ES2436344A1 - Pharmaceutical composition comprising diacetylmorphine and naloxone for oral administration - Google Patents
Pharmaceutical composition comprising diacetylmorphine and naloxone for oral administration Download PDFInfo
- Publication number
- ES2436344A1 ES2436344A1 ES201230814A ES201230814A ES2436344A1 ES 2436344 A1 ES2436344 A1 ES 2436344A1 ES 201230814 A ES201230814 A ES 201230814A ES 201230814 A ES201230814 A ES 201230814A ES 2436344 A1 ES2436344 A1 ES 2436344A1
- Authority
- ES
- Spain
- Prior art keywords
- naloxone
- diacetylmorphine
- hydrochloride
- heroin
- document
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- A61K9/2022—Organic macromolecular compounds
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- Organic Chemistry (AREA)
- Psychiatry (AREA)
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Abstract
Description
Composición farmacéutica de diacetilmorfina y naloxona para administración oral. Pharmaceutical composition of diacetylmorphine and naloxone for oral administration.
Objeto de la invención. Object of the invention.
La presente invención se refiere a una composición farmacéutica de diacetilmorfina y naloxona para administración oral. Dicha composición se caracteriza porque la relación ponderal entre diacetilmorfina y naloxona está comprendida entre 24:1 y 26:1, lo que permite conseguir una buena eficacia en el tratamiento sustitutivo en drogadicción, con una mayor seguridad frente a su uso indebido por inyección. También se refiere a un comprimido que comprende la composición, y al uso de la composición y del comprimido para la preparación de un medicamento para el tratamiento de la adicción a sustancias opioides. The present invention relates to a pharmaceutical composition of diacetylmorphine and naloxone for oral administration. Said composition is characterized in that the weight ratio between diacetylmorphine and naloxone is between 24: 1 and 26: 1, which makes it possible to achieve a good efficacy in the substitute treatment in drug addiction, with greater safety against its abuse by injection. It also refers to a tablet comprising the composition, and the use of the composition and the tablet for the preparation of a medicament for the treatment of addiction to opioid substances.
Campo de aplicación de la invención. Field of application of the invention.
La invención es aplicable en la preparación de medicamentos para el tratamiento de la adicción a sustancias opioides. The invention is applicable in the preparation of medicaments for the treatment of addiction to opioid substances.
Estado de la técnica. State of the art
La dependencia a sustancias opioides, y en particular a la heroína, es un reconocido problema de salud que lleva asociados, además, graves complicaciones de tipo social. Dependence on opioid substances, and in particular on heroin, is a recognized health problem that also has serious social complications.
Una estrategia habitualmente empleada para afrontar la problemática de la dependencia a heroína o a otros opioides es el tratamiento sustitutivo, que consiste en administrar a los individuos dependientes un agonista opioide sustitutivo, por vía oral, en una dosis relativamente estable y bajo control médico y que habitualmente se complementa con terapias de tipo social y psicológico. Dicho tratamiento tiene el objetivo de evitar el consumo abusivo de heroína y evitar así los riesgos médicos derivados dicho uso, como su adulteración, sobredosis, y riesgo de infección por el virus de la inmunodeficiencia humana, y se pretende en definitiva, la normalización e inserción social de los pacientes drogodependientes. A strategy usually used to address the problem of dependence on heroin or other opioids is the replacement treatment, which consists of administering to the dependent individuals an opioid agonist substitute, orally, in a relatively stable dose and under medical control and that usually It is complemented with social and psychological therapies. Said treatment has the objective of avoiding the abusive consumption of heroin and thus avoiding the medical risks derived from said use, such as adulteration, overdose, and risk of infection by the human immunodeficiency virus, and it is ultimately intended, normalization and insertion social of drug dependent patients.
El agonista opioide más utilizado tradicionalmente como tratamiento sustitutivo en drogadicción es la metadona. No obstante, dado que no todos los pacientes responden favorablemente a dicho tratamiento, ha sido necesario desarrollar nuevos opioides aptos para dicha indicación, para así poder disponer de terapias alternativas a la metadona, tal como se describe, por ejemplo, en el artículo Castellano Gómez M., Hacia la diversificación de los tratamientos con agonistas opiáceos, Trastornos adictivos, 2003, 5 (4), 291-4. The opioid agonist most traditionally used as a substitute treatment in drug addiction is methadone. However, since not all patients respond favorably to such treatment, it has been necessary to develop new opioids suitable for this indication, in order to have alternative therapies to methadone, as described, for example, in the article Castellano Gómez M., Towards the diversification of opioid agonist treatments, Addictive disorders, 2003, 5 (4), 291-4.
Así pues, se ha descrito el uso de otros agonistas opioides para el tratamiento sustitutivo en drogodependencia como, por ejemplo, la buprenorfina, la morfina, el levo alfa acetilmetadol, la hidrocodeína y la diacetilmorfina (heroína). Thus, the use of other opioid agonists has been described for substitute treatment in drug dependence such as, for example, buprenorphine, morphine, levo alpha acetyl methadol, hydrocodeine and diacetylmorphine (heroin).
