MX2009013534A - Compositions containing an antiviral agent. - Google Patents

Abstract

The present invention describes compositions containing neuraminidase inhibitors, particularly oseltamivir.

Description

COMPOSITIONS CONTAINING AN AGENT ???? VIRAI- TECHNICAL FIELD The present invention relates to compositions containing neuraminidase inhibitors, particularly compositions containing oseltamivir and to the treatment of viral infections. The compositions of the invention are particularly suitable for the prevention of secondary bacterial infections, for example, but not limited to infections of the lower respiratory tract.

BACKGROUND Influenza, more commonly known as influenza, is an acute, viral infection of the respiratory tract that explains significant levels of morbidity and mortality. The Centers for Disease Control and Prevention (CDC) estimates that approximately 10% to 20% of the population in the United States are afflicted with influenza annually resulting in approximately 20,000 deaths associated with influenza and more than 110,000 hospitalizations ( Neuzil, et al., N. MED J. (2000) 342: 225-231). The simple flu is characterized by the sudden onset of symptoms constitutional, for example: fever, myalgia, headache, severe and respiratory discomfort, ie, non-productive cough, sore throat and rhinitis. The flu 'is particularly dangerous for children, young people, older individuals, and for patients with chronic diseases. Direct costs are associated with medical assistance for individuals afflicted with influenza, estimated between $ 1 billion and $ 3 billion annually. Influenza viruses cause disease in all groups of the same age. Children experience the highest incidence of influenza and are a common source of its spread. However, rates of serious illness are higher among individuals over 65, and people of any age who have ailments that put them at high risk for complications from the flu. Although healthy adults under the age of 65 have comparatively little risk for severe illness, the flu can result in substantial mortality, frequent visits to health centers, and loss of workdays. Estimates of indirect annual costs, considering absenteeism in school and work leads to the loss of productivity estimated at $ 10 to $ 15 billion dollars. Otitis, bacterial sinusitis, and pneumonia are common complications of an infection with viral flu. Otitis and acute bacterial sinusitis are two of the five conditions that explain most of the use of antibiotics in non-hospitalized patients in the United States. Data from the National Center for Health Statistics indicate that approximately 75% of all prescriptions for non-hospitalized patients receiving antibiotics are aimed at. treat otitis, sinusitis, bronchitis, pharyngitis and nonspecific infection of the upper respiratory tract. The existence of a deadly synergy between the influenza virus and bacteria such as S. pneumoniae has been appreciated since the late nineteenth century, which explains excess mortality during influenza epidemics throughout the world.

Oseltamivir (ethyl ((3R, 4R, 5S) -4-Acetylamino-5-amino-3- (1-ethylpropoxy) -1-cyclohexen-1-carboxylate, Formula I) is a selective antiviral prodrug against human papilloma virus. influenza. Oseltamivir was first described in U.S. Patent No. 5,763,483 published June 9, 1998, Gilead Sciences, Inc. It is currently produced by Hoffmann-La Roche under the trademark Tamiflu. Its action is based on the inhibition of the neuraminidases present in the influenza virus. These neuraminidases are responsible for releasing to the virus of the infected cells, and thus favor their dissemination, being these in the virion. This compound is active against the two varieties of influenza virus, A and B, is currently considered the most effective drug to treat the influenza virus AHiNj .. Does not modify the immune and humoral response against the virus and other antigens not related Once administered, oseltamivir decreases the tune of patients with recently acquired influenza and reduces the incidence of the symptoms of a confirmed influenza, such as bacterial infections: bronchitis, sinusitis and pneumonia.

Oseltamivir is completely absorbed orally, becoming the active metabolite by the action of intestinal and hepatic esterases. It is easily distributed, being able to find in the lungs, the nasal pituitary, the middle ear and the trachea. The maximum plasma concentration is between 2 and 3 hours after ingestion, this concentration being more than 20 times higher than that of the prodrug, oseltamivir. The conversion of oseltamivir to the active metabolite is estimated at 75%, the concentration being proportional to the dose. Due to these characteristics, it is considered essential to have pharmaceutical formulations that rapidly release the drug, in order to have an optimal absorption of the organism, for a quick action, taking into account the clinical picture presented by those infected with the influenza virus? ???? .

The active metabolite does not continue to be transformed and is excreted with urine (90%) and feces.

Its main side effects are vomiting, insomnia, headache, nausea and abdominal pain. Less frequently, diarrhea, nasal congestion, cough, vertigo, sore throat, dizziness and fatigue.

This compound has no significant interactions with other drugs, due to its low level of affinity with plasma proteins. It does not interact with cimetidine (it is not a substrate of cytochrome P-450) and can be administered together with common medications such as paracetamol, ibuprofen, acetylsalicylic acid or erythromycin without having to see its affected pharmacokinetics.

