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EP1239923A2 - Compositions veterinaires stabilisees, contenant plusieurs agents antiviraux - Google Patents

Compositions veterinaires stabilisees, contenant plusieurs agents antiviraux

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Publication number
EP1239923A2
EP1239923A2 EP00983353A EP00983353A EP1239923A2 EP 1239923 A2 EP1239923 A2 EP 1239923A2 EP 00983353 A EP00983353 A EP 00983353A EP 00983353 A EP00983353 A EP 00983353A EP 1239923 A2 EP1239923 A2 EP 1239923A2
Authority
EP
European Patent Office
Prior art keywords
composition according
volume
weight
ribavirin
amount
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.)
Withdrawn
Application number
EP00983353A
Other languages
German (de)
English (en)
Inventor
Abdul Rahman Shoa'a
El-Banna Hossny
Da'as Kefah
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NEW PHARMA RESEARCH SWEDEN AB
Original Assignee
New Pharma Research Sweden AB
Newpharmaresearch Sweden AB
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by New Pharma Research Sweden AB, Newpharmaresearch Sweden AB filed Critical New Pharma Research Sweden AB
Priority to EP00983353A priority Critical patent/EP1239923A2/fr
Publication of EP1239923A2 publication Critical patent/EP1239923A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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 present invention concerns compositions comprising ribavirin and at least another antiviral agent as essential active ingredients, and a stabilizing agent, the compositions being intended to be used preferably in veterinary medicine.
  • RNA and DNA viruses like the Newcastle disease, infectious bursal disease (Gumboro disease) , infectious bronchitis, influenza disease or Marek' s viral disease, are known to cause heavy losses in the poultry industry due to high mortality and the rapid spreading of the disease to healthy flocks.
  • Newcastle disease is an acute, highly contagious rapidly spreading viral disease caused by a group of viruses which form the avian paramyxovirus of type 1.
  • Previous studies made on chickens have shown that the incubation period of the virus is generally of between 2 and 15 days.
  • the virus is generally transmitted through the upper respiratory system, from which it will penetrate into the blood. There will then follow a damage of the blood vessels and a spreading of the virus to other organs (spleen, liver, bone marrow) . After generally three days, all organs are infected, including the nervous system.
  • the clinical signs of the disease are greenish diarrhea (due to haemorrhagic lesions present in the intestinal tract), respiratory symptoms (difficult respiration, coughing, sneezing, rales due to inflammation, oedema and mucoid exudate present in the trachea and pharynx) and nervous signs (stiff neck, dropped wings, absence of coordination, paralysis) , which leads generally to the death of the animal.
  • a decrease of egg production in layers or even a cessation of laying have also been observed.
  • the virus can also infect humans and cause severe conjunctivitis.
  • the infectious bursal disease (or Gumboro disease) is an important viral disease of poultry caused by a group of viruses called birnaviruses . It affects young chickens and is characterized by a sudden onset and a short course with massive destruction of lymphocytes, particularly in the bursa .
  • Infectious bronchitis is a highly infectious and contagious respiratory disease of chickens. In some cases and with some virus strains, the infection may also affect the oviduct or the kidneys. A significant decrease in egg production and egg quality in layers and a decrease of production in broilers is observed in infected flocks.
  • influenza disease is caused by a viral infection originated by viruses belonging to the orthomyxoviruses family. Diseases specific to some animal species have been described, like for example the avian influenza, turkey influenza, swine influenza or equine influenza. The clinical signs of the disease are broncho-intestinal pneumonia and lung lesions. Many different subtypes of viruses have been described and isolated. These subtypes may be introduced from one species to another species, like for example from birds to mammals, and may then cause major pandemics in the unprotected population.
  • Marek' s viral disease is a widespread disease affecting domestic chickens in all sections of the world. It is characterized by lesions affecting the nervous system (demyelination of peripheral nerves leading to progressive paralysis of the wings and legs), organs and other tissues. Young chickens under sixteen weeks of age are most susceptible. Once the birds are infected, there is no known treatment to stop or reduce the infection. In its acute form, the disease leads to the death of the animal. The only actual treatment available is by vaccination.
  • vaccination against the viral agents causing the disease has been shown to be helpful, but however insufficient.
  • the vaccination is made either by intraocular or intra-nasal instillation, by inhalation (spray or aerosol) , by adding the vaccine to the feed or by injection.
  • agents like amantadine, methisazone or cytarabine have been described. However, these agents have only a limited spectrum antiviral activity. These agents also have the drawback of being toxic to the animal when administered at an effective therapeutic or prophylactic dosage, which is not desirable, especially if they are intended to be used for prophylaxis.
  • an antiviral agent developed against viral human diseases, ribavirin or tribavirin (sold under the name