Un posible problema derivado del tratamiento sustitutivo con agonistas opioides por vía oral, es el uso indebido que puede hacerse de ellos, especialmente mediante su administración intravenosa incorrecta, ya sea por parte del propio paciente, o bien a través de su distribución ilícita. Es por ello que se han desarrollado formulaciones orales más seguras, basadas en la combinación de dichos agonistas opiáceos con sustancias antagonistas opioides de baja biodisponibilidad oral, de manera que la administración oral de la combinación solamente desencadena el efecto farmacológico deseado del agonista, mientras que, en caso de una hipotética administración intravenosa incorrecta, el agente antagonista opioide actuaría bloqueando la acción del agonista, lo que resultaría en un efecto disuasorio para el uso indebido del fármaco. A possible problem derived from the substitute treatment with opioid agonists by oral route is the improper use that can be made of them, especially through incorrect intravenous administration, either by the patient himself, or through their illegal distribution. That is why safer oral formulations have been developed, based on the combination of said opioid agonists with opioid antagonist substances of low oral bioavailability, so that oral administration of the combination only triggers the desired pharmacological effect of the agonist, while, In case of a hypothetical incorrect intravenous administration, the opioid antagonist would act by blocking the action of the agonist, which would result in a deterrent effect for drug abuse.
En el estado de la técnica se han descrito algunas combinaciones de agonistas y antagonistas opioides para conseguir un tratamiento oral de mantenimiento en drogadicción más seguro. La naloxona es el antagonista opioide más utilizado en este ámbito. Así por ejemplo, en el artículo Shearer et al., The acceptability, safety, and tolerability of methadone/naloxone in a 50:1 ratio, Exp. Clin. Psychopharmacol., 2009; 17 (3), 146-53, se describe el uso de la combinación metadona/naloxona como tratamiento sustitutivo en drogadicción. Some combinations of agonists and opioid antagonists have been described in the prior art to achieve a safer oral maintenance drug treatment. Naloxone is the most commonly used opioid antagonist in this area. For example, in the article Shearer et al., The acceptability, safety, and tolerability of methadone / naloxone in a 50: 1 ratio, Exp. Clin. Psychopharmacol., 2009; 17 (3), 146-53, describes the use of the methadone / naloxone combination as a substitute treatment in drug addiction.
Así mismo, la especialidad farmacéutica Suboxone® consiste en la combinación de buprenorfina y naloxona en forma de comprimidos para administración sublingual, y está indicada para la terapia sustitutiva en dependencia a opioides, de manera que la naloxona tiene la función de evitar su uso intravenoso incorrecto. Likewise, the Suboxone® pharmaceutical specialty consists of the combination of buprenorphine and naloxone in the form of tablets for sublingual administration, and is indicated for replacement therapy in opioid dependence, so that naloxone has the function of preventing improper intravenous use .
La solicitud de patente internacional WO-A-2007/082935 se refiere a la combinación de morfina y un antagonista opioide de baja disponibilidad oral, preferiblemente naloxona. La naloxona tiene una función principalmente disuasoria frente a un uso abusivo no oral de la composición, a la vez que tiene un efecto preventivo del desarrollo de tolerancia a la morfina, así como de alguno de sus efectos adversos, como estreñimiento y disfunción sexual. La combinación está en una forma farmacéutica caracterizada porque ambos componentes no pueden separarse fácilmente de forma manual, para evitar la separación indebida de la morfina. International patent application WO-A-2007/082935 refers to the combination of morphine and a low oral availability opioid antagonist, preferably naloxone. Naloxone has a mainly deterrent function against an abusive non-oral use of the composition, while having a preventive effect of the development of morphine tolerance, as well as of some of its adverse effects, such as constipation and sexual dysfunction. The combination is in a pharmaceutical form characterized in that both components cannot be easily separated manually, to avoid undue separation of morphine.
La solicitud de patente Europea EP-A-1810714 se refiere a la combinación de heroína y naloxona para su administración no-intravenosa, en el tratamiento sustitutivo de la drogadicción. La naloxona ejerce la mencionada función disuasoria y, adicionalmente, reduce el estreñimiento causado por la heroína y también reduce el riesgo de desarrollo de tolerancia a la heroína. La cantidad de naloxona se dice que puede estar entre 0,1 mg y 8 mg de naloxona por cada 100 mg de heroína, si bien en este documento no se describe ninguna composición específica de dicha combinación. European patent application EP-A-1810714 refers to the combination of heroin and naloxone for non-intravenous administration, in the substitute treatment of drug addiction. Naloxone exerts the aforementioned deterrent function and, additionally, reduces the constipation caused by heroin and also reduces the risk of developing heroin tolerance. The amount of naloxone is said to be between 0.1 mg and 8 mg of naloxone per 100 mg of heroin, although no specific composition of such combination is described herein.
Pese a las diversas formulaciones propuestas en el estado de la técnica, subsiste la necesidad de poder disponer de una composición alternativa para el tratamiento sustitutivo en pacientes con dependencia a sustancias opioides, que sea efectiva y a la vez que sea segura, de manera que se consiga minimizar el riesgo de un uso indebido de la composición. Despite the various formulations proposed in the state of the art, there remains a need to have an alternative composition for substitute treatment in patients with dependence on opioid substances, which is effective and at the same time is safe, so as to achieve minimize the risk of improper use of the composition.
Descripción de la invención Description of the invention
El objeto de la presente invención es una composición farmacéutica para administración oral que comprende diacetilmorfina o una de sus sales farmacéuticamente aceptables, naloxona o una de sus sales farmacéuticamente aceptables y al menos un excipiente farmacéuticamente aceptable, en donde la relación ponderal entre diacetilmorfina :naloxona está comprendida entre 24:1 y 26:1. The object of the present invention is a pharmaceutical composition for oral administration comprising diacetylmorphine or a pharmaceutically acceptable salt thereof, naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the weight ratio between diacetylmorphine: naloxone is between 24: 1 and 26: 1.
