of the drug at effective nanometric levels where effective therapeutic effects are preserved and having managed to fuse lidocaine with drugs that may be antibiotics preferably for respiratory tract infections, complex B and Steroidal and non-steroidal disinflammatory analgesics, and thus finding a way to develop a new range of transformed drugs where the amount of active ingredient required to treat pathologies is significantly reduced, since the final substrate obtained contains a nanometric amount of the principle active but with an increase in potency so that it retains the efficacy and therapeutic effect of the drug that was taken to form the complex together with lidocaine, likewise this product can be implanted every eight days since it is the time it lasts its release and therapeutic function through injection It is close to the specific receptors, that is, close to the affected organs thus skipping the physiological barriers and with this the loss of the active principle that remains in these barriers. All this provides the following advantages compared to traditional drugs.
1. Retomando el dato en donde se hace referencia, que se usa una cantidad del fármaco no transformado equivalente a una dosis adulto, el cual se hace reaccionar con una cantidad de 10 a 40 mi de lidocaína al 1 % o al 2%. De esta mezcla se obtiene nanodosis del fármaco transformado que puede ser aplicado por implante mediante inyección cerca de los receptores específicos de los tejidos u órganos afectados, el implante no es invasivo ni doloroso, el implante puede realizarse cada 8 a 10 días ya que durante este tiempo será liberado constantemente el complejo lidocaína-fármaco, al término de este período en caso de ser necesario se realizara un nuevo implante, de esta forma se administra una nanodosis del complejo lidocaína-fármaco de mejor biodisponibilidad que los fánnacos no transformados. Esto nos permite aplicar los complejos lidocaína-fármacos por tiempos prologados sin presentar efectos tóxicos, adversos ni colaterales, no daña órganos, en el caso de los antibióticos el hecho de aplicarlos por largos períodos nos permite eliminar las bacterias y así evitar las recaídas o infecciones respiratorias recurrentes. 1. Taking up the reference data, that an amount of the non-transformed drug equivalent to an adult dose is used, which is reacted with an amount of 10 to 40 ml of 1% or 2% lidocaine. From this mixture nanodosis of the transformed drug is obtained that can be applied by implant by injection near the specific receptors of the affected tissues or organs, the implant is not invasive or painful, the implant can be performed every 8 to 10 days since during this the lidocaine-drug complex will be constantly released at the end of this period, if necessary a new implant will be performed, in this way a nanodose of the lidocaine-drug complex of better bioavailability is administered than the non-transformed drugs. This allows us to apply the lidocaine-drug complexes for prolonged times without presenting toxic, adverse or collateral effects, it does not damage organs, in the case of antibiotics the fact of applying them for long periods allows us to eliminate the bacteria and thus avoid relapses or recurrent respiratory infections.
2. Como se observa en la fusión entre la molécula de la lidocaína con uno o más fármacos, el producto que se obtiene es un fármaco transformado que presenta una biodisponibilidad mejorada, ya que su capacidad de traspasar la membrana es mayor por ser más liposoluble pues el núcleo aromático de la lidocaína se adiciona y como la cadena hidrocarbonatada aumento de tamaño esto hace al fármaco más potente y con mayor duración en su acción. 2. As observed in the fusion between the lidocaine molecule with one or more drugs, the product obtained is a transformed drug that has an improved bioavailability, since its ability to transfer the membrane is greater because it is more liposoluble because The aromatic nucleus of lidocaine is added and as the hydrocarbon chain increases in size this makes the drug more potent and with longer duration in its action.
3. Las macromoléculas que se forman son complejos, en donde sus partículas están unidas por fuerzas de Van der Waals, que al entrar al cuerpo estos por condiciones fisiológicas se separan dejando libre las pequeñas partículas del fármaco , que se unen a los receptores específicos realizando su acción terapéutica. Esta condición nos otorga una liberación continua y prolongada del fármaco, misma que dura de 8 a 10 días, lo que se traduce en una mejora en la biodisponibilidad. 3. The macromolecules that are formed are complex, where their particles are joined by forces of Van der Waals, which when entering the body these by physiological conditions are separated leaving free small particles of the drug, which bind to specific receptors by performing Its therapeutic action. This condition gives us a continuous and prolonged release of the drug, which lasts 8 to 10 days, which translates into an improvement in bioavailability.
