WO2005067941A1 - Topical aciclovir formulation - Google Patents

Topical aciclovir formulation Download PDF

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Publication number
WO2005067941A1
WO2005067941A1 PCT/IB2005/000118 IB2005000118W WO2005067941A1 WO 2005067941 A1 WO2005067941 A1 WO 2005067941A1 IB 2005000118 W IB2005000118 W IB 2005000118W WO 2005067941 A1 WO2005067941 A1 WO 2005067941A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
esters
topical pharmaceutical
acyclovir
Prior art date
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PCT/IB2005/000118
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Spanish (es)
French (fr)
Inventor
Maria Jacqueline Sepulveda
Carlos Guillermo Von Plessing
Galo Cardenas
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Universidad De Concepcion
Epic Ltda
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Application filed by Universidad De Concepcion, Epic Ltda filed Critical Universidad De Concepcion
Publication of WO2005067941A1 publication Critical patent/WO2005067941A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the objective of the present invention is the development of a topical formulation, useful in the treatment of dermal and mucosal viral infections.
  • This composition contains as active ingredient 9- (2-hydroxymethoxymethyl) guanine, a compound that is known in the art as “acyclovir” and also N, O-carboxymethyl chitosan, which promotes the absorption of the active substance.
  • Acyclovir and its salts derived from esters are widely known for their antiviral action, which is widely explained in GB1523865 which is currently in the public domain.
  • EP 0 044 543 B1 describes an acyclovir formulation in which the vehicle is an oil / water mixture, which contains at least 30% water-miscible polyvalent alcohol.
  • Another related application is WO97 / 34607 which describes a topical formulation, where the vehicle is a formulation similar to European application 44543, but in this case the formulation of this invention patent application is characterized in that the vehicle being used is found in an oil-in-water emulsion containing at least 10% polyethylene glycol / monoethylether commercially known as Transcutol ® (Gattefosse SA).
  • the present patent application relates to a topical formulation for the administration of acyclovir.
  • the composition contains a chitosan derivative as an element that promotes the absorption of the active substance through the skin.
  • the chitosan derivative used is N, O-carboxymethyl chitosan (NOCMC).
  • NOCMC N, O-carboxymethyl chitosan
  • US4619995 N, O-carboxymethyl chitosan
  • the degree of substitution is typically between 0.6-1.0.
  • the NOCMC is soluble in solutions whose pH is above 6 and under 2.
  • NOCMC is soluble in water, is derived from a natural and biodegradable polysaccharide, so it has excellent characteristics to be used as an absorption promoter in this topical formulation.
  • the topical formulation to be protected comprises from 1 to 10% w / w acyclovir for any of its salts or esters, from 1 to 40% w / w NOCMC and from 20 to 40% water, incorporated into the mixture in any oil phase
  • the lipid component of the emulsion is constituted by known substances and is emulsified with the aqueous component in accordance with the processes known for this purpose in the state of the art.
  • One or more emulsifying agents can be added as an ingredient to the lipid phase, this component can be fatty or oily, and its function is to grant stability to the emulsion over time.
  • the oil phase ingredients of this pharmaceutical composition have been predominantly selected on the basis of desired cosmetological characteristics in the final product, provided that the solubility of acyclovir in the oil phase and the aqueous phase is limited.
  • Some lipid substances that can be used for this formulation can be of linear or branched chemical structure, mono or dialkyl esters of fatty acid esters such as, isopropylmiristate and isopropylpalmitate, mixtures of the cetyl group and the stearyl alcohol group known by the name of Cromadol ® , which have high molecular weight and lipids such as white paraffins or liquid paraffins and other mineral oils.
  • Agents that allow an emulsion to be obtained include cetyl alcohols, sodium lauryl sulfate, stearyl alcohol, polyoxyethylene alkyl ethers such as Brij ® 72 and 721 (ICI, United Kingdom) and polyoxiestearyl esters such as Steareth 2 or 21. All these compounds may be used to obtain the desired emulsion in this topical formula.
  • the aqueous phase of the composition may also contain other components such as glycerin and glycol. These components are added to the aqueous phase to be used in the emulsion in order to increase the solubility of acyclovir in the aqueous phase.
  • glycerin and glycol are added to the aqueous phase to be used in the emulsion in order to increase the solubility of acyclovir in the aqueous phase.
  • glycol is a peculiar skin dehydrator. This point is particularly important when the preparation is to be applied to areas of skin that are not healthy as in the case of conditions caused by Herpes lablalis.
  • N, O-carboxymethyl chitosan it has been found, and it is the purpose of this invention, that the addition of N, O-carboxymethyl chitosan to the remaining ingredients of the formulation, in that percentage (1 to 40% w / w of N, O-carboxymethyl chitosan), it can reduce the presence of glycol in the formulation, specifically below 30% and even eliminated, while increasing the cosmetological and pharmaceutical efficacy of the formulation thanks to the ability of N, O-carboxymethyl.
  • Chitosan to act as a promoter of the absorption of the active substance through the skin.
  • N, O-carboxymethyl chitosan has a water solubility that is particularly useful in helping the formation of oil-water emulsions.