  • Ribavirin is a synthetic non-interferon inducing broad- spectrum antiviral agent, which is used against many viral human diseases including type A hepatitis, measles and influenza B. Ribavirin has been shown to have a significant effect against respiratory syncytial virus (RSV) , parainfluenza and influenza B viruses, and a lesser activity against herpes, varicella, Lassa fever, infectious hepatitis, dengue fever, measles and AIDS viruses.
  • RSV respiratory syncytial virus
  • ribavirin has been shown to be active against influenza virus types A and F infections in mice.
  • ribavirin is 1- -D-Ribofuranosyl-lH-1, 2, 4- triazole-3-carboxamide, a synthetic nucleoside. Due to its analogy with the nucleosides used for the replication of the virus in the target infected cell, this molecule intervenes as an inhibitor of the 5' capping of viral mRNA, so that ultimately viral protein synthesis of both DNA and RNA viruses are affected.
  • Ribavirin is sold as a powder. At 25 °C, the maximum aqueous solubility of ribavirin is 142 mg/ml and the drug is slightly soluble in alcohol.
  • the drug ribavirin is approved for use only in the medical treatment of severe upper respiratory infections caused by RSV in infants and children.
  • Ribavirin has also demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted (rodents and rabbits) . Studies in which the drug has been administered systemically demonstrate that ribavirin is concentrated in the red blood cells and persists for the life of the erythrocyte .
  • the composition becomes turbid or a precipitate forms, which is not desirable in certain forms of administration or for storage, as will be explained hereafter.
  • the compound is administered in a specific form, generally selected from injection, topical application, inhalation, ingestion or spraying.
  • a specific form generally selected from injection, topical application, inhalation, ingestion or spraying.
  • the spraying or inhalation form by way of an aerosol will be most preferable in the case of viral respiratory diseases where the broncho-pulmonary epithelium is primarily affected, since the administration of the active substance through the respiratory tract in the form of micronized particles (the size of the particles is generally comprised between 0.3 and 5 micrometers for an aerosol and 5 to 100 micrometers for a spray) will be most effective. Therefore, in the case of aerosol administration, the stability of the active compound in the composition is of upmost importance, since precipitates from aerosols can interfere with the optimal operation of respirators or spraying apparatus.
  • antiviral agents whose activity is based on an inhibition of the viral DNA polymerase enzyme of the virus have been developed by the pharmaceutical industry, like
  • acyclovir 9- [2-hydroxyethoxymethyl) guanine] .
  • This chemical agent is known for its activity against a limited number of viruses, the herpes simplex virus type 1 and type 2, the varicella zoster virus and the Epstein-Barr virus.
  • Acyclovir is sold in its sodium salt form as a white, crystalline powder.
  • the solubility of acyclovir sodium in water exceeds 100 mg/ml and shows a pH of approximately 11. However, at physiologic pH, acyclovir exists as the non- ionized form and has only a maximum solubility of 2.5 mg/ml .
  • Blough also mentions in the same patent that it is preferred to administer the compounds separately to the patient, i.e. not in the same composition.
  • Pancheva et al . (Acta Microbiologica Bulgaria, 1993, Vol. 29, pp. 61-64) disclosed that a combined treatment with acyclovir and ribavirin is more effective for the treatment of herpes simplex keratoconjunctivitis in rabbits than the treatment with the individual drugs.
  • this reference does not address the problem of combining antiviral agents in a single composition and the problem of the stability upon storage of a composition which would comprise the active agents or the problems related to the way of administration of such a composition.
  • antibiotics are chemical compounds which are active against bacteria, but have generally no activity against viruses. Therefore, viral and bacterial diseases are generally treated separately and with distinctive agents, and the compositions which are intended to be used to treat viral diseases do not contain antibiotics, as well as antibiotic compositions do generally not contain antiviral agents.
  • a composition comprising essentially as active ingredients ribavirin and at least another antiviral agent like acyclovir is effective as treatment or prophylaxis of the Newcastle disease, infectious bursal disease (Gumboro disease) , infectious bronchitis, influenza disease or Marek' s viral disease in poultry.
  • compositions are effective against other animal viral diseases and are therefore broad- spectrum antiviral compositions.
  • compositions comprising the active analogue chemical derivatives of ribavirin or of the at least other antiviral agent are also effective as broad-spectrum antiviral compositions .
  • the inventors of the present invention have also found that when combined with a vaccination treatment the efficacy of the treatment with the compositions in accordance with the present invention is improved and a synergistic effect is observed.
  • the inventors of the present invention have also found that when adding other agents like quinolone-type antibiotics in the compositions, the efficacy of the composition as broad- spectrum antiviral is similar or even improved.