En el transcurso de los últimos catorce años, se realizo una investigación retrospectiva en base a tratamientos hechos a pacientes de distintas edades, pacientes que padecían de infecciones respiratorias crónicas, neuropatías y enfermedades donde se presentan dolores crónicos. Los medicamentos utilizados fueron los complejos de lidocaína-fosfomicina, lidocaína-lincomicina, lidocaína- complejo B y lidocaína-dexametasona, así como el uso de otros antibióticos y desinflamatorios no esteríodeos en donde se uso uno o más fármacos aprobados por la FDA y la COFEPRIS. During the last fourteen years, a retrospective investigation was carried out based on treatments made to patients of different ages, patients suffering from chronic respiratory infections, neuropathies and diseases where chronic pain occurs. The medications used were the lidocaine-fosfomycin, lidocaine-lincomycin, lidocaine-B-complex and lidocaine-dexamethasone complexes, as well as the use of other antibiotics and non-sterilized anti-inflammatory drugs where one or more FDA-approved drugs and COFEPRIS were used .
Generalidades de la Investigación Research Overview
Considerando solo una tercera parte del total de pacientes tratados, esta investigación retrospectiva abarca el período de 1Θ95 al 2009. Considering only one third of the total number of patients treated, this retrospective investigation covers the period from 1-95 to 2009.
Desglosa por enfermedad. Breakdown by disease.
AMIGDALITIS CRÓNICA: CHRONIC AMIGDALITIS:
• Se revisaron 200 casos por año, los pacientes recibieron una nanodosis del complejo lidocaína-fosfomicina o complejo lidocaína-lincomicina. Se agruparon por edades a) 50 pacientes de 3 a 12 años. • 200 cases were reviewed per year, patients received a nanodosis of the lidocaine-fosfomycin complex or lidocaine-lincomycin complex. They were grouped by ages a) 50 patients from 3 to 12 years old.
b) 50 pacientes de 13 a 25 años.  b) 50 patients from 13 to 25 years.
c) 50 pacientes de 26 a 40 años.  c) 50 patients from 26 to 40 years.
d) 50 pacientes de más de 40 años.  d) 50 patients over 40 years.
Criterios de selección por grupo Selection criteria by group
A los pacientes antes de ser sometidos al tratamiento se les solicito Biometría Hemática completa, Exudado faríngeo, y Antiestreptolisinas. Patients were asked for complete Hematic Biometrics, Pharyngeal Exudate, and Antistreptolysins before undergoing treatment.
1 ) Más de 5 cuadros de amigdalitis aguda al año. 1) More than 5 cases of acute tonsillitis per year.
2) Persistencia de alguna actividad infecciosa en intervalos asintomáticos tales como hipertrofia de amígdalas, hiperemia de amígdalas, presencia de ganglios en cuello, cabeza y retroauriculares, sensación de cuerpo extraño en faringe.  2) Persistence of some infectious activity at asymptomatic intervals such as tonsil hypertrophy, tonsil hyperemia, presence of nodes in the neck, head and retroauricular, foreign body sensation in the pharynx.
3) Exudados faríngeos positivos a bacterias patógenas.  3) Positive pharyngeal exudates to pathogenic bacteria.
4) Pacientes que no respondieron a tratamientos con antibióticos. 4) Patients who did not respond to antibiotic treatments.
5) Pacientes que no presentaran inmunodeficiencias. 5) Patients who will not have immunodeficiencies.
6) Pacientes con biometría hemática completa normal.  6) Patients with normal complete blood count.
Tratamiento Treatment
El tratamiento llevado a cabo tuvo una duración de 12 semanas y consto de una nanodosis aplicada por semanal del complejo lidocaína-fosfomicina o lidocaína- lincomicina dependiendo de la bacteria patógena, para combatir la amigdalitis crónica en el individuo. The treatment carried out lasted 12 weeks and consisted of a weekly applied nanodose of the lidocaine-fosfomycin or lidocaine-lincomycin complex depending on the pathogenic bacteria, to combat chronic tonsillitis in the individual.