  • Composition ranges (w / w) used for the formulation and administration of acyclovir according to the present invention include: N, O-carboxymethyl chitosan 1- 40%, acyclovir 0.5-10%, cetroesaric alcohol 3-10%, 5-15% mineral oil, Steareth-21 2-5%, 0.1-1% sodium lauryl sulfate, and purified water required to reach 100%.
  • preservatives such as: p-oxybenzoates, benzoate Sodium, benzalkonium chloride, and others can be added to this formulation as a precautionary supplement in case of long-term storage.
  • a process for preparing the aforementioned formulation is also part of this invention. This process consists in stirring acyclovir or any of its salts or esters, N, O, carboxymethyl chitosan, the excipients constituted by the oil phase and the aqueous phase until the formation of the oil / water emulsion.
  • oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of acyclovir in most of the oils used in pharmaceutical emulsions formulations is very low.
  • the cream should preferably be a non-greasy product that does not stain and is washable, with a consistent consistency to prevent it from leaking out of the tubes or other containers.
  • Monobasic or dibasic, straight or branched chain alcohol esters can be used, such as isocetyl di-isoadipate, propylene glycol diester and coconut fatty acids, isopropyl myristate, isopropyl palmitate, butyl stearate or mixed acid ester 2- ethylhexanoic with a mixture of cetyl or stearyl alcohols, all three being last preferred for this pharmaceutical formulation. These can be used alone or in combination, depending on the required properties. Alternatively, high melting point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, can be used.
  • acyclovir may initially be incorporated completely in conjunction with the N, O-carbaoxymethyl chitosan in the aqueous portion, in which it may form a solution or a mixture of solution / suspension and then emulsify With the base of ointment.
  • acyclovir can be included in the emulsifying ointment, before emulsifying it with the aqueous phase.
  • the apparatus used for the formation of an emulsion is a turboemulsifier, which allows agitation under vacuum conditions, thus avoiding the incorporation of air and subsequent bubble formation in the final cream.
  • the topical formulation of the present invention patent application is prepared to be used for the treatment and prevention of viral infections by Herpes sp.
  • the tests carried out indicate that it is useful in cases of Herpes labialis and Herpes genitalis.
  • the formulation should be applied to the skin 2 to 5 times daily, preferably 3 or 4 times. It is obvious that the formulation referred to in this application for invention has been conceived for the particular administration of acyclovir and its derivatives, but this base formula can easily be adapted for the topical administration of other acyclovir analogue topical antiviral drugs such as, famciclovir, penciclovir, valacyclovir, and their synergistic combinations with other antivirals.
  • Part of this invention is the method of treating viral infections, particularly Herpes sp, which comprises the administration of a topical application formulation.
  • the oil phase was prepared by melting at 60 ° C solid petrolatum, beeswax and ketostearyl alcohol.
  • the aqueous phase was prepared with sodium lauryl sulfate, glycerin, methyl and propylparaben and water in which acyclovir has been heated to 70 ° C and suspended, subsequently added to the oil phase.
  • the mixing of the phases was slow under stirring and the whole system subjected to heat, once equilibrium was reached, the composition is cooled to room temperature.
  • the cream once formed was packaged in 10g tubes.
  • the cream described in example 1 was compared with the commercial cream Zovirax ® (GlaxoSmithKIine, Brentford, United Kingdom) using a Franz cell to measure permeation through artificial membrane and rat skin.
  • the artificial membrane and rat skin were mounted in Franz's cell, with a contact surface of 2.0 cm 2 . To this surface an amount of cream equal to 900-960mg was applied.
  • a Soerensen solution of pH 7.4 was used as a receiving solution for a period of 8 hours.
  • Several fractions were collected every 0.2h. The collected fractions were analyzed by the reverse phase high resolution liquid chromatography method described in J. Of Chromatography B, 791 (2003) 257-363.
  • the permeation test results are shown in the following tables.
  • Table 3 Pharmacokinetic parameters of the invented formulation obtained from rat skin tests.

Abstract

The invention relates to a pharmaceutical formulation for the topical administration of aciclovir, which can be used for the preventive and therapeutic treatment of viral infections. The inventive formulation comprises a chitosan derivative as an absorption promoter of the active principle, preferably N,O-carboxymethyl chitosan.

Description

MEMORIA DESCRIPTIVA. FORMULACIÓN TÓPICA DE ACICLOVIRDESCRIPTIVE MEMORY. TOPICAL FORMULATION OF ACICLOVIR
El objetivo de la presente invención es el desarrollo de una formulación tópica, útil en el tratamiento de infecciones vírales dérmicas y de las mucosas. Esta composición contiene como principio activo 9-(2-hidroximetoximetil)guanina, compuesto que es conocido en el estado del arte como "aciclovir" y además N,O-carboximetil quitosano, el cual promueve la absorción del principio activo.The objective of the present invention is the development of a topical formulation, useful in the treatment of dermal and mucosal viral infections. This composition contains as active ingredient 9- (2-hydroxymethoxymethyl) guanine, a compound that is known in the art as "acyclovir" and also N, O-carboxymethyl chitosan, which promotes the absorption of the active substance.