In the patent application 20090176877 of the United States published on July 9, 2009, entitled "Method of granulation and to prepare oseltamivir phosphate", a method of granulation and preparation of oseltamivir phosphate is described. The granule comprises 1.97-19.8% by weight of oseltamivir phosphate, 75.0-97.5% by weight of diluent, 0.1-5.0% by weight of coating layer, optionally 1.0-5.0% of flavor, sweetener and / or colorant. The granule is prepared using 30-55% v / v of an aqueous solution of ethanol as a wetting agent.

In the patent application 20090220611 of the United States published on September 3, 2009, named; Microparticles with modified release for at least one active ingredient and an oral pharmaceutical form comprising them; a system of microparticles for the release of oral active ingredients. The invention aims to provide a new mechanism of pharmaceutical release dependent on time and pH, allowing: a) a latent period prior to the release of the active ingredient in the stomach; b) that the pH determines the release of the active principle in the intestine; c) modify the release rate of the active principle. This is achieved with the use of microparticles coated with a cover of two films A and B. comprises: a film-forming polymer (Al) insoluble in liquids of the gastrointestinal tract; a polymer of ethylcellulose (A2) soluble in liquids of the gastrointestinal tract; a polyvidone plasticizer (A3); castor oil, and optionally a lubricant and / or magnesium stearate surfactant (A4). B comprises a polymer (Bl) with hydrophilic ionic groups with neutral pH (EUDRAGIT® L100-55) and a hydrophobic compound (B2) (LUBRI ®). The invention also relates to medicaments based on said microparticles.

In the Mexican application number 2008/010106, entitled PHARMACEUTICAL COMPOSITION COMPRISING OSELTAMIVIR FOSFATO; described is a pharmaceutical composition comprising at least one excipient selected from a sugar and a sugar alcohol each having a moisture content of equilibrium of 1% by weight or less at 25 ° C and 70% relative humidity and oseltamivir phosphate, wherein the sugar or sugar alcohol contains glucose and flour as impurities each in an amount of 0.01% by weight or less with regarding the weight of sugar or sugar alcohol.

For its part in the Mexican application serial number 2000/002761, called; COMPOUNDS CONTAINING RINGS OF SIX MEMBERS, PROCESSES FOR PREPARATION, AND USE AS MEDICATIONS; new compounds are disclosed, the compounds generally comprise an acidic group, a basic group, an amino or substituted N-acyl and a group having an optionally hydroxylated alkane portion. Also disclosed are pharmaceutical compositions which comprise the inhibitors of the invention and neuraminidase is also described in the samples suspected of containing neuramidase. Also described are antigenic materials, polymers, antibodies, labels, and test methods to detect the activity of neuraminidase.

The 'Mexican patent 201990, named; NEW SELECTIVE INHIBITORS OF VIRAL OR BACTERIAL NEUROAMINIDASES; novel compounds are described. The compounds in general they comprise an acidic group, a basic group, a substituted amino or N-acyl and a group having an optionally hydroxylated alkane portion. Also disclosed are pharmaceutical compositions comprising the inhibitors of the invention. Methods of inhibiting neuraminidase are also described in samples suspected of containing neuraminidase. Also described are antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels or labels, and test methods for detecting neuraminidase activity.

In Canadian Patent No. 2632890 describes a method for the preparation of a pharmaceutical composition comprising the steps of: (a) preparing a solution or a homogeneous dispersion of a liquid and a compound selected from the group consisting of one or more active pharmaceutical compounds , among which is the oseltamivir. Also disclosed are pharmaceutical compositions comprising from 0.2% to 10% w / w of a mixture of ethanol-water, orlistat of 1-96% w / w, maltodextrin from 3.7 to 98.7% and from 0.1 to 95% w / w p of one or more pharmaceutically acceptable excipients or 0.2% w / w up to 10% w / w of isopropyl alcohol, from 1 to 98.8% of oseltamivir and polymethacrylate from 1 to 98.8% w / w.

Object of the invention The object of the present invention is to provide a novel antiviral granular composition containing oseltamvir as an active principle, which has an optimal dissolution rate to be quickly absorbed by the organism.

Detailed description of the invention.

The compositions object of the present invention involve the formulation in the form of granules of oseltamivir and / or their pharmaceutically acceptable salts, preferably the phosphate salt. Wherein the granules further comprise a superdisintegrant, a binder, a glidant and a lubricant, in suitable proportions to allow rapid and efficient disintegration of the granules contained in capsules.

The use and application of a superdisintegrant, such as croscamellose sodium, favors the disintegration of the granules and the dissolution of the active principle, which is essential for the release of the active ingredient and to obtain a adequate bid availability. The contribution of the binder, aims to obtain a consistent granule of uniform size that allows a good flow during the filling of the capsule, consequently the adequate selection of the superdisintegrant and the binder constitutes a critical variable for the achievement of the optimal release of the binder. active, in the same way it is important to select them appropriately in order to avoid an unnecessary increase of the. production costs or that one interferes with the other.