Resultados Results
La mejoría de salud en el paciente tratado se presenta desde la primera aplicación y a partir de la cuarta semana el paciente ya no presenta recaídas evidentes, al cabo de la semana 8 el paciente presenta una mejoría total, se continuo con el tratamiento hasta la semana 12 al finalizar el tratamiento se les solicito a los pacientes nuevos estudios de laboratorio. Obteniéndose los siguientes resultados: a) Exudado faríngeo negativo a bacterias patógenas. The improvement of health in the treated patient is presented from the first application and as of the fourth week the patient no longer shows obvious relapses, after week 8 the patient presents a total improvement, treatment continued until week 12 At the end of the treatment, patients were asked for new laboratory studies. Obtaining the following results: a) Pharyngeal exudate negative to pathogenic bacteria.
b) Antiestreptolisinas negativas. c) Biometría Hemática completa normal. b) Negative antistreptolysins. c) Normal complete blood count.
En el transcurso de estos 14 años se han tratado más de 4600 pacientes  In the course of these 14 years, more than 4600 patients have been treated
ENFERMEDADES CON DOLOR CRONICO DISEASES WITH CHRONIC PAIN
En las enfermedades relacionadas a dolor crónico, se estudio a 100 pacientes por año los que recibieron nanodosis de complejos lidocaína-dexametasona o lidocaína-diclofenaco ; quienes se agruparon de la siguiente manera: a) 25 pacientes de artritis reumatoide. In chronic pain-related diseases, 100 patients were studied per year who received nanodosis of lidocaine-dexamethasone or lidocaine-diclofenac complexes; who were grouped as follows: a) 25 patients with rheumatoid arthritis.
b) 25 pacientes de osteoartritis.  b) 25 osteoarthritis patients.
c) 25 de pacientes de lumbalgias.  c) 25 patients of low back pain.
d) 25 de pacientes con dolor del nervio ciático.  d) 25 patients with sciatic nerve pain.
Criterios de selección por grupo Selection criteria by group
Los criterios de selección fueron los siguientes: a) Pacientes con dolor de más de un mes. The selection criteria were the following: a) Patients with pain of more than one month.
b) Pacientes con una respuesta pobre o nula a los analgésicos desinflamatorios esteroideos y no esteroideos.  b) Patients with a poor or no response to steroidal and non-steroidal anti-inflammatory analgesics.
c) Pacientes que no presentaran inmunodeficiencias.  c) Patients who will not have immunodeficiencies.
d) Pacientes con biometría hemática completa normal.  d) Patients with normal complete blood count.
A los pacientes se les solicito Biometría hemática completa. Tratamiento Patients were asked for complete blood count. Treatment
El tratamiento tuvo una duración de 6 a 8 semanas y consto de una implantación de nanodosis cada semana del complejo lidocaína-dexametasona o lidocaína-diclofenaco, desarrollado para combatir dolor crónico en el individuo. The treatment lasted 6 to 8 weeks and consisted of a nanodose implantation every week of the lidocaine-dexamethasone or lidocaine-diclofenac complex, developed to combat chronic pain in the individual.
Resultados Results
Se observo mejoría inmediata es decir a los primeros 10 minutos con una duración de analgesia de 8-10 días, al 60 % de los pacientes les regresa el dolor al terminarse el fármaco, después de la cuarta semana de tratamiento solo el 30 % de los pacientes refirió un dolor moderado observándose una recuperación total desde la 6a semana. Al finalizar el tratamiento se solicitaron nuevamente biometría hemática completa, la cual reporto resultados normales. Ya que son enfermedades crónicas degenerativas el dolor puede presentarse a los 6 meses, por lo que suelen someterse al tratamiento nuevamente. Immediate improvement was observed, that is, in the first 10 minutes with a duration of analgesia of 8-10 days, 60% of patients returned the pain at the end of the drug, after the fourth week of treatment only 30% of patients patients reported moderate pain observed full recovery from the 6th week. At the end of the treatment, complete blood count was requested again, which reported normal results. Since they are chronic degenerative diseases, pain can occur at 6 months, so they usually undergo treatment again.
A lo largo de 14 años se han tratado más de 3000 pacientes con enfermedades en donde se presentan dolores crónicos. Over 14 years have treated more than 3000 patients with diseases where chronic pain occurs.
NEUROPATÍA PERIFÉRICA DIABÉTICA DIABETIC PERIPHERAL NEUROPATHY
En el caso de neuropatía diabética periférica se observo una muestra de 100 pacientes adultos por año. Se les administro nanodosis del complejo lidocaína- neurobión, por medio de implante atreves de una inyección por semana. In the case of peripheral diabetic neuropathy, a sample of 100 adult patients per year was observed. They were administered nanodosis of the lidocaine-neurobion complex, through implants through one injection per week.