Los autores de la presente invención han desarrollado una composición farmacéutica para administración oral que comprende la combinación de diacetilmorfina y naloxona en una proporción ponderal tal que presenta un efecto mejorado en relación a las composiciones descritas en el estado de la técnica, ya que permite una acción terapéutica sustitutiva eficaz de la diacetilmorfina mediante su administración oral y a la vez asegura una inhibición completa del efecto opioide de la diacetilmorfina por parte de la naloxona en el hipotético caso de una administración intravenosa indebida. The authors of the present invention have developed a pharmaceutical composition for oral administration comprising the combination of diacetylmorphine and naloxone in a weight ratio such that it has an improved effect in relation to the compositions described in the state of the art, since it allows an action Effective replacement therapy of diacetylmorphine by oral administration and at the same time ensures a complete inhibition of the opioid effect of diacetylmorphine by naloxone in the hypothetical case of undue intravenous administration.
Diacetilmorfina Diacetylmorphine
La diacetilmorfina es la Denominación Común Internacional (DCI) correspondiente al diacetato de (5a,6a)-7,8dideshidro-4,5-epoxi-17-metilmorfinan-3,6-diol. Se trata de un opioide derivado de la morfina, concretamente es el 15 diester 3,6-diacetato de morfina, también conocido por las denominaciones heroína, diamorfina, acetomorfina, o diacetato de morfina. Diacetylmorphine is the International Common Denomination (INN) corresponding to the diacetate of (5th, 6th) -7,8dideshydro-4,5-epoxy-17-methylmorphinan-3,6-diol. It is an opioid derived from morphine, specifically the diester 3,6-morphine diacetate, also known by the names heroin, diamorphine, acetomorphine, or morphine diacetate.
La diacetilmorfina puede obtenerse a partir de la morfina, por ejemplo, según se describe en el artículo Small L., Chemistry of the Opium Alkaloids, Public Health Reports, Washington,1932, Supplement No. 103. Diacetylmorphine can be obtained from morphine, for example, as described in the article Small L., Chemistry of the Opium Alkaloids, Public Health Reports, Washington, 1932, Supplement No. 103.
La diacetilmorfina es un potente analgésico opiáceo que puede emplearse médicamente para el tratamiento del dolor severo. También se utiliza como terapia sustitutiva en drogadicción. Diacetylmorphine is a potent opioid analgesic that can be used medically for the treatment of severe pain. It is also used as a substitute therapy in drug addiction.
En el contexto de la presente invención, el término diacetilmorfina se refiere en forma amplia a la diacetilmorfina como tal, así como a cualquiera de sus formas solvatadas o formas polimórficas. In the context of the present invention, the term "diacetylmorphine" refers broadly to diacetylmorphine as such, as well as to any of its solvated forms or polymorphic forms.
Las sales farmacéuticamente aceptables de la diacetilmorfina se refieren a las sales de adición con ácidos, las cuales pueden prepararse según métodos convencionales bien conocidos por el experto en la materia, empleando ácidos orgánicos o inorgánicos farmacéuticamente aceptables y sustancialmente no tóxicos. Tales ácidos incluyen el ácido clorhídrico, ácido nítrico, ácido sulfúrico, ácido fosfórico, ácido acético, ácido propiónico, ácido maleico, ácido malónico, ácido succínico, ácido cítrico, ácido tartárico, ácido málico, ácido salicílico, ácido ftálico, etc. Preferiblemente, se emplea ácido clorhídrico.Pharmaceutically acceptable salts of diacetylmorphine refer to acid addition salts, which can be prepared according to conventional methods well known to those skilled in the art, using pharmaceutically acceptable organic or inorganic acids and substantially non-toxic. Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, salicylic acid, phthalic acid, etc. Preferably, hydrochloric acid is used.
En una realización preferida de la invención, la diacetilmorfina está en forma de su sal hidrocloruro. In a preferred embodiment of the invention, diacetylmorphine is in the form of its hydrochloride salt.
Naloxona Naloxone
El término naloxona es la Denominación Común Internacional (DCI) por la que se conoce habitualmente el producto 17-alilo-4,5 a-epoxi-3,14-dihidroximorfinan-6-ona. Se trata de un antagonista opioide específico. The term naloxone is the International Common Denomination (INN) by which the product 17-allyl-4,5 a-epoxy-3,14-dihydroximorfinan-6-one is commonly known. It is a specific opioid antagonist.
La naloxona puede prepararse, por ejemplo, según el procedimiento descrito en la solicitud de patente británica GBA-939287.Naloxone can be prepared, for example, according to the procedure described in British patent application GBA-939287.
En el contexto de la presente invención, el término naloxona incluye también sus formas solvatadas y polimórficas. In the context of the present invention, the term naloxone also includes its solvated and polymorphic forms.
Las sales farmacéuticamente aceptables de la naloxona se refieren a las sales de adición con ácidos, las cuales pueden prepararse según métodos convencionales bien conocidos por el experto en la materia, empleando ácidos orgánicos o inorgánicos farmacéuticamente aceptables y sustancialmente no tóxicos. Tales ácidos incluyen el ácido clorhídrico, ácido nítrico, ácido sulfúrico, ácido fosfórico, ácido acético, ácido propiónico, ácido maleico, ácido malónico, ácido succínico, ácido cítrico, ácido tartárico, ácidomálico, ácido salicílico, ácido ftálico, etc. Preferiblemente, se emplea ácido clorhídrico.Pharmaceutically acceptable salts of naloxone refer to acid addition salts, which can be prepared according to conventional methods well known to those skilled in the art, using pharmaceutically acceptable organic or inorganic acids and substantially non-toxic. Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, acidic acid, salicylic acid, phthalic acid, etc. Preferably, hydrochloric acid is used.
