WO2010045700A1 - Procédé de préparation d'une formulation de suspension vétérinaire pour l'administration d'un médicament insoluble dans l'eau - Google Patents

Procédé de préparation d'une formulation de suspension vétérinaire pour l'administration d'un médicament insoluble dans l'eau Download PDF

Info

Publication number
WO2010045700A1
WO2010045700A1 PCT/BR2009/000351 BR2009000351W WO2010045700A1 WO 2010045700 A1 WO2010045700 A1 WO 2010045700A1 BR 2009000351 W BR2009000351 W BR 2009000351W WO 2010045700 A1 WO2010045700 A1 WO 2010045700A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
water
suspension
flubendazole
temperature
Prior art date
Application number
PCT/BR2009/000351
Other languages
English (en)
Portuguese (pt)
Inventor
Karina Sayuri Ohnishi
Original Assignee
Formil Veterinária Ltda.
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 Formil Veterinária Ltda. filed Critical Formil Veterinária Ltda.
Publication of WO2010045700A1 publication Critical patent/WO2010045700A1/fr

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • WATER The present invention relates to a homogeneously dispersible veterinary suspension formulation containing a therapeutic and prophylactic medication comprising an active compound, in this case a benzoimidazole class anthelmintic, specifically flubenzol, suitable for administration to a animal and a process for preparing said veterinary formulation.
  • an active compound in this case a benzoimidazole class anthelmintic, specifically flubenzol, suitable for administration to a animal and a process for preparing said veterinary formulation.
  • the invention aims to obtain stable and effective aqueous formulations of flubendazole for dispensing in a water distribution system by dispensing into water tanks, automatic dosing equipment or controlled or uncontrolled dispensing drinking water tanks.
  • Drinking water administration of drugs is intended as an attractive alternative to solve the administration of benzimidazole-like compounds to pigs and poultry, whose administration is generally limited orally, in the form of a food cover or by mixing. at the same.
  • - medicated feed may not be available when animals become ill
  • the present invention aims to overcome such difficulties by administering drugs via drinking water and is an attractive alternative, provided that the treatment efficiency is linked to the following parameters:
  • Flubenzol or flubendazole is the generic name for methyl [5- (4-fluorobenzoyl) -1H-benzimidazol-2-yl) carbamate, known for its anthelmintic action, as a veterinary pharmaceutical as described in US Pat. 3-3 657 267.
  • Flubenzol being water-insoluble, is generally in the form of palatable or chewable tablets, granules, formulated pills or formulations and mixed with feeds and also used in aqueous but unstable suspensions for oral administration.
  • Flubenzol besides being insoluble in water, has an unpleasant taste, which required the development of various forms of administration.
  • use in animal husbandry requires that it be administered in a manner that allows for greater availability of the active ingredient and remains stable for storage.
  • US-A-4,719,239, to BERND W. MULLER discloses stable, well-bioavailable multicomponent pharmaceutical formulations for various forms of drug application at room temperature. environment, either parenterally, dermally or in the form of baths.
  • the technology described in the document seeks to solve drug homogenization and bioavailability problems by dissolving the active ingredient that is poorly or moderately soluble in liquid medium. They then suggest the use of polar additives. If the drug has basic or acidic radicals, there is a possibility of dissolution. It shows that the selection of additives becomes important so as not to interfere with the bioavailability of the drug.
  • humectants or lubricants selected from nonionic lignosulfonates or ethoxylates through the use of ⁇ -cyclodextrin derivatives, preferably ⁇ -cyclodextrin complexes to increase water solubility.
  • flubendazole is mentioned in column 3, row 27.
  • the method consists of dissolving the active ingredient in ⁇ -cyclodextrin ether, dissolution drying at temperatures from 15 to 35 ° C. Stir the mixture with water containing a product between sodium or potassium chloride, glucose, mannitol, xylitol or phosphate, acetate or citrate buffer solutions.
  • Brazilian patent PI9506681 teaches the use of suspoemulsions, consisting of an oil-in-water emulsion comprising. 0.01-50% by weight of the total preparation, preferably 0.1-10%, of a lipid galacto material as emulsifier.
  • the lipid galacto material consists of at least 50% digalactosyl diacyl glycerols, the remainder being other polar lipids, capable of therapeutically effective use of veterinary medicinal products in aqueous media, among other applications, with excellent stability when stored at low and high temperatures for a long period of time, exhibiting excellent dispersibility and diffusibility on the water surface and in the water.
  • EP-A-760 648 whose Brazilian correspondent is PI9507637, owned by Janssen Pharmaceuticals, shows the use of emulsifiers in formulation, such as polyethylene glycol, hydrogenated vegetable oil, sodium stearyl fumarate or magnesium stearate, in amounts of 0.1 to 1.5% by weight, with flavoring.
  • the active ingredient is also mixed with a co-solvent chosen from DMSO, NMP, tetraglycol, or propylene glycol and added to another natural emulsifier, which may be a castor or other polyethoxylated fatty acid, controlled stirring or heating so as not to compromise the stability of the active ingredient in the formulation at temperatures ranging from 25 ° C to 50 ° C. Stresses the importance of agitation.
  • a co-solvent chosen from DMSO, NMP, tetraglycol, or propylene glycol
  • another natural emulsifier which may be a castor or other polyethoxylated fatty acid
  • anthelmintics notably benzimidazoles
  • benzimidazoles are difficult to dissolve except in appropriate solvents, which makes them unfeasible for dilution in drinking water evenly and long enough for correct dosing.