Criterios de selección por grupo Selection criteria by group
Los criterios de selección fueron: a) Pacientes con diabetes de más de 10 años de evolución The selection criteria were: a) Patients with diabetes more than 10 years old
b) Pacientes con dolor profundo con mayor frecuencia en pies y piernas, c) Pacientes con pérdida de la sensación de calor o frío.  b) Patients with deep pain more frequently in feet and legs, c) Patients with loss of heat or cold sensation.
d) Pacientes que presentaban calambres musculares, en miembros inferiores.  d) Patients presenting with muscle cramps in the lower limbs.
e) Pacientes con entumecimiento de miembros inferiores.  e) Patients with numbness of lower limbs.
f) Pacientes con hormigueo o sensación de dolor ardoroso, especialmente de pies.  f) Patients with tingling or burning pain sensation, especially of feet.
g) Pacientes con otras complicaciones tardías diabéticas. Tratamiento  g) Patients with other late diabetic complications. Treatment
En este caso el diagnostico fue solo clínico, el tratamiento consto de una aplicación cada semana de nanodosis del complejo lidocaína-neurobion desarrollado para combatir la neuropatía diabética periférica en el individuo. In this case, the diagnosis was only clinical, the treatment consisted of a weekly application of nanodosis of the lidocaine-neurobion complex developed to combat peripheral diabetic neuropathy in the individual.
La aplicación del complejo se llevó a cabo de la siguiente manera; una aplicación semanal durante 12 semanas, tiempo suficiente en que se regeneran las terminales nerviosas. Se observó franca mejoría desde la segunda aplicación con una remisión total de los síntomas a la semana 12. Cabe destacar que la patología causal de la neuropatía si no está controlada nuevamente volverá a lesionar las terminales nerviosas, así fue informado el paciente, se recomienda recibir el tratamiento cada 6 meses. The application of the complex was carried out as follows; a weekly application for 12 weeks, enough time for nerve terminals to regenerate. There was a clear improvement since the second application with a total remission of symptoms at week 12. It should be noted that the pathology of neuropathy if not controlled again will return to injuring the nerve terminals, the patient was informed, it is recommended to receive treatment every 6 months.
Al observar la eficacia de este tratamiento con el complejo lidocaína-neurobion destinado para tal fin, se convirtió en el tratamiento médico de primera elección para los pacientes con neuropatías periféricas secundarias a diabetes mellitus, infecciones por herpes zoster, lesiones quirúrgicas, neuralgias del trigémino etc. Upon observing the efficacy of this treatment with the lidocaine-neurobion complex intended for this purpose, it became the medical treatment of first choice for patients with peripheral neuropathies secondary to diabetes mellitus, herpes zoster infections, surgical lesions, trigeminal neuralgia, etc. .
A lo largo de 14 años se han tratado más de 2000 pacientes con neuropatías periféricas. Over 14 years, more than 2000 patients with peripheral neuropathies have been treated.

Claims

REIVINDICACIONES
1. - Es un procedimiento específico que se basa en la gnosis de las cantidades adecuadas de lidocaína como reactivo; y fármacos alópatas convencionales para la transformación y producción de nuevos complejos de fármacos. La farmacocinética de los nuevos complejos lidocaína-fármaco permite un mejor desempeño que se refleja en su biodisponibilidad, de tal forma que la posología del complejo se administra en concentraciones nano a través de implantes por inyección en los receptores cercanos ó en el sitio especifico donde realizará su actividad terapéutica, de la misma forma, mantiene una liberación sistémica, constante, prolongada y segura del complejo en el sitio de acción; así mismo, los implantes por inyección cerca de los receptores específicos evitan barreras fisiológicas, de tal forma que se aprovecha en su totalidad el fármaco, la inyección no es invasiva ni dolorosa; el fármaco al entrar al cuerpo tiene una liberación prolongada que dura de 8 a 10 días lo que representa bienestar en el tratamiento, considerando esto como una nueva gama de fármacos transformados, esta formulación es ideal para ser implantada como nanodosis mediante una inyección, cerca de los receptores específicos, puede ser; vía bucal, vía nasal, vía intramuscular, vía intradérmica y vía rectal. 1. - It is a specific procedure that is based on the gnosis of adequate amounts of lidocaine as a reagent; and conventional allopathic drugs for the transformation and production of new drug complexes. The pharmacokinetics of the new lidocaine-drug complexes allow a better performance that is reflected in its bioavailability, so that the posology of the complex is administered in nano concentrations through implants by injection in nearby receptors or at the specific site where it will perform its therapeutic activity, in the same way, maintains a systemic, constant, prolonged and safe release of the complex at the site of action; likewise, the implants by injection near the specific receptors avoid physiological barriers, in such a way that the drug is fully used, the injection is not invasive or painful; The drug when entering the body has a prolonged release that lasts from 8 to 10 days which represents well-being in the treatment, considering this as a new range of transformed drugs, this formulation is ideal to be implanted as a nanodose by injection, near the specific receptors, it can be; buccal, nasal, intramuscular, intradermal and rectal.