En una realización preferida de la invención, la naloxona está en forma de su sal hidrocloruro. In a preferred embodiment of the invention, naloxone is in the form of its hydrochloride salt.
Composiciones Compositions
La composición farmacéutica de la invención se caracteriza porque la diacetilmorfina y la naloxona están en una relación ponderal comprendida entre 24:1 y 26:1, es decir, que por cada unidad de peso de naloxona, hay entre 24 y 26 unidades de peso de diacetilmorfina. The pharmaceutical composition of the invention is characterized in that diacetylmorphine and naloxone are in a weight ratio between 24: 1 and 26: 1, that is to say, for each unit of weight of naloxone, there are between 24 and 26 units of weight of diacetylmorphine
La composición farmacéutica de la invención puede prepararse empleando métodos que son bien conocidos por el experto en la materia, como los que figuran en manuales de tecnología farmacéutica, como el libro Remington The Science and Practice of Pharmacy, 20ª edición, Lippincott, Williams & Wilkins, Filadelfia, 2000 [ISBN: 0-683-306472]. Preferiblemente la composición de la invención se prepara por mezcla directa de los principios activos y los excipientes. The pharmaceutical composition of the invention can be prepared using methods that are well known to those skilled in the art, such as those contained in pharmaceutical technology manuals, such as the Remington The Science and Practice of Pharmacy book, 20th edition, Lippincott, Williams & Wilkins , Philadelphia, 2000 [ISBN: 0-683-306472]. Preferably the composition of the invention is prepared by direct mixing of the active ingredients and excipients.
Para la preparación de la composición farmacéutica de la invención es importante que los dos principios activos estén íntimamente mezclados, juntamente con el/los excipiente(s) correspondiente(s), de manera que se obtenga una mezcla homogénea que no permita la separación de los dos principios activos, requisito imprescindible para garantizar su uso seguro, y evitar una administración intravenosa no indicada de la diacetilmorfina por separado. For the preparation of the pharmaceutical composition of the invention it is important that the two active ingredients are intimately mixed, together with the corresponding excipient (s), so that a homogeneous mixture is obtained that does not allow the separation of the two active ingredients, a prerequisite to ensure its safe use, and to avoid an undesired intravenous administration of diacetylmorphine separately.
Entre los excipientes farmacéuticamente aceptables que se pueden incluir en la composición farmacéutica se encuentran, por ejemplo, agentes antiapelmazantes como sílice coloidal, fosfato cálcico tribásico, silicato cálcico, silicato de magnesio, trisilicato de magnesio o talco; agentes diluyentes como lactosa anhidra, latosa monohidrato, fosfato cálcico, hidrógeno fosfato de calcio anhidro, hidrógenofosfato de calcio dihidrato, sulfato cálcico, carbonato cálcico, carboximetilcelulosa cálcica, celulosa microcristalina o en polvo, acetato de celulosa, dextratos, dextrinas, dextrosa, fructosa, gliceril palmitoestearato, caolín, lactitol, carbonato magnésico, óxido de magnesio, maltitol, maltodextrinas, maltosa, polimetacrilatos, almidón pregelatinizado, cloruro de sodio, almidón, sucrosa o sacarosa; agentes lubrificantes como estearato de magnesio, estearato de calcio, gliceril palmitoestearato, poloxámeros, óxido de magnesio, benzoato de sodio, sílice coloidal, lauril sulfato de sodio, estearil fumarato de sodio, ácido esteárico, talco o behenato de glicerina; agentes suspensores como goma xantana, goma guar, ácido algínico, bentonita, carbómeros, carboximetilcelulosa sódica o cálcica, hidroxietilcelulosa, hidroxipropilcelulosa, hidroxipropilmetilcelulosa, hidroxipropil alginato, celulosa microcristalina o en polvo, sílice coloidal anhidra, dextrinas, gelatinas, caolín, silicato alumínico magnésico, maltitol, povidona, ésteres sorbitanos o tragacanto; agentes aglutinantes como trisilicato de magnesio, celulosa, almidón, dextrina, dextrosa, polidextrosa, maltosa, matodextrina, etilcelulosa, metilcelulosa, polimetacrilatos, talco, povidona, ácido esteárico o sacarosa; agentes disgregantes como hidroxipropilcelulosa de bajo grado de sustitución, fosfato de calcio tribásico, carboximetilcelulosa sódica o cálcica, croscarmelosa sódica, crospovidona o metilcelulosa; agentes dispersantes como poloxámeros o ésteres de sorbitán; agentes edulcorantes como aspartamo, manitol, sorbitol, sacarina de sodio, ciclamato de sodio, sacarosa, dextrosa, fructosa, glucosa, inulina, isomaltosa, lactitol, maltosa, maltol, manitol, sucralosa, trehalosa, xilitol o taumatina; agentes aromatizantes y saborizantes, y/o mezclas de los mismos. Among the pharmaceutically acceptable excipients that can be included in the pharmaceutical composition are, for example, anti-caking agents such as colloidal silica, tribasic calcium phosphate, calcium silicate, magnesium silicate, magnesium trisilicate or talc; diluting agents such as anhydrous lactose, lactose monohydrate, calcium phosphate, hydrogen anhydrous calcium phosphate, calcium hydrogen phosphate dihydrate, calcium sulfate, calcium carbonate, calcium carboxymethylcellulose, microcrystalline or powdered cellulose, cellulose acetate, dextrates, dextrins, dextrose, fructose glyceryl palmitoestearate, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, polymethacrylates, pregelatinized starch, sodium chloride, starch, sucrose or sucrose; lubricating agents such as magnesium stearate, calcium stearate, glyceryl palmostearate, poloxamers, magnesium oxide, sodium benzoate, colloidal silica, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc or glycerin behenate; suspending agents such as xanthan gum, guar gum, alginic acid, bentonite, carbomers, sodium or calcium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl alginate, microcrystalline or powdered cellulose, colloidal anhydrous silica, catholic magnesium dextrin, aluminasic silica, aluminasic silica, aluminasic silica, aluminas, silica maltitol, povidone, sorbitan esters or tragacanth; binding agents such as magnesium trisilicate, cellulose, starch, dextrin, dextrose, polydextrose, maltose, matodextrin, ethyl cellulose, methylcellulose, polymethacrylates, talc, povidone, stearic acid or sucrose; disintegrating agents such as low-grade hydroxypropylcellulose, tribasic calcium phosphate, sodium or calcium carboxymethylcellulose, croscarmellose sodium, crospovidone or methylcellulose; dispersing agents such as poloxamers or sorbitan esters; sweetening agents such as aspartame, mannitol, sorbitol, sodium saccharin, sodium cyclamate, sucrose, dextrose, fructose, glucose, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol or thaumatine; flavoring and flavoring agents, and / or mixtures thereof.