El aciclovir y sus sales derivadas de esteres, son ampliamente conocidas por su acción antiviral, la que es explicada ampliamente en la patente GB1523865 que es de dominio público en la actualidad.Acyclovir and its salts derived from esters, are widely known for their antiviral action, which is widely explained in GB1523865 which is currently in the public domain.
En el mercado existen innumerables formulaciones que contienen aciclovir, como se ha descrito en el estado del arte. En particular la patente EP 0 044 543 B1 describe una formulación de aciclovir en la que el vehículo es una mezcla aceite/agua, la cual contiene al menos un 30% de alcohol polivalente miscible con agua. Otra solicitud relacionada es la WO97/34607 que describe una formulación tópica, donde el vehículo es una formulación similar a la solicitud europea 44543, pero en este caso la formulación de esta solicitud de patente de invención es caracterizada porque el vehículo que es utilizado se encuentra en una emulsión aceite en agua que contiene al menos 10% de polietilenglicol/monoetileter conocido comercialmente como Transcutol® (Gattefosse SA).In the market there are innumerable formulations containing acyclovir, as described in the state of the art. In particular, EP 0 044 543 B1 describes an acyclovir formulation in which the vehicle is an oil / water mixture, which contains at least 30% water-miscible polyvalent alcohol. Another related application is WO97 / 34607 which describes a topical formulation, where the vehicle is a formulation similar to European application 44543, but in this case the formulation of this invention patent application is characterized in that the vehicle being used is found in an oil-in-water emulsion containing at least 10% polyethylene glycol / monoethylether commercially known as Transcutol ® (Gattefosse SA).
La presente solicitud de patente de invención relaciona una formulación tópica para la administración de aciclovir. La composición contiene un derivado de quitosano como elemento que promueve la absorción del principio activo a través de la piel.The present patent application relates to a topical formulation for the administration of acyclovir. The composition contains a chitosan derivative as an element that promotes the absorption of the active substance through the skin.
El derivado de quitosano utilizado es N,O-carboximetil quitosano (NOCMC). Este compuesto se encuentra protegido por la patente US4619995, y es obtenido por la reacción del quitosano con ácido monocloroacetico bajo condiciones alcalinas. El grado de substitución se encuentra típicamente entre 0.6-1.0. El NOCMC es soluble en soluciones cuyo pH esta sobre 6 y bajo 2. EL NOCMC es soluble en agua, es derivado de un polisacarido natural y biodegradable, por lo que presenta características inmejorables para ser utilizado como promotor de absorción en esta formulación tópica.The chitosan derivative used is N, O-carboxymethyl chitosan (NOCMC). This compound is protected by US4619995, and is obtained by the reaction of chitosan with monochloroacetic acid under alkaline conditions. The degree of substitution is typically between 0.6-1.0. The NOCMC is soluble in solutions whose pH is above 6 and under 2. NOCMC is soluble in water, is derived from a natural and biodegradable polysaccharide, so it has excellent characteristics to be used as an absorption promoter in this topical formulation.
Descripción de la InvenciónDescription of the Invention
Los autores de esta solicitud de patente de invención han encontrado que tras adicionar el derivado de quitosano a ingredientes de formulaciones tópicas para la administración de aciclovir vía mezclas emulsionadas de lípidos en agua, esas formulaciones llegan a ser particularmente efectivas en mejorar la absorción y la tolerancia del aciclovir, comparado a las formulaciones comerciales anteriormente descritas en la memoria descriptiva de esta solicitud de patente de invención.The authors of this patent application have found that after adding the chitosan derivative to ingredients of topical formulations for the administration of acyclovir via emulsified mixtures of lipids in water, these formulations become particularly effective in improving absorption and tolerance of acyclovir, compared to the commercial formulations described above in the specification of this patent application.
La formulación tópica que se desea proteger comprende desde 1 a10% p/p de aciclovir para cualquiera de sus sales o esteres, desde 1 a 40% p/p de NOCMC y desde 20 a 40% de agua, incorporada a la mezcla en cualquier fase oleosa.The topical formulation to be protected comprises from 1 to 10% w / w acyclovir for any of its salts or esters, from 1 to 40% w / w NOCMC and from 20 to 40% water, incorporated into the mixture in any oil phase
El componente lípídico de la emulsión esta constituido por sustancias conocidas y es emulsificado con el componente acuoso en concordancia con los procesos conocidos para este fin en el estado del arte. Uno o más agentes emulsionantes pueden ser adicionados como ingrediente a la fase lipídica, este componente puede ser grasoso o aceitoso, y su función es otorgar estabilidad a la emulsión en el tiempo.The lipid component of the emulsion is constituted by known substances and is emulsified with the aqueous component in accordance with the processes known for this purpose in the state of the art. One or more emulsifying agents can be added as an ingredient to the lipid phase, this component can be fatty or oily, and its function is to grant stability to the emulsion over time.