2. - proceso para la obtención de complejos lidocaína-fármaco, se logra a través de procedimientos mecánicos de inyección-succión-agitación, se introduce en un recipiente adiatérmico de vidrio herméticamente cerrado una cantidad equivalente de 10 a 40 mi de lidocaína al 1 o al 2 % (en donde la lidocaína al 1% contiene 10mg de lidocaína diluida en 1 ml de agua y la lidocaína al 2 % contiene 20mg de lidocaína diluida en 1 ml de agua) y un fármaco en una dosis terapéutica para adulto. Para este ejemplo se utilizo Alin depot de 8 mg 2. - process for obtaining lidocaine-drug complexes, is achieved through mechanical injection-suction-agitation procedures, an equivalent amount of 10 to 40 ml of lidocaine 1 or 1 is placed in a tightly closed glass adiatermic vessel 2% (where 1% lidocaine contains 10mg of lidocaine diluted in 1 ml of water and 2% lidocaine contains 20mg of lidocaine diluted in 1 ml of water) and a drug in a therapeutic dose for adults. For this example, 8 mg Alin depot was used
Para el efecto de la reivindicación 2 en cuanto a los fármacos liofilizados, se debe diluir previamente el fármaco, hasta obtener una substancia liquida homogénea, se introduce la lidocaína a un recipiente adiatérmico de vidrio herméticamente cerrado y posterior un fármaco, a través de un mecanismo de inyección-succión-agitación se mezcla los dos: lidocaína, una cantidad de 30 a 60mg, y una dosis terapéutica adulto de un fármaco en su presentación comercial (liofilizada) para este ejemplo en especifico se utilizo un antibiótico. For the effect of claim 2 as regards the lyophilized drugs, the drug must be previously diluted, until a homogeneous liquid substance is obtained, the lidocaine is introduced into a tightly closed glass adiatermic glass container and subsequently a drug, through a mechanism Injection-suction-agitation the two are mixed: lidocaine, an amount of 30 to 60mg, and an adult therapeutic dose of a drug in its commercial presentation (lyophilized) for this specific example an antibiotic was used.
PCT/MX2011/000059 2010-05-19 2011-05-16 Lidocaine as a transformer and producer of transformed complexes of drugs delivered in nano-dosages using injection implants as prolonged release devices WO2011145914A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4866050A (en) * 1988-04-27 1989-09-12 Ben Amoz Daniel Ultrasonic transdermal application of steroid compositions
US20060223788A1 (en) * 2005-03-29 2006-10-05 Cathcart Clifton H Analgesic composition for topical use
WO2009066138A2 (en) * 2007-11-22 2009-05-28 Promed Research Centre Stabilization of vitamin b complex and lidocaine hydrochloride injection
US7601707B1 (en) * 2003-03-05 2009-10-13 Minks William J Method for instantly relieving tissue inflammation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4866050A (en) * 1988-04-27 1989-09-12 Ben Amoz Daniel Ultrasonic transdermal application of steroid compositions
US7601707B1 (en) * 2003-03-05 2009-10-13 Minks William J Method for instantly relieving tissue inflammation
US20060223788A1 (en) * 2005-03-29 2006-10-05 Cathcart Clifton H Analgesic composition for topical use
WO2009066138A2 (en) * 2007-11-22 2009-05-28 Promed Research Centre Stabilization of vitamin b complex and lidocaine hydrochloride injection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HUSEYIN SEN ET AL.: "The analgesic effect of paracetamol when added to lidocaine for intravenous regional anesthesia", INTERNATIONAL ANESTHESIA RESEARCH SOCIETY., vol. 109, no. 4, 4 October 2009 (2009-10-04), pages 1327 - 1330 *

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