Las características físico-químicas de los excipientes, así como el nombre de los productos comerciales bajo los que se comercializan se pueden encontrar en el libro R.C. Rowe et al., Handbook of Pharmaceutical Excipients, 4ª edición, Pharmaceutical Press, Londres, 2003 [ISBN: 0-85369-472-9]. The physical-chemical characteristics of the excipients, as well as the name of the commercial products under which they are marketed, can be found in the R.C. Rowe et al., Handbook of Pharmaceutical Excipients, 4th edition, Pharmaceutical Press, London, 2003 [ISBN: 0-85369-472-9].
La composición farmacéutica de la invención puede estar en cualquier forma apta para su administración oral. Preferiblemente está en forma de polvo o granulado para suspensión oral, comprimidos o cápsulas. Más preferiblemente la composición farmacéutica está en forma de comprimidos. Preferiblemente los comprimidos se preparan por compresión directa de la mezcla que comprende los principios activos y los excipientes. The pharmaceutical composition of the invention may be in any form suitable for oral administration. Preferably it is in powder or granulate form for oral suspension, tablets or capsules. More preferably the pharmaceutical composition is in the form of tablets. Preferably the tablets are prepared by direct compression of the mixture comprising the active ingredients and the excipients.
La composición farmacéutica de la invención se dosifica según una forma de dosificación unitaria, que contiene una dosis terapéuticamente efectiva de los principios activos. Cada forma de dosificación unitaria corresponde, por ejemplo, a un comprimido, una cápsula o un sobre monodosis de polvo o granulado para suspensión. The pharmaceutical composition of the invention is dosed according to a unit dosage form, which contains a therapeutically effective dose of the active ingredients. Each unit dosage form corresponds, for example, to a tablet, a capsule or a single-dose powder or granules for suspension.
Preferiblemente, la composición farmacéutica de la invención se dosifica según una forma de dosificación unitaria que contiene: entre 25 mg y 500 mg de diacetilmorfina, expresado como peso equivalente de hidrocloruro de diacetilmorfina, y entre 0,97 y 20,8 mg de naloxona, expresado como peso equivalente de hidrocloruro de naloxona, más preferiblemente entre 100 mg y 300 mg de diacetilmorfina y entre 3,9 y 12,5 mg de naloxona, y aún más preferiblemente 200 mg de diacetilmorfina y 8 mg de naloxona. Preferably, the pharmaceutical composition of the invention is dosed according to a unit dosage form containing: between 25 mg and 500 mg of diacetylmorphine, expressed as equivalent weight of diacetylmorphine hydrochloride, and between 0.97 and 20.8 mg of naloxone, expressed as equivalent weight of naloxone hydrochloride, more preferably between 100 mg and 300 mg of diacetylmorphine and between 3.9 and 12.5 mg of naloxone, and even more preferably 200 mg of diacetylmorphine and 8 mg of naloxone.
En una realización aún más preferida, la diacetilmorfina está en forma de su sal hidrocloruro y la naloxona está en forma de su sal hidrocloruro. In an even more preferred embodiment, the diacetylmorphine is in the form of its hydrochloride salt and the naloxone is in the form of its hydrochloride salt.
Esto es, en una realización aún más preferida la composición farmacéutica de la invención se dosifica según una forma de dosificación unitaria que contiene: entre 25 mg y 500 mg de hidrocloruro de diacetilmorfina, y entre 0,97 y 20,8 mg de hidrocloruro de naloxona, más preferiblemente entre 100 mg y 300 mg de hidrocloruro de diacetilmorfina y entre 3,9 y 12,5 mg de hidrocloruro de naloxona, y aún más preferiblemente 200 mg de hidrocloruro de diacetilmorfina y 8 mg de hidrocloruro de naloxona. That is, in an even more preferred embodiment the pharmaceutical composition of the invention is dosed according to a unit dosage form containing: between 25 mg and 500 mg of diacetylmorphine hydrochloride, and between 0.97 and 20.8 mg of hydrochloride. naloxone, more preferably between 100 mg and 300 mg of diacetylmorphine hydrochloride and between 3.9 and 12.5 mg of naloxone hydrochloride, and even more preferably 200 mg of diacetylmorphine hydrochloride and 8 mg of naloxone hydrochloride.