  • Attempts using special formulations, which have been demonstrated above, are economically unviable and provide segregation of the active ingredient in the dispensing water.
  • Said WO 01/17504 which corresponds to the Brazilian document PI0013754-5, belongs to Janssen Pharmacistica, proposes a solution to such problems, with the stable veterinary formulation, in which the weakly soluble or water-insoluble active ingredient is dissolved in liquid. not miscible in water, usually vegetable oil, including sunflower oil, and having a density close to that of water to decrease the creaminess or precipitation of the active compound during storage, and suspending the mixture in an aqueous liquid, a formulation prepared with the following constituents: citric acid (1 wt%), potassium sorbate (0.1 wt%), sodium benzoate (0.1 wt%), EDTA (0.01 wt%) and 2 M NaOH solution, the pH being adjusted to 5. Then, the gum arabic and xanthan gum are added to the aqueous phase, the mixture being added to the oil phase containing the active ingredient, at a content of 10% by weight / volume. This formulation is administered via drinking water in water distribution systems.
  • this suspoemulsion needs further high pressure homogenization in three cycles for complete mixing.
  • the present invention proposes the suspension of flubendazole in miscible liquids. , with certain particle size, which is then added to another aqueous solution, with agitation and temperature control, so that the desired suspension occurs without the use of high pressure homogenizers.
  • suspensions of the present invention obtained by simple and rapid processes, are suitable for use in water distribution systems, where maximum availability of the drug occurs, in precise and homogeneous dosage, with stability of the active ingredient, regardless of the quality of the product. water used.
  • the invention thus consists of a process for preparing a veterinary anthelmintic formulation, and suitable to provide the desired solubility.
  • the present invention consists of the steps of:
  • a second aqueous solution by mixing a commercially available emulsifier property which may be chosen from lactose, sucrose, mannitol, starch, preferably using xanthan gum in the proportion of 0.1 to 0.3%, and promoting dispersion at temperatures around 60 ° C;
  • a commercially available emulsifier property which may be chosen from lactose, sucrose, mannitol, starch, preferably using xanthan gum in the proportion of 0.1 to 0.3%, and promoting dispersion at temperatures around 60 ° C;
  • a bactericidal preservative chosen from hydroxybenzoic acid esters such as Nipagin, Nipasol, benzalkonium chloride or potassium sorbate, preferably potassium sorbate, in the proportion of ( 0.1 to 0.5% by weight, stirring at constant temperature at about 60 ° C until complete homogenization;
  • the final suspension is prepared by adding the second aqueous solution obtained over the first solution, maintaining the temperature ranging from 40 to 60 ° C, preferably at 50 ° C, cooling to 20-25 ° C. under agitation.
  • the surfactant is preferably a water-soluble nonionic surfactant consisting of fatty acid esters containing ethoxylated radicals, preferably Barafood 80.
  • the present invention consists in a process of "preparation of veterinary formulations suspensions in preparing a first solution by micronization of particulate flubendazole with less than 15 ⁇ m, with 5% by weight of propylene glycol added for homogenization at a temperature of around 50 ° C and after complete mixing, add Berafood EH800 0.5% by weight under stirring at a preferred temperature of 50 ° C; in a second reactor, a second aqueous suspension is prepared by mixing a 0.3% xanthan gum emulsifier and dispersing at a temperature of about 60 ° C; thereafter 0.1% by weight of potassium sorbate, a bactericidal preservative, is added and stirring is maintained at a constant temperature around 60 ° C until complete homogenization; finally the final formulation is obtained by adding the second aqueous solution obtained over the first suspension at the preferred temperature of 50 ° C and cooling to 20-25 ° C under stirring.
  • the present invention innovates the others of the state of the art in the preparation of the formulation that does not require special homogenization equipment and can be performed in glass reactors with stirring paddles.
  • the organic suspension A is prepared in a vitrified vessel, 240 kg of propylene glycol is charged and heated to 55 ° C. Then add 20 kg of flubendazole with a particle size profile 100% smaller than 15 ⁇ , stirring for 30 minutes at 55 ° C for complete product distribution.
  • Preparation of aqueous solution B In another vitrified vessel, 235 kg of demineralized water is charged at 20 ° C, 1.75 kg of an emulsifier, xanthan gum is added and stirred for 20 minutes for complete dispersion. and heat to 60 ° C.
  • the dosage was calculated based on the estimated weight of the entire batch to be treated as follows:
  • Dilutions were prepared with the volume of water to be consumed by the stock during the first two hours of the day. A total of 141 liters of 4% Fluverm Suspension was used in the study to treat two groups of birds. 1500 L of water containing the active ingredient was administered to each of the treated Bird groups.
  • Fluverm Suspension 1 L of Fluverm Suspension has 40 g of flubendazole. 7 L Fluverm Suspension has 280 g of flubendazole.
  • the Flubendazole Concentration in the Drinking Water administered is 0.19 mg / mL.
  • the mixture was stirred manually and the concentration of flubendazole was determined. After one hour, the mixture was again analyzed for quantitation of flubendazole. . At the end of another hour, a new analysis was performed to determine the sample concentration.
  • the concentration of flubendazole in water is almost identical after two hours of dissolution in water.
  • the small difference shown in the last result can be attributed to small variations in sampling or even sample preparation.