The uniform flow of the composition both for its handling and for the uniform filling of the capsules is achieved through an adequate selection of lubricant and slider. The water-soluble lubricants prevent the formation of a hydrophobic layer of the lubricant, which can normally be talc or the like, on the granule that would prevent the proper dissolution of the granule, that is, the water-soluble lubricant breaks the layer formed by the lubricant and therefore both ensures the correct dissolution of oseltamivir. Consequently, even when the pharmaceutical additives used in the composition object of the present invention are known in the state of the art, their selection and application are conditioned by their interaction, that affects the bioavailability of the active component thereof and limits the selection of the other additives.

The composition object of the present invention comprises from 55 to 65% by weight of a pharmaceutically acceptable salt of oseltamivir, such that it allows to have an equivalent of approximately 40 to 50% of oseltamivir, wherein the oseltamivir salt is preferably the salt of phosphate; from 5 to 7% by weight of a superdisintegrant selected from the group of methylcelluloses, corn starch, sodium starch glycolate, methylcellulose, bentonite, starch lauryl sulfate, preferably sodium croscamellose; from 30 to 33% by weight of a binder selected from the group consisting of starch, pregelatinized starch, cellulose and lactose, preferably pregelatinized starch, from 1 to 1.5% by weight of a glidant selected from the group consisting of colloidal silicon dioxide, talc, magnesium stearate, preferably talc; and a lubricant selected from the group consisting of sodium benzoate, sodium acetate, sterile sodium fumarate, sodium chloride, leucine, polyethylene glycol 4000, preferably sterile sodium fumarate.

The granules of the composition described above are achieved by methods known in the state of the art, using ethanol as a wetting agent, which is removed during the drying phase. In the same way, the granules are encapsulated in hard gelatin capsules of number two (2) commercially available.

Example : A composition containing 98.5 mg of oseltamivir phosphate, equivalent to 75 mg of oseltamivir; 10 mg of sodium croscamellose; 52.5 mg of pregelatinized starch; 2 mg of talc and 2 mg of sodium stearyl fumarate, was subjected to a granulation process adding 0.06 ml of ethanol as a wetting agent, the granules were dried and the No. 2 hard gelatin capsules were filled.

The stability of the capsules, as well as of the granules was tested in periods of 12 and 24 months, at 65% relative humidity and at temperatures between 15 and 30 ° C, according to the applicable standards. Under the conditions indicated, the stability of the capsules, measured through the parameters recognized for these tests, demonstrated a stability of 100% at the end of the 24-month period.

The dissolution tests show that the selection of additives allows an immediate bioavailability of oseltamivir at the level of the intestinal tract, which allows its rapid absorption and performance. The solubility tests were carried out in a buffer solution of 0.05 M monosodium phosphate, pH 6. These dissolution tests included samples of Tamiflu, the drug currently on the market whose active ingredient is oseltamivir in its phosphate salt form . The results obtained are shown below and are the averages obtained from 12 tests according to the applicable standards.

As can be seen, the dissolution time of the composition object of the present invention initially measured shows that the capsule has been dissolved and released more than 50% of oseltamivir, which upon reaching the lower intestinal tract has been completely released from its cover and available for absorption, this rate of release significantly exceeds that of Tamiflu.

Claims (3)

1. - A composition containing an antiviral agent, characterized in that it comprises from 55 to 65% by weight of a pharmaceutically acceptable salt of oseltamivir, such that it allows to have an equivalent of approximately 40 to 50% of oseltamivir, wherein the oseltamivir salt is preferably the phosphate salt; from 5 to 7% by weight of a superdisintegrant selected from the group of methylcelluloses, corn starch, sodium starch glycolate, methylcellulose, bentonite, starch lauryl sulfate, preferably sodium croscamellose; from 30 to 33% by weight of a binder selected from the group consisting of starch, pregelatinized starch, cellulose and lactose, preferably pregelatinized starch, from 1 to 1.5% by weight of a glidant selected from the group consisting of colloidal silicon dioxide, talc, magnesium stearate, preferably talc; and a lubricant selected from the group consisting of sodium benzoate, sodium acetate, sterile sodium fumarate, sodium chloride, leucine, polyethylene glycol 4000, preferably sterile sodium fumarate.

2. - The composition according to claim 1, characterized in that it comprises 98.5 mg of oseltamivir phosphate, equivalent to 75 mg of oseltamivir; 10 mg of sodium croscamellose; 52.5 mg of pregelatinized starch; 2 mg of talc and 2 mg of sodium stearyl fumarate.

3. - The composition according to claim 1, characterized in that it is used for the prevention of lower respiratory tract infections.