En una realización de la invención, la forma de dosificación unitaria permite fácilmente su subdivisión en dosis fraccionadas inferiores, para facilitar un mejor ajuste de la dosis terapéutica adecuada durante el tratamiento. Así, cuando la forma de dosificación unitaria es un comprimido, éste puede estar ranurado de manera que pueda dividirse cómodamente en la mitad, una cuarta parte, o tres cuartas partes de la dosis, por ejemplo. Preferiblemente los comprimidos están ranurados. In one embodiment of the invention, the unit dosage form easily allows its subdivision into lower fractional doses, to facilitate a better adjustment of the appropriate therapeutic dose during treatment. Thus, when the unit dosage form is a tablet, it can be grooved so that it can be conveniently divided into half, a quarter, or three quarters of the dose, for example. Preferably the tablets are grooved.
En una realización preferida, los comprimidos de la invención comprenden como excipientes: hidrógenofosfato de calcio, povidona, celulosa microcristalina, croscarmelosa sódica, dióxido de silicio, estearato magnésico y talco. In a preferred embodiment, the tablets of the invention comprise as excipients: calcium hydrogen phosphate, povidone, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and talc.
En otra realización preferida, los comprimidos de la invención comprenden como excipientes: lactosa monohidrato, povidona, celulosa microcristalina, croscarmelosa sódica, dióxido de silicio, estearato magnésico y talco. In another preferred embodiment, the tablets of the invention comprise as excipients: lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and talc.
En una realización preferida el contenido de hidrógenofosfato de calcio y de lacto está comprendido entre el 5% y el 25% en peso con respecto al peso total de la composición, la povidona entre el 3% y el 7% en peso con respecto al peso total de la composición, la celulosa microcristalina entre el 10% y el 40% en peso con respecto al peso total de la composición, la croscarmelosa sódica entre el 3% y el 7% en peso con respecto al peso total de la composición, y el dióxido de silicio, el estearato magnésico y el talco entre el 1% y el 5% en peso con respecto al peso total de la composición. La suma de los porcentajes de los diferentes excipientes y de los ingredientes activos es 100%. In a preferred embodiment the content of calcium and lacto hydrogen phosphate is between 5% and 25% by weight with respect to the total weight of the composition, povidone between 3% and 7% by weight with respect to weight. total composition, microcrystalline cellulose between 10% and 40% by weight with respect to the total weight of the composition, croscarmellose sodium between 3% and 7% by weight with respect to the total weight of the composition, and silicon dioxide, magnesium stearate and talc between 1% and 5% by weight with respect to the total weight of the composition. The sum of the percentages of the different excipients and the active ingredients is 100%.
El peso del comprimido puede estar comprendido entre 300 mg y 1000 mg, preferiblemente entre 400 mg y 600 mg, y aún más preferiblemente son 500 mg. The weight of the tablet may be between 300 mg and 1000 mg, preferably between 400 mg and 600 mg, and even more preferably 500 mg.
Los autores de la invención han desarrollado una composición farmacéutica que comprende diacetilmorfina y naloxona en una proporción tal que le confiere un perfil de seguridad mejorado, ya que la relación entre ambas sustancias es la idónea para permitir una inhibición completa por vía intravenosa, por parte de la naloxona, del efecto opioide de la diacetilmorfina, según se desprende de la publicación Moro Sánchez et al. Opioides I. Farmacología. Intoxicación aguda, en: Drogodependencias. Farmacología. Patología. Psicología. Legislación. Capítulo 6. Eds: Lorenzo P, Ladero J.M., Leza J.C., Lizasoain I., 2009., Editorial Médica Panamericana, pág. 117The authors of the invention have developed a pharmaceutical composition comprising diacetylmorphine and naloxone in such a proportion that it gives an improved safety profile, since the relationship between both substances is ideal for allowing a complete intravenous inhibition, by naloxone, from the opioid effect of diacetylmorphine, as can be seen from the publication Moro Sánchez et al. Opioids I. Pharmacology. Acute intoxication, in: Drug dependence. Pharmacology. Pathology. Psychology. Legislation. Chapter 6. Eds: Lorenzo P, Ladero J.M., Leza J.C., Lizasoain I., 2009., Pan American Medical Editorial, p. 117
129. 129.
Es por ello que también forma parte de la invención el uso de la composición o del comprimido de la invención para la preparación de un medicamento para el tratamiento de la adicción a sustancias opioides.That is why the use of the composition or tablet of the invention for the preparation of a medicament for the treatment of addiction to opioid substances is also part of the invention.
O dicho de otro modo, también forma parte de la invención la composición y comprimido de la invención para su uso en el tratamiento de la adicción a sustancias opioides. Or put another way, the composition and tablet of the invention is also part of the invention for use in the treatment of addiction to opioid substances.