Los ingredientes de la fase oleosa de esta composición farmacéutica han sido seleccionados predominantemente sobre la base de características cosmetologicas deseadas en el producto final, siempre que la solubilidad del aciclovir en la fase oleosa y la fase acuosa sea limitada. Algunas sustancias lipídicas que pueden ser utilizadas para esta formulación, pueden ser de estructura química lineal o ramificada, mono o dialquilesteres de esteres de ácidos grasos tales como, isopropilmiristato e isopropilpalmitato, las mezclas de grupo cetil y del grupo estearil alcoholes conocidos por el nombre de Cromadol®, que presentan alto peso molecular y lípidos tales como parafinas blancas o parafinas líquidas y otros aceites minerales.The oil phase ingredients of this pharmaceutical composition have been predominantly selected on the basis of desired cosmetological characteristics in the final product, provided that the solubility of acyclovir in the oil phase and the aqueous phase is limited. Some lipid substances that can be used for this formulation, can be of linear or branched chemical structure, mono or dialkyl esters of fatty acid esters such as, isopropylmiristate and isopropylpalmitate, mixtures of the cetyl group and the stearyl alcohol group known by the name of Cromadol ® , which have high molecular weight and lipids such as white paraffins or liquid paraffins and other mineral oils.
Ejemplos de Agentes que permiten obtener una emulsión incluyen a cetil alcoholes, lauril sulfato de sodio, alcohol estearílico, polioxietilen alquiléteres tales como Brij®72 y 721 (ICI, Reino Unido) y polioxiestearil esteres tales como Steareth 2 o 21. Todos estos compuestos pueden ser utilizados para obtener la emulsión deseada en esta formula tópica.Examples of Agents that allow an emulsion to be obtained include cetyl alcohols, sodium lauryl sulfate, stearyl alcohol, polyoxyethylene alkyl ethers such as Brij ® 72 and 721 (ICI, United Kingdom) and polyoxiestearyl esters such as Steareth 2 or 21. All these compounds may be used to obtain the desired emulsion in this topical formula.
La fase acuosa de la composición también puede contener otros componentes tales como glicerina y glicol. Estos componentes son adicionados a la fase acuosa para ser usados en la emulsión con el fin de incrementar la solubilidad del aciclovir en la fase acuosa. Sin embargo, la presencia de una cantidad de un glicol en cantidades más altas que el 30% pueden causar pobre tolerancia dérmica, ocasionando reacciones debido a la acción disecante, es decir el glicol es un deshidratante cutáneo peculiar. Este punto es particularmente importante cuando la preparación es para ser aplicada en áreas de la piel que no están sanas como en el caso de afecciones causadas por Herpes lablalis.The aqueous phase of the composition may also contain other components such as glycerin and glycol. These components are added to the aqueous phase to be used in the emulsion in order to increase the solubility of acyclovir in the aqueous phase. However, the presence of an amount of a glycol in amounts higher than 30% can cause poor dermal tolerance, causing reactions due to the dissecting action, that is, glycol is a peculiar skin dehydrator. This point is particularly important when the preparation is to be applied to areas of skin that are not healthy as in the case of conditions caused by Herpes lablalis.
Ha sido encontrado, y es el propósito de esta invención, que la adición de N,O- carboximetil quitosano a los restantes ingredientes de la formulación, en ese porcentaje (1 a 40% p/p de N,O-carboximetil quitosano), puede reducir la presencia de glicol en la formulación, específicamente por debajo de 30% y hasta eliminada, al mismo tiempo que se incrementa la eficacia cosmetológica y farmacéutica de la formulación gracias a la habilidad del N,O-carboximetil . quitosano a actuar como promotor de la absorción del principio activo a través de la piel. El N,O-carboximetil quitosano presenta una solubilidad en agua que es particularmente útil en ayudar a la formación de emulsiones aceite-agua. Los rangos de composición (p/p) utilizados para la formulación y administración de aciclovir acorde a la presente invención incluye: N,O-carboximetil quitosano 1- 40%, aciclovir 0,5-10%, alcohol cetroestearico 3-10%, aceite mineral 5-15%, Steareth-21 2-5%, lauril sulfato de sodio 0.1-1%, y agua purificada requerida para alcanzar el 100%.It has been found, and it is the purpose of this invention, that the addition of N, O-carboxymethyl chitosan to the remaining ingredients of the formulation, in that percentage (1 to 40% w / w of N, O-carboxymethyl chitosan), it can reduce the presence of glycol in the formulation, specifically below 30% and even eliminated, while increasing the cosmetological and pharmaceutical efficacy of the formulation thanks to the ability of N, O-carboxymethyl. Chitosan to act as a promoter of the absorption of the active substance through the skin. N, O-carboxymethyl chitosan has a water solubility that is particularly useful in helping the formation of oil-water emulsions. Composition ranges (w / w) used for the formulation and administration of acyclovir according to the present invention include: N, O-carboxymethyl chitosan 1- 40%, acyclovir 0.5-10%, cetroesaric alcohol 3-10%, 5-15% mineral oil, Steareth-21 2-5%, 0.1-1% sodium lauryl sulfate, and purified water required to reach 100%.