  • the inventors of the present invention have also found that the stability of the composition comprising ribavirin and at least another antiviral agent like acyclovir as essential active ingredients is achieved when a stabilizing agent is added to the composition, the stabilizing agent being preferably benzyl alcohol, N- methylpyrrolidone, glacial acetic acid, 2-pyrrolidone , dimethylacetamate (DMA) or dimethylformamide (DMF) or a combination thereof.
  • a stabilizing agent being preferably benzyl alcohol, N- methylpyrrolidone, glacial acetic acid, 2-pyrrolidone , dimethylacetamate (DMA) or dimethylformamide (DMF) or a combination thereof.
  • the main object of the present invention is to provide new compositions which are effective as antiviral agents, and preferably as broad-spectrum antiviral agents effective as treatment or prophylaxis of viral diseases in animals in general, and specifically in poultry, like the Newcastle, infectious bursal (Gumboro) , infectious bronchitis, influenza or Marek' s viral diseases.
  • Another object of the present invention is to provide these compositions as compositions which are stable upon storage.
  • a further object of the present invention is to provide compositions effective as treatment or prophylaxis of viral diseases in animals which do not interact negatively with other treatments, like for example vaccination, and which can be used in an effective manner without being toxic to the treated animal.
  • One of the advantages of the present invention is therefore that the composition can be stored in a stable manner in the form in which it will be administered.
  • composition is efficient against the viral diseases at doses which are not toxic to the treated animal.
  • therapeutic index of the composition is increased.
  • composition can be used for the treatment or prophylaxis of viral diseases in animal even if a treatment by vaccination or with antibiotics is already applied on the animal. Both treatments can coexist and generally will show an improved efficacy.
  • the present invention provides a solution to the aforementioned problems.
  • the aforementioned object is achieved by a composition having the features defined in claim 1 and comprising as essential active ingredients ribavirin and at least another antiviral agent like acyclovir, and a stabilizing agent, the stabilizing agent being preferably benzyl alcohol, N- methylpyrrolidone, glacial acetic acid, 2-pyrrolidone or a combination thereof.
  • the aforementioned object is also achieved by the use of the compositions for the treatment of viral diseases, and preferably animal viral diseases, and most preferably those affecting poultry.
  • Preferred embodiments of the invention including the use of chemical derivatives of the essential compounds of the composition, i.e. ribavirin and the other antiviral agents, the addition of optional ingredients in the composition like for example quinolone-type antibiotics, preservatives, vitamins or further stabilizing agents, or the use of the composition for the treatment of specific viral diseases in animal are defined in the dependent claims.
  • compositions are defined as weight per volume.
  • Viruses are classified according to the type of nucleic acid they contain, i.e. RNA or DNA. Further subdivision is made into groups based upon physical and biochemical properties.
  • RNA viruses are subdivided into the families paramixoviridae, orthomyxoviridae, coronaviridae, arenaviridae, retroviridae, reoviridae, birnarividae, picornaviridae, toroviridae, caliciviridae, togaviridae, bunyaviridae, filoviridae and rhabdoviridae .
  • the DNA viruses are subdivided into poxviridae, herpesviridae, papovaviridae, adenoviridae, hepadoviridae, parvoviridae and circoviridae .
  • Adenoviruses are responsible of diseases such as the infectious canine hepatitis and infectious canine tracheobronchitis .
  • Herpesviruses are subdivided into alpha-, beta- and gamma- herpesviruses.
  • Alpha-herpesviruses are associated with numerous diseases affecting different animal species such as infectious bovine rhinotracheitis, infectious pustular vulvovaginitis, haemorrhagic disease of pups, feline viral rhinotracheitis, infectious laryngotracheitis (due to avian herpesvirus 1), Marek' s disease (due to avian herpesvirus 2) and duck plague (due to duck herpesvirus 1).
  • Orthomyxoviruses are responsible of influenza diseases such as equine influenza, swine influenza and avian influenza.
  • Paramyxoviruses are associated with the Newcastle disease.
  • Birnaviruses are associated with the infectious chicken bursal disease.
  • the viral diseases which can be treated by the compositions according to the present invention are any viral diseases already known which affect humans or animals, and more specifically those which affect poultry.
  • the diseases caused by the following viruses are aimed at being treated: Newcastle disease virus (NDV) , Marek' s disease virus, infectious bursal disease (IBD; synonym Gumboro disease) virus, infectious bronchitis virus (IBV), avian pneumovirus (APV) , equine herpes virus type 2 (EHV-2), transmissible gastroenteritis (TGE) virus, porcine respiratory coronavirus (PRCV) , bovine parainfluenza-3 virus, lymphocytic choriomeningitis (LCM) virus, bovine viral diarrhoea virus (BVDV) , equine arteritis virus (EAV) , porcine parvovirus (PPV), classical swine fever virus (CSFV; synonym: hog cholera virus, HCV) , border disease virus (B
  • EHV-1 and EHV-4 feline coronavirus
  • FCV feline coronavirus
  • rotaviruses rotaviruses
  • poxviruses like fowl poxvirus, turkey poxvirus, pigeon poxvirus, quail poxvirus, sparrow poxvirus
  • avian influenza A viruses turkey influenza virus, chicken anaemia virus, duck enteritis virus and Aleutian disease virus .