Abstract

La présente invention concerne une formulation de suspension vétérinaire pouvant être dispersée de manière homogène dans l'eau, contenant un médicament thérapeutique et prophylactique, comprenant un composé actif, notamment un anthelminthique de type benzoimidazol, et plus particulièrement du flubendazol, et pouvant être administrée à un animal, ainsi qu'un procédé de préparation de ladite formulation vétérinaire. La présente invention vise à résoudre les problèmes liés à l'administration de médicaments par l'eau de boisson, et constitue une alternative intéressante, dès lors que l'efficacité du traitement est liée aux paramètres suivants: disponibilité maximale du médicament; séparation minimale du composé actif dans le système d'abreuvement; dosage précis et homogène dans la distribution d'eau; stabilité de l'ingrédient actif dans le système d'abreuvement, indépendamment de la qualité de l'eau utilisée.
PCT/BR2009/000351 2008-10-23 2009-10-23 Procédé de préparation d'une formulation de suspension vétérinaire pour l'administration d'un médicament insoluble dans l'eau WO2010045700A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI0804639-5 2008-10-23
BRPI0804639-5A BRPI0804639A2 (pt) 2008-10-23 2008-10-23 processo para preparação de formulação de suspensão veterinária para administração de medicamento insolúvel em água, por meio de sistemas de distribuição de água e respectiva formulação de suspensão veterinária para administração de medicamento insolúvel em água

Publications (1)

Publication Number Publication Date
WO2010045700A1 true WO2010045700A1 (fr) 2010-04-29

Family

ID=42118863

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2009/000351 WO2010045700A1 (fr) 2008-10-23 2009-10-23 Procédé de préparation d'une formulation de suspension vétérinaire pour l'administration d'un médicament insoluble dans l'eau

Country Status (2)

Country Link
BR (1) BRPI0804639A2 (fr)
WO (1) WO2010045700A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012004308A1 (fr) 2010-07-06 2012-01-12 Krka, D.D., Novo Mesto Formulations aqueuses stables comprenant des ingrédients actifs faiblement solubles dans l'eau
US8777134B2 (en) 2006-06-14 2014-07-15 Intervet International B.V. Suspension comprising benzimidazole carbamate and a polysorbate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0045655A2 (fr) * 1980-08-04 1982-02-10 Merck & Co. Inc. Solubilisation de l'ivermectine dans l'eau
WO2005074914A1 (fr) * 2004-02-03 2005-08-18 Wyeth Composition anthelminthique
WO2007144362A1 (fr) * 2006-06-14 2007-12-21 Intervet International B.V. Suspension contenant du carbamate de benzimidazole et un polysorbate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0045655A2 (fr) * 1980-08-04 1982-02-10 Merck & Co. Inc. Solubilisation de l'ivermectine dans l'eau
WO2005074914A1 (fr) * 2004-02-03 2005-08-18 Wyeth Composition anthelminthique
WO2007144362A1 (fr) * 2006-06-14 2007-12-21 Intervet International B.V. Suspension contenant du carbamate de benzimidazole et un polysorbate

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8777134B2 (en) 2006-06-14 2014-07-15 Intervet International B.V. Suspension comprising benzimidazole carbamate and a polysorbate
WO2012004308A1 (fr) 2010-07-06 2012-01-12 Krka, D.D., Novo Mesto Formulations aqueuses stables comprenant des ingrédients actifs faiblement solubles dans l'eau
EP2409683A1 (fr) 2010-07-06 2012-01-25 KRKA, D.D., Novo Mesto Formulations aqueuses stables comprenant des ingrédients actifs faiblement solubles dans l'eau
US9017702B2 (en) 2010-07-06 2015-04-28 Krka, D.D., Novo Mesto Stable aqueous formulations comprising poorly water soluble active ingredients

Also Published As

Publication number Publication date
BRPI0804639A2 (pt) 2010-07-20

Similar Documents

Publication Publication Date Title
JP6448001B2 (ja) 液体配合剤
KR101593579B1 (ko) 치료용 조성물
US20120135069A1 (en) Nanonized testosteron formulations for improved bioavailability
DE102005026755A1 (de) Herstellung von festen Lösungen schwerlöslicher Wirkstoffe durch