Opcionalmente, aunque ha sido encontrado que la adición de esos preservantes no es estrictamente necesario para mantener en almacenaje por un tiempo prolongado la formulación tópica, que se ha descrito en la presente invención, uno o más preservantes, tales como: p-oxibenzoatos, benzoato de sodio, cloruro de benzalconio, y otros pueden adicionarse a esta formulación como un complemento precaucional en caso de almacenaje a largo plazo.Optionally, although it has been found that the addition of these preservatives is not strictly necessary to keep the topical formulation, which has been described in the present invention, stored for a long time, one or more preservatives, such as: p-oxybenzoates, benzoate Sodium, benzalkonium chloride, and others can be added to this formulation as a precautionary supplement in case of long-term storage.
Un proceso para preparar la formulación antes mencionada, también es parte de esta invención. Este proceso consiste en agitar aciclovir o cualquiera de sus sales o esteres, N,O, carboximetil quitosano, los excipientes constituidos por la fase oleosa y la fase acuosa hasta la formación de la emulsión aceite/agua.A process for preparing the aforementioned formulation is also part of this invention. This process consists in stirring acyclovir or any of its salts or esters, N, O, carboxymethyl chitosan, the excipients constituted by the oil phase and the aqueous phase until the formation of the oil / water emulsion.
La elección de aceites o grasas adecuados para la formulación se basa en conseguir las propiedades cosméticas deseadas, ya que la solubilidad del aciclovir en la mayor parte de los aceites que se utilizan en las formulaciones de emulsiones farmacéuticas, es muy escasa.The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of acyclovir in most of the oils used in pharmaceutical emulsions formulations is very low.
Por lo tanto, la crema debe ser, preferiblemente, un producto no graso, que no manche y que sea lavable, con una consistencia adecuada para evitar que se salga de los tubos o de otros recipientes. Pueden utilizarse esteres alcohólicos monobásicos o dibásicos, de cadena recta o ramificada, tales como di-isoadipato estearato de isocetilo, diéster de propilenglicol y ácidos grasos de coco, miristato de isopropilo, palmitato de isopropilo, estearato de butilo o éster mixto de ácido 2- etilhexanoico con una mezcla de alcoholes cetílico o estearílico, siendo los tres últimos los preferidos para esta formulación farmacéutica. Estos pueden utilizarse solos o en combinación, dependiendo de las propiedades requeridas. Alternativamente, pueden utilizarse lípidos de alto punto de fusión, tales como parafina blanda blanca y/o parafina líquida u otros aceites minerales.Therefore, the cream should preferably be a non-greasy product that does not stain and is washable, with a consistent consistency to prevent it from leaking out of the tubes or other containers. Monobasic or dibasic, straight or branched chain alcohol esters can be used, such as isocetyl di-isoadipate, propylene glycol diester and coconut fatty acids, isopropyl myristate, isopropyl palmitate, butyl stearate or mixed acid ester 2- ethylhexanoic with a mixture of cetyl or stearyl alcohols, all three being last preferred for this pharmaceutical formulation. These can be used alone or in combination, depending on the required properties. Alternatively, high melting point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, can be used.
La manera de formular esta emulsión variará desde luego de acuerdo con la cantidad y naturaleza de los constituyentes, pero sigue, no obstante, las técnicas conocidas en la tecnología de la emulsión (The Pharmaceutical Codex, Londres, The Pharmaceutical Press (1979) y en A.R. Gennaro, Remington: The Science and Practice of Pharmacv. 19th Ed., Ch. 21 , 282-291 , Mack Publ. Co.(1985)).The manner of formulating this emulsion will of course vary according to the quantity and nature of the constituents, but nevertheless follows the techniques known in emulsion technology (The Pharmaceutical Codex, London, The Pharmaceutical Press (1979) and in AR Gennaro, Remington: The Science and Practice of Pharmacv. 19 th Ed., Ch. 21, 282-291, Mack Publ. Co. (1985)).
En el proceso de fabricación de esta formulación farmacéutica el aciclovir puede inicialmente incorporarse por completo en conjunto con el N,O-carbaoximetil quitosano en la porción acuosa, en la que puede formar una solución o una mezcla de solución/suspensión y, seguidamente, emulsionarse con la base de ungüento. En otra técnica para el mismo proceso, el aciclovir puede incluirse en el ungüento emulsivo, antes de emuslionarlo con la fase acuosa. Al utilizar estos métodos, es preferible calentar la porción acuosa y la base de ungüentos a unos 40° a 80°C, preferiblemente 50° a 70°C, antes de emulsionarlos. Con ambos procedimientos se consigue el mismo resultado.In the manufacturing process of this pharmaceutical formulation, acyclovir may initially be incorporated completely in conjunction with the N, O-carbaoxymethyl chitosan in the aqueous portion, in which it may form a solution or a mixture of solution / suspension and then emulsify With the base of ointment. In another technique for the same process, acyclovir can be included in the emulsifying ointment, before emulsifying it with the aqueous phase. When using these methods, it is preferable to heat the aqueous portion and base of ointments to about 40 ° to 80 ° C, preferably 50 ° to 70 ° C, before emulsifying them. With both procedures the same result is achieved.