  • compositions according to the present invention comprise as essential active ingredients ribavirin or an active chemical derivative thereof and at least another antiviral agent or an active chemical derivative thereof and at least one stabilizing agent.
  • the amount of ribavirin or its active chemical derivative in the composition is preferably between 2.5 and 20% weight/volume. Most preferably, the composition contains 10% weight/volume of ribavirin.
  • the other antiviral agent or its active chemical derivative is present in the composition in amounts of preferably between 0.1 and 20% weight/volume. Most preferably, the composition contains between 1 and 10% weight/volume of the other antiviral agent or of its active chemical derivative. If more than one antiviral agent or active chemical derivative thereof is added, the above proportions apply individually to each antiviral agent or active chemical derivative thereof added.
  • the antiviral agent can be selected from known antiviral agents, like for example acyclovir ( 9— [2— hydroxyethoxymethyl) guanine] ) , amantadine (tricyclo [3.3.1.1 (3, 7) ] decane-1-amine) , udicil (4-amino-l-
  • the purpose of adding another antiviral agent is to obtain a synergistic and/or additive therapeutic or prophylactic effect.
  • the composition will contain as other antiviral agent 4% weight/volume of acyclovir or a combination of 4% weight/volume of acyclovir and 1% weight/volume of amantadine.
  • the stabilizing agent can be selected from benzyl alcohol, N-methylpyrrolidone, glacial acetic acid or another natural fruit vinegar, 2-pyrrolidone, dimethylacetamate (DMA) or dimethylformamide (DMF) .
  • the amount of stabilizing agent in the composition is preferably between 2.5 and 97.4% weight/volume.
  • the stabilizing agent is benzyl alcohol, N-methylpyrrolidone, glacial acetic acid, 2- pyrrolidone or a combination thereof.
  • the amount of benzyl alcohol in the composition is preferably 4% weight/volume .
  • the amount of N-methylpyrrolidone in the composition is preferably between 5 and 40% weight/volume, but can also reach an amount of up to 70% weight/volume.
  • the amount of glacial acetic acid in the composition is preferably between 2.5 and 90% weight/volume .
  • the composition contains a combination of 4% weight/volume of benzyl alcohol and 70% weight/volume of N- methylpyrrolidone .
  • compositions according to the present invention optionally comprise one or more quinolone-type antibiotics.
  • the antibiotic is selected preferably from enrofloxacin, ciprofloxacin, ofloxacin, flumequine, norfloxacin, nalidixic acid, cinoxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, miloxacin, nadifloxacin, pefloxacin, pipemidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin or trovafloxacin .
  • the amount of antibiotic in the composition is preferably either 5% or
  • enrofloxacin will be used, at a concentration of 5% or 10% weight/volume.
  • the effect obtained by the combination is a higher efficiency in the treatment or prophylaxis of the disease.
  • vaccine i.e. the inactivated virus against which a treatment or prophylaxis is aimed at
  • IBV infectious bronchitis virus
  • NDV Newcastle disease virus
  • compositions may also comprise optionally other agents like vitamins, preservatives, thickeners or any other agent or additive commonly used in veterinary or medical compositions which is for example useful for the stability of the composition or permits to improve the formulation for a specific way of administration without altering the antiviral activity.
  • agents like vitamins, preservatives, thickeners or any other agent or additive commonly used in veterinary or medical compositions which is for example useful for the stability of the composition or permits to improve the formulation for a specific way of administration without altering the antiviral activity.
  • sodium hydroxide or potassium hydroxide may be added in the composition in order to adjust the pH and/or improve the stability of the composition.
  • sodium hydroxide or potassium hydroxide will be added in an amount of 1% weight/volume.
  • composition When necessary, the composition is generally complemented to the required final volume by the addition of deionized water .
  • compositions are administered depends upon the particular virus infection to be treated.
  • the mode of treatment is preferably by spray, for example by aerosol spray, since this mode of administration delivers the agent to the site of infection.
  • injection or oral therapy may be also indicated.
  • Topical application may be used in the case of infections of a topical nature, such as herpesvirus infections.
  • the composition is administered in order that ribavirin is given at a daily dose of about 5 to 10 mg/kg body weight, one time each day and for two days in the case of poultry and between three and ten days in the case of other animals.
  • the amounts of ingredients are given in % of weight/volume The volume is adjusted by addition of deionized water.
  • a composition comprising: Ribavirin 10%
  • a composition comprising:
  • compositions in accordance with, for example, examples 1 or 2 of the present invention were made to evaluate the impact of the compositions in accordance with, for example, examples 1 or 2 of the present invention on the pathogenesis of the disease and the replication of the virus in the case of an infection of chickens with either the Newcastle disease virus or the infectious bronchitis virus.