Ejemplos Examples
Ejemplo 1: Comprimidos de diacetilmorfina y naloxona Example 1: Diacetylmorphine and naloxone tablets
Se prepararon los comprimidos utilizando los componentes que se detallan en la siguiente tabla: The tablets were prepared using the components detailed in the following table:
- Componentes Components
- Cantidad (mg) Función Amount (mg) Function
- Hidrocloruro de diacetilmorfina Diacetylmorphine hydrochloride
- 200,00 Sustancia activa 200.00 Active substance
- Hidrocloruro de naloxona Naloxone hydrochloride
- 8,00 Sustancia activa 8.00 Active substance
- Hidrógenofosfato de calcio Calcium hydrogen phosphate
- 77,00 Diluyente 77.00 Diluent
- Povidona (PVP K25) Povidone (PVP K25)
- 25,00 Aglutinante 25.00 Binder
- Celulosa microcristalina Microcrystalline cellulose
- 150,00 Diluyente 150.00 Diluent
- Croscarmelosa sódica Croscarmellose sodium
- 25,00 Disgregante 25.00 Disintegrating
- Dióxido de silicio coloidal (Aerosil®) Colloidal Silicon Dioxide (Aerosil®)
- 5,00 Lubricante 5.00 Lubricant
- Estearato magnésico Magnesium stearate
- 5,00 Lubricante 5.00 Lubricant
- Talco talcum powder
- 5,00 Lubricante 5.00 Lubricant
- Total Total
- 500,00 500.00
En una mezcladora se incorporaron hidrocloruro de diacetilmorfina, hidrocloruro de naloxona, hidrógenofosfato de calcio, povidona y celulosa microcristalina, croscarmelosa sódica y se mezclaron hasta obtener una mezcla 5 homogénea. Se incorporaron a continuación sílice coloidal, estearato de magnesio y talco, y se mezcló de nuevo el conjunto. Con la mezcla obtenida, se prepararon unos comprimidos, que tenían un peso de 500 mg cada uno. In a mixer, diacetylmorphine hydrochloride, naloxone hydrochloride, calcium hydrogen phosphate, povidone and microcrystalline cellulose, croscarmellose sodium were incorporated and mixed until a homogeneous mixture was obtained. Colloidal silica, magnesium stearate and talc were then incorporated, and the whole was mixed again. With the mixture obtained, tablets were prepared, each weighing 500 mg.
Cada comprimido contenía 200 mg de hidrocloruro de diacetilmorfina y 8 mg de hidrocloruro de naloxona. Teniendo en cuenta los pesos moleculares del hidrocloruro de diacetilmorfina (405,87), hidrocloruro de naloxona (363,84) diacetilmorfina (369,41) y naloxona (327,37), cada comprimido comprende 182 mg de diacetilmorfina y 7,2 mg de Each tablet contained 200 mg of diacetylmorphine hydrochloride and 8 mg of naloxone hydrochloride. Taking into account the molecular weights of diacetylmorphine hydrochloride (405.87), naloxone hydrochloride (363.84) diacetylmorphine (369.41) and naloxone (327.37), each tablet comprises 182 mg of diacetylmorphine and 7.2 mg from
10 naloxona, con lo que la relación ponderal diacetilmorfina:naloxona es de 25,28:1. 10 naloxone, so that the weight ratio diacetylmorphine: naloxone is 25.28: 1.
Ejemplo 2: Comprimidos de diacetilmorfina y naloxona Example 2: Diacetylmorphine and naloxone tablets
Se prepararon los comprimidos siguiendo sustancialmente el procedimiento descrito en el Ejemplo 1 utilizando los componentes que se detallan en la siguiente tabla: The tablets were prepared following substantially the procedure described in Example 1 using the components detailed in the following table:
- Componentes Components
- Cantidad (mg) Función Amount (mg) Function
- Hidrocloruro de diacetilmorfina Diacetylmorphine hydrochloride
- 200,00 Sustancia activa 200.00 Active substance
- Hidrocloruro de naloxona Naloxone hydrochloride
- 8,00 Sustancia activa 8.00 Active substance
- Lactosa monohidrato Lactose monohydrate
- 77,00 Diluyente 77.00 Diluent
- Povidona (PVP K25) Povidone (PVP K25)
- 25,00 Aglutinante 25.00 Binder
- Celulosa microcristalina Microcrystalline cellulose
- 150,00 Diluyente 150.00 Diluent
- Croscarmelosa sódica Croscarmellose sodium
- 25,00 Disgregante 25.00 Disintegrating
- Dióxido de silicio coloidal (Aerosil®) Colloidal Silicon Dioxide (Aerosil®)
- 5,00 Lubricante 5.00 Lubricant
- Estearato magnésico Magnesium stearate
- 5,00 Lubricante 5.00 Lubricant
- Talco talcum powder
- 5,00 Lubricante 5.00 Lubricant
- Total Total
- 500,00 500.00
Cada comprimido contenía 200 mg de hidrocloruro de diacetilmorfina y 8 mg de hidrocloruro de naloxona, lo que corresponde a una relación ponderal de hidrocloruro de diacetilmorfina:hidrocloruro de naloxona de 25:1, y a una relación ponderal de diacetilmorfina:naloxona de 25,28:1. Each tablet contained 200 mg of diacetylmorphine hydrochloride and 8 mg of naloxone hydrochloride, which corresponds to a weight ratio of diacetylmorphine hydrochloride: naloxone hydrochloride of 25: 1, and a weight ratio of diacetylmorphine: naloxone of 25.28: one.