El aparato utilizado para la formación de una emulsión es un turboemulsificador, el cual permite la agitación bajo condiciones de vacío, así se evita la incorporación de aire y la subsecuente formación de burbujas en la crema final.The apparatus used for the formation of an emulsion is a turboemulsifier, which allows agitation under vacuum conditions, thus avoiding the incorporation of air and subsequent bubble formation in the final cream.
La formulación tópica de la presente solicitud de patente de invención es preparada para ser usada para el tratamiento y prevención de infecciones vírales por Herpes sp. En particular los ensayos realizados indican que es útil en casos de Herpes labialis y Herpes genitalis . La formulación debe ser aplicada sobre la piel 2 a 5 veces diariamente, preferentemente 3 o 4 veces. Es obvio que la formulación referida en esta solicitud de invención ha sido concebida para la administración en particular de aciclovir y sus derivados, pero esta formula base puede fácilmente ser adaptada para la administración tópica de otras drogas antivirales de uso tópico análogos de aciclovir tales como, famciclovir, penciclovir, valaciclovir, y sus combinaciones sinergéticas con otros antivirales.The topical formulation of the present invention patent application is prepared to be used for the treatment and prevention of viral infections by Herpes sp. In particular, the tests carried out indicate that it is useful in cases of Herpes labialis and Herpes genitalis. The formulation should be applied to the skin 2 to 5 times daily, preferably 3 or 4 times. It is obvious that the formulation referred to in this application for invention has been conceived for the particular administration of acyclovir and its derivatives, but this base formula can easily be adapted for the topical administration of other acyclovir analogue topical antiviral drugs such as, famciclovir, penciclovir, valacyclovir, and their synergistic combinations with other antivirals.
Es parte de esta invención el método de tratamiento de infecciones vírales particularmente Herpes sp que comprende la administración de una formulación de aplicación tópica.Part of this invention is the method of treating viral infections, particularly Herpes sp, which comprises the administration of a topical application formulation.
A continuación se presentan ejemplos que describen mejor la formulación objeto de la presente solicitud de patente de invención y muestran las ventajas y su aplicabilidad en la industria farmacéutica, pero sin ser una limitación por si mismas. Below are examples that best describe the formulation object of the present invention patent application and show the advantages and their applicability in the pharmaceutical industry, but without being a limitation in themselves.
Ejemplos de aplicaciónApplication examples
1. EJEMPLO DE COMPOSICIÓN FARMACÉUTICA1. EXAMPLE OF PHARMACEUTICAL COMPOSITION
ACICLOVIR 5.00%ACICLOVIR 5.00%
ALCOHOL CETOSTEARÍLICO 4.30%KETOSTEARILIC ALCOHOL 4.30%
VASELINA SÓLIDA 5.08%SOLID VASELINE 5.08%
CERA DE ABEJAS 0.05%BEE WAX 0.05%
GLICERINA 1.70%GLYCERINE 1.70%
N,O-CARBOXIMETIL QUITOSANO 25.00%N, O-CARBOXIMETIL QUITOSANO 25.00%
LAURILSULFATO DE SODIO 0.15%SODIUM LAURYL SULFATE 0.15%
METILPARABENO 1.00%METHYLPARABEN 1.00%
PROPIL PARABENO 1.00%PARABEN PROPIL 1.00%
AGUA DESTILADA c.s.p. 100%DISTILLED WATER c.s.p. 100%
PROCESO DE FABRICACIÓNFABRICATION PROCESS
La fase oleosa fue preparada fundiendo a 60°C vaselina sólida, cera de abejas y alcohol cetoestearílico. La fase acuosa fue preparada con Lauril sulfato de sodio, glicerina, metil y propilparabeno y agua en la cual el aciclovir ha sido calentado hasta 70°C y suspendido, posteriormente se adicionó a la fase oleosa. La mezcla de las fases fue lenta bajo agitación y todo el sistema sometido a calor, una vez alcanzado el equilibrio, la composición es enfriada a temperatura ambiente. La crema una vez formada fue envasada en tubos de 10g.The oil phase was prepared by melting at 60 ° C solid petrolatum, beeswax and ketostearyl alcohol. The aqueous phase was prepared with sodium lauryl sulfate, glycerin, methyl and propylparaben and water in which acyclovir has been heated to 70 ° C and suspended, subsequently added to the oil phase. The mixing of the phases was slow under stirring and the whole system subjected to heat, once equilibrium was reached, the composition is cooled to room temperature. The cream once formed was packaged in 10g tubes.