  • the aim of these studies was to evaluate the protective activity of the compositions according to the present invention against the replication of the Newcastle disease virus or the infectious bronchitis virus in chickens, the effect of the composition on the clinical signs of the disease and the immunostimulating activity of the composition. These effects were evaluated with different routes of administration (spraying and injection) and with or without a combined treatment with a vaccine.
  • compositions in accordance with the present invention have clearly a prophylactic and therapeutic effect on chickens infected by the Newcastle disease virus or the infectious bronchitis virus, and a higher immunostimulating effect on chickens infected by the Newcastle disease virus or the infectious bronchitis virus than the effect which can be obtained by vaccination alone. Furthermore, a synergistic effect is obtained when a combined treatment by vaccination and with a composition according to the invention is used.
  • the method monitors the presence of the active ingredients in the composition in their native active and/or in their degraded inactive form. By varying the conditions of storage of the composition (temperature and time) , the results give a good indication of the stability of the compositions over different temperatures and shorter or longer periods of time.
  • compositions to be assayed are stored in different conditions of temperature (40°C or 60°C) in an incubator. Samples are collected at different times, from 0 days to 52 days, and analysed for their composition by HPLC (high pressure liquid chromatography) . The elution profile of the samples are compared to elution profiles of standard compositions containing the active ingredients either in their native active form or in their degraded inactive form. The results are quantified by measurement of the area of the different peaks of elution in the different samples and comparison of the obtained results.
  • HPLC high pressure liquid chromatography
  • a Shimadzu HPLC chromatograph class-VP equipped with an UV detector, and auto-sampler with computing software class-VP 5.03.
  • Chromatography column stainless steel C-18 silica based Luna column, particle size 5 ⁇ m.
  • Chromatography conditions flow rate 1.2 ml/min, wavelength of measurement 235 nm, temperature 30°C, injection volume 20 ⁇ l, run time 11 minutes, other parameters adjusted to get peak heigh of ca . 80% of scale.
  • Ribavirin standard stock solution 100 mg of ribavirin is dissolved in 50 ml of deionized water; then 1 ml of this solution is diluted again in 50 ml deionized water to get a final concentration of 40 ⁇ g/ml.
  • Acyclovir standard stock solution 40 mg of acyclovir is dissolved in 50 ml of deionized water; then 1 ml of this solution is diluted again in 50 ml deionized water to get a final concentration of 16 ⁇ g/ml.
  • composition to be tested (composition of example 1 in the present case) is stored in an incubator at either 40°C or 60°C.
  • 1 ml of sample is collected from the composition and is diluted in 50 ml of deionized water; then 1 ml of this solution is diluted again in 50 ml deionized water to get a final concentration of ribavirin in the sample of 40 ⁇ g/ml.
  • active ingredient mg/ml (peak area of test sample / peak area of standard sample) x (weight of standard sample in mg / volume of sample in ml) x dilution factor difference between standard sample and test sample
  • active ingredient mg/ml (peak area of test sample / peak area of standard sample) x (weight of standard sample in mg / volume of sample in ml) x dilution factor difference between standard sample and test sample
  • the % of acyclovir is given by active ingredient (mg/ml) /40 mg/ml x 100
  • the % of ribavirin is given by active ingredient (mg/ml) /100 mg/ml x 100.
  • composition according to example 1 of the present invention is stable upon storage at 40°C for up to 52 days with almost no detectable degradation of the active agents acyclovir and ribavirin, and at 60°C for up to 9 days with a degradation of the active agent ribavirin of less than 3% and with no detectable degradation of the active agent acyclovir.
  • compositions according to the present invention can be used to treat animals infected by the aforementioned viral diseases at an industrial level.
  • compositions of examples 1 or 2 can be used to treat the Newcastle disease, the infectious bursal disease (Gumboro disease), Marek' s disease or the infectious bronchitis, in poultry or in turkeys (administration by spray or orally) , with or without a combined treatment by vaccination.
  • Newcastle disease the infectious bursal disease (Gumboro disease)
  • Marek' s disease the infectious bronchitis
  • poultry or in turkeys administration by spray or orally
  • compositions in accordance with the present invention can also be used for the treatment of viral active diarrhea, calf scours, foot-and-mouth disease and foot diarrhea affecting calves (mainly due to rota- and coronaviruses) , as well as similar diseases affecting foals, sheep, goats, dogs, cats or pigs, equine infectious anaemia, equine herpesvirus, equine encephalomyelitis of horses, rift valley fever affecting most domestic animals such as cattle, sheep and goats, the disease caused by the bovine respiratory syncitial virus and affecting calves, bovine leukosis, blue tongue, caprine arthritis and encephalitis, malignant catarrhal fever, cattle plague, bovine pneumonia, infectious bovine rhinotracheitis, infectious vesicular stomatitis, sheep pox, goat pox, bovine herpesvirus type 2, vulvovaginitis and "peste desproductive ruminants", feline respiratory disease and other viral diseases of dogs or cats due