Claims (16)
- Categoría Category
- 56 Documentos citados Reivindicaciones afectadas 56 Documents cited Claims Affected
- X X
- EP 1810714 A1 (HERMANN, HOLGER LARS) 25.07.2007, página 4, columna 5, párrafo 26; reivindicaciones. 1-15 EP 1810714 A1 (HERMANN, HOLGER LARS) 25.07.2007, page 4, column 5, paragraph 26; claims. 1-15
- X X
- EP 1897544 A1 (HERMANN, HOLGER LARS) 12.03.2008, columna 8, párrafos 33,34,35; reivindicaciones. 1-15 EP 1897544 A1 (HERMANN, HOLGER LARS) 12.03.2008, column 8, paragraphs 33,34,35; claims. 1-15
- A TO
- WO 03013479 A1 (EURO-CELTIQUE, S.A.) 20.02.2003, páginas 10, líneas 15-33. 1-15 WO 03013479 A1 (EURO-CELTIQUE, S.A.) 02.20.2003, pages 10, lines 15-33. 1-15
- A TO
- US 20110027455 A1 (BOEHM, G.) 03.05.2011, página 5, párrafo 42; página 6, párrafos 52,53. 1-15 US 20110027455 A1 (BOEHM, G.) 03.05.2011, page 5, paragraph 42; page 6, paragraphs 52.53. 1-15
- A TO
- US 20120101118 A1 (FLEISCHER et al.) 26.04.2012, reivindicaciones. 1-15 US 20120101118 A1 (FLEISCHER et al.) 26.04.2012, claims. 1-15
- Categoría de los documentos citados X: de particular relevancia Y: de particular relevancia combinado con otro/s de la misma categoría A: refleja el estado de la técnica O: referido a divulgación no escrita P: publicado entre la fecha de prioridad y la de presentación de la solicitud E: documento anterior, pero publicado después de la fecha de presentación de la solicitud Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application
- El presente informe ha sido realizado • para todas las reivindicaciones • para las reivindicaciones nº: This report has been prepared • for all claims • for claims no:
- Fecha de realización del informe 19.06.2013 Date of realization of the report 06.19.2013
- Examinador H. Aylagas Cancio Página 1/4 Examiner H. Aylagas Cancio Page 1/4
- Novedad (Art. 6.1 LP 11/1986) Novelty (Art. 6.1 LP 11/1986)
- Reivindicaciones Reivindicaciones 1-15 SI NO Claims Claims 1-15 IF NOT
- Actividad inventiva (Art. 8.1 LP11/1986) Inventive activity (Art. 8.1 LP11 / 1986)
- Reivindicaciones Reivindicaciones 1-15 SI NO Claims Claims 1-15 IF NOT
- Documento Document
- Número Publicación o Identificación Fecha Publicación Publication or Identification Number publication date
- D01 D01
- EP 1810714 A1 (HERMANN, HOLGER LARS) 25.07.2007 EP 1810714 A1 (HERMANN, HOLGER LARS) 07.25.2007
- D02 D02
- EP 1897544 A1 (HERMANN, HOLGER LARS) 12.03.2008 EP 1897544 A1 (HERMANN, HOLGER LARS) 12.03.2008
- D03 D03
- WO 03013479 A1 (EURO-CELTIQUE, S.A.) 20.02.2003 WO 03013479 A1 (EURO-CELTIQUE, S.A.) 02.20.2003
- D04 D04
- US 20110027455 A1 (BOEHM, G.) 03.05.2011 US 20110027455 A1 (BOEHM, G.) 03.05.2011
- D05 D05
- US 20120101118 A1 (FLEISCHER et al.) 26.04.2012 US 20120101118 A1 (FLEISCHER et al.) 04.24.2012
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES201230814A ES2436344B1 (en) | 2012-05-29 | 2012-05-29 | Pharmaceutical composition of diacetylmorphine and naloxone for oral administration |
| PCT/ES2013/070272 WO2013178846A1 (en) | 2012-05-29 | 2013-04-30 | Pharmaceutical composition comprising diacetylmorphine and naloxone for oral administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES201230814A ES2436344B1 (en) | 2012-05-29 | 2012-05-29 | Pharmaceutical composition of diacetylmorphine and naloxone for oral administration |
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| ES2436344A1 true ES2436344A1 (en) | 2013-12-30 |
| ES2436344B1 ES2436344B1 (en) | 2014-08-07 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003013479A1 (en) * | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Compositions and methods to prevent abuse of opioids |
| EP1810714A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Use of a combination of heroin and naloxon for drug substitution |
| EP1897544A1 (en) * | 2006-09-05 | 2008-03-12 | Holger Lars Hermann | Opioid agonist and antagonist combinations |
| US20110027455A1 (en) * | 2002-09-20 | 2011-02-03 | Garth Boehm | Sequestering subunit and related compositions and methods |
| US20120101118A1 (en) * | 2006-01-27 | 2012-04-26 | Euro-Celtique S.A. | Tamper resistant dosage forms |
-
2012
- 2012-05-29 ES ES201230814A patent/ES2436344B1/en not_active Expired - Fee Related
-
2013
- 2013-04-30 WO PCT/ES2013/070272 patent/WO2013178846A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003013479A1 (en) * | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Compositions and methods to prevent abuse of opioids |
| US20110027455A1 (en) * | 2002-09-20 | 2011-02-03 | Garth Boehm | Sequestering subunit and related compositions and methods |
| EP1810714A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Use of a combination of heroin and naloxon for drug substitution |
| US20120101118A1 (en) * | 2006-01-27 | 2012-04-26 | Euro-Celtique S.A. | Tamper resistant dosage forms |
| EP1897544A1 (en) * | 2006-09-05 | 2008-03-12 | Holger Lars Hermann | Opioid agonist and antagonist combinations |
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| ES2436344B1 (en) | 2014-08-07 |
| WO2013178846A1 (en) | 2013-12-05 |
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