2. EJEMPLO DE ENSAYOS BIOLÓGICOS2. EXAMPLE OF BIOLOGICAL TESTS
La crema descrita en el ejemplo 1 fue comparada con la crema comercial Zovirax® (GlaxoSmithKIine, Brentford, Reino Unido) usando una celda de Franz para medir la permeación a través de membrana artificial y piel de rata. La membrana artificial y la piel de rata fueron montadas en la celda de Franz, con una superficie de contacto de 2,0 cm2. A esta superficie se le aplicó una cantidad de crema igual a 900-960mg. Una solución Soerensen de pH 7.4 fue utilizada como solución receptora durante un periodo de 8 horas. Varias fracciones fueron recopiladas cada 0.2h. Las fracciones colectadas fueron analizadas por el método de cromatografía líquida de alta resolución en fase reversa descrito en el J. Of Chromatography B, 791 (2003) 257-363. Los resultados del test de permeación son mostrados en las tablas siguientes.The cream described in example 1 was compared with the commercial cream Zovirax ® (GlaxoSmithKIine, Brentford, United Kingdom) using a Franz cell to measure permeation through artificial membrane and rat skin. The artificial membrane and rat skin were mounted in Franz's cell, with a contact surface of 2.0 cm 2 . To this surface an amount of cream equal to 900-960mg was applied. A Soerensen solution of pH 7.4 was used as a receiving solution for a period of 8 hours. Several fractions were collected every 0.2h. The collected fractions were analyzed by the reverse phase high resolution liquid chromatography method described in J. Of Chromatography B, 791 (2003) 257-363. The permeation test results are shown in the following tables.
Tabla N°1 Los resultados del test de permeación en piel artificial y piel de rataTable No. 1 The results of the permeation test on artificial skin and rat skin
Figure imgf000009_0001
Figure imgf000009_0001
Tabla N°2: Parámetros farmacocinéticos de la formulación obtenida desde estudios de membrana artificial.Table N ° 2: Pharmacokinetic parameters of the formulation obtained from artificial membrane studies.
Figure imgf000009_0002
Table 3: Parámetros farmacocinéticos de la formulación inventada obtenidos desde ensayos en piel de rata .
Figure imgf000009_0002
Table 3: Pharmacokinetic parameters of the invented formulation obtained from rat skin tests.
Figure imgf000010_0001
Figure imgf000010_0001
Ejemplo N°3 COMPORTAMIENTO DE LA FORMULACIÓN REIVINDICADA EN ESTA SOLICITUD DE PATENTE DE INVENCIÓN VERSUS ZOVIRAX® Example N ° 3 BEHAVIOR OF THE FORMULATION REIVINDICATED IN THIS INVENTION PATENT APPLICATION VERSUS ZOVIRAX ®
Los Gráficos son obtenidos de datos de estudios cromatográficos los cuales demostraron que la transferencia de la formulación inventada v/s la formulación de Zovirax® es mayor. La formulación descrita en esta memoria descriptiva demostró que se optimizaba la transferencia y permeación de aciclovir tanto utilizando piel artificial, así como piel de rata. Medio receptor Tampón pH 6,8 Temperatura 35°C ± 0.5°C Agitación constante 0.1 -24h/ Volumen del medio receptor 11 mL Volumen de alícuota 1 mL La figura 1 muestra la transferencia de aciclovir de dos formulaciones en estudio a través de membrana artificial, donde se puede visualizar que tras 240 min la transferencia de la fórmula inventada (A) es mayor que Zovirax® (formulación B). La figura 2 muestra la Transferencia de aciclovir de dos formulaciones en estudio a través de piel de rata. Del mismo modo la dinámica exhibida por la formulación inventada v/s Zovirax® muestra el mismo patrón de transferencia, por lo que se ve optimizado la permeación del principio activo. The Graphs are obtained from data from chromatographic studies which demonstrated that the transfer of the invented formulation v / s the Zovirax® formulation is greater. The formulation described in this specification demonstrated that acyclovir transfer and permeation was optimized both using artificial skin, as well as rat skin. Receiving medium Buffer pH 6.8 Temperature 35 ° C ± 0.5 ° C Constant agitation 0.1 -24h / Volume of the receiving medium 11 mL Aliquot volume 1 mL Figure 1 shows the transfer of acyclovir from two formulations under study through artificial membrane , where it can be seen that after 240 min the transfer of the invented formula (A) is greater than Zovirax® (formulation B). Figure 2 shows the Acyclovir Transfer of two formulations under study through rat skin. Similarly, the dynamics exhibited by the invented formulation v / s Zovirax ® show the same transfer pattern, so that permeation of the active substance is optimized.

Claims

REIVINDICACIONES: CLAIMS:
1. Una composición farmacéutica tópica, CARACTERIZADA porque comprende aciclovir o cualquiera de sus sales o esteres, una mezcla de ingredientes lipidíeos con una fase acuosa, y contiene desde 0.1 a 35% p/p de un quitosano.1. A topical pharmaceutical composition, CHARACTERIZED because it comprises acyclovir or any of its salts or esters, a mixture of lipid ingredients with an aqueous phase, and contains from 0.1 to 35% w / w of a chitosan.
2. Una composición farmacéutica tópica según reivindicación 1 , CARACTERIZADA porque la mezcla comprende una emulsión conformada por una fase lipídica, una fase acuosa, uno o más emulsificantes, y uno o más agentes estabilizantes de la emulsión.2. A topical pharmaceutical composition according to claim 1, CHARACTERIZED in that the mixture comprises an emulsion formed by a lipid phase, an aqueous phase, one or more emulsifiers, and one or more emulsion stabilizing agents.