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions destinées au traitement prophylactique et/ou thérapeutique de maladies virales, de préférence chez les volailles, comprenant comme ingrédients actifs essentiels la ribavirine et au moins un autre agent antiviral ou ses dérivés chimiques actifs et un agent stabilisant. Eventuellement, les compositions comprennent également un ou plusieurs antibiotiques du type quinolone, des vitamines et/ou des conservateurs. Les compositions sont stables lors du stockage sous la forme sous laquelle elles sont destinées à être administrées aux volailles, c'est-à-dire par injection, par voie orale ou par pulvérisation. Une thérapie combinée avec un vaccin ou une combinaison avec des antibiotiques est également possible. L'invention concerne également l'utilisation combinée de la ribavirine et d'autres agents antiviraux dans le traitement de maladies virales animales.
EP00983353A 1999-12-20 2000-12-20 Compositions veterinaires stabilisees, contenant plusieurs agents antiviraux Withdrawn EP1239923A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP00983353A EP1239923A2 (fr) 1999-12-20 2000-12-20 Compositions veterinaires stabilisees, contenant plusieurs agents antiviraux

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99125414 1999-12-20
EP99125414 1999-12-20
PCT/EP2000/013017 WO2001045727A2 (fr) 1999-12-20 2000-12-20 Compositions veterinaires
EP00983353A EP1239923A2 (fr) 1999-12-20 2000-12-20 Compositions veterinaires stabilisees, contenant plusieurs agents antiviraux