3. Una composición farmacéutica tópica según reivindicación 2, CARACTERIZADA porque el ingrediente de la fase lipídica puede ser de cadena lineal o ramificada.3. A topical pharmaceutical composition according to claim 2, CHARACTERIZED in that the ingredient of the lipid phase can be straight or branched chain.
4. Una composición farmacéutica tópica según reivindicación 2, CARACTERIZADA porque el ingrediente de la fase lipídica puede ser mono o dialquiléster, o esteres de ácidos grasos, mezcla de cetil y estearil alcoholes o lípidos de alto peso molecular.4. A topical pharmaceutical composition according to claim 2, CHARACTERIZED in that the ingredient of the lipid phase can be mono or dialkyl ester, or esters of fatty acids, mixture of cetyl and stearyl alcohols or high molecular weight lipids.
5. Una composición farmacéutica tópica según reivindicación 1 y 2, CARACTERIZADA porque uno o más de los emulsificantes y uno o más de los agentes estabilizantes de la emulsión están constituidos por un grupo de cetil alcoholes, lauril sulfato de sodio, alcohol esterilico, alcohol cetoestearico, polioxietileno, alquileteres y esteres polioxiestearicos.5. A topical pharmaceutical composition according to claim 1 and 2, CHARACTERIZED in that one or more of the emulsifiers and one or more of the emulsion stabilizing agents are constituted by a group of cetyl alcohols, sodium lauryl sulfate, sterile alcohol, ketostearic alcohol , polyoxyethylene, alkylether and polyoxystearic esters.
6. Una composición farmacéutica tópica según reivindicación 1 , CARACTERIZADA porque el quitosano utilizado en la formulación es N,O-carboximetil quitosano (NOCMC). 6. A topical pharmaceutical composition according to claim 1, CHARACTERIZED in that the chitosan used in the formulation is N, O-carboxymethyl chitosan (NOCMC).
7. Una composición farmacéutica tópica según reivindicación 4, CARACTERIZADA porque los esteres de los ácidos de la fase lipídica son derivados de un grupo compuesto por ácido mirístico, ácido oleico, ácido palmítico y ácido esteárico.7. A topical pharmaceutical composition according to claim 4, CHARACTERIZED in that the esters of the acids of the lipid phase are derived from a group consisting of myristic acid, oleic acid, palmitic acid and stearic acid.
8. Una composición farmacéutica tópica según reivindicación 2, CARACTERIZADA porque comprende los siguientes porcentajes p/p en su composición:8. A topical pharmaceutical composition according to claim 2, CHARACTERIZED in that it comprises the following w / w percentages in its composition:
- aciclovir o cualquiera de sus sales y o sus esteres desde 0.1% a 10%; - N,O-carboximetil quitosano desde 1 - 40%; - fase acuosa en mezcla con los ingredientes activos de la fase lipídica desde 20% a un 40%.- acyclovir or any of its salts and or esters from 0.1% to 10%; - N, O-carboxymethyl chitosan from 1-40%; - aqueous phase in admixture with the active ingredients of the lipid phase from 20% to 40%.
9. Una composición farmacéutica tópica según reivindicación 1 , CARACTERIZADA porque la relación p/p es: - aciclovir o cualquiera de sus sales y o sus esteres 0.5-10%; - N,O-carboximetil quitosano 1-40%; - alcohol cetoestéarico 3-10%; - lauril sufato de sodio 0.1-10%; - aceite mineral 1-15%; - petrolato 2-8%; - agua para llegar al 100%.9. A topical pharmaceutical composition according to claim 1, CHARACTERIZED in that the w / w ratio is: - acyclovir or any of its salts and or its esters 0.5-10%; - N, O-carboxymethyl chitosan 1-40%; - 3-10% ketosteary alcohol; - sodium lauryl 0.1-10%; - mineral oil 1-15%; - 2-8% petrolatum; - water to reach 100%.
10. Un proceso para la preparación de la composición farmacéutica según reivindicaciones 1 a 9, CARACTERIZADO porque comprende las siguientes etapas: - agitación del aciclovir o cualquiera de su sales o esteres y adición de N,O- carboximetilquitosano en fase acuosa; - emulsificación de los excipientes de las fases lipídicas y acuosas; - estabilización de la emulsión. 10. A process for the preparation of the pharmaceutical composition according to claims 1 to 9, CHARACTERIZED in that it comprises the following steps: - stirring of acyclovir or any of its salts or esters and addition of N, O-carboxymethylchitosan in aqueous phase; - emulsification of the excipients of the lipid and aqueous phases; - emulsion stabilization.
PCT/IB2005/000118 2004-01-08 2005-01-07 Topical aciclovir formulation WO2005067941A1 (en)

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RU2128503C1 (en) * 1992-09-09 1999-04-10 А/С Геа Фармасьютиск Фабрик Antiviral pharmaceutical emulsion of type "oil-in-water"
WO2003043612A1 (en) * 2001-11-21 2003-05-30 Besins International Belgique Micronized film-forming powder comprising an active substance
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