Publications (1)

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EP1239923A2 true EP1239923A2 (fr) 2002-09-18

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EP00983353A Withdrawn EP1239923A2 (fr) 1999-12-20 2000-12-20 Compositions veterinaires stabilisees, contenant plusieurs agents antiviraux

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EP (1) EP1239923A2 (fr)
AU (1) AU2012101A (fr)
WO (1) WO2001045727A2 (fr)

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EP1782826A1 (fr) 2005-11-08 2007-05-09 GBF Gesellschaft für Biotechnologische Forschung mbH PQS, c-diGMP et leurs conjugués utilisés comme adjuvants et leur emploi dans des compositions pharmaceutiques
US7981930B2 (en) 2007-03-13 2011-07-19 Adamas Pharmaceuticals, Inc. Compositions and kits for treating influenza
CN105021756B (zh) * 2015-07-01 2017-03-01 山东世通检测评价技术服务有限公司 一种禽蛋中金刚烷胺、金刚乙胺、利巴韦林、吗啉胍残留的多联检测方法
CN110740785A (zh) * 2017-05-01 2020-01-31 I·E·基亚尼 抗病毒组合物和方法
CN109431981B (zh) * 2018-11-26 2020-02-14 天津市中升挑战生物科技有限公司 一种恩诺沙星注射液及其制备方法
CN117379491B (zh) * 2023-11-17 2025-08-05 广东温氏大华农生物科技有限公司 一种防控猪蓝耳病的中药口服液及其制备方法

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WO1998017282A1 (fr) * 1996-10-23 1998-04-30 Vertex Pharmaceuticals Incorporated Procedes d'utilisation d'un octosulfate de saccharose pour le traitement ou la prevention d'une infection a virus enveloppe

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AU5885690A (en) * 1989-07-11 1991-01-17 Union Carbide Chemicals And Plastics Company Inc. Emulsions comprising aminopolysaccharides
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JPH11513393A (ja) * 1995-10-12 1999-11-16 ジーエス ディベロップメント エービー 皮膚又は粘膜表面へのもしくは介する活性物質の投与用医薬組成物
CA2206047A1 (fr) * 1997-05-23 1998-11-23 Romeo Rang (Deceased) Compositions immunomodulantes pour le traitement de troubles attribuables aux virus

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WO1998017282A1 (fr) * 1996-10-23 1998-04-30 Vertex Pharmaceuticals Incorporated Procedes d'utilisation d'un octosulfate de saccharose pour le traitement ou la prevention d'une infection a virus enveloppe

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See also references of WO0145727A3 *

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WO2001045727A3 (fr) 2002-06-06
AU2012101A (en) 2001-07-03
WO2001045727A2 (fr) 2001-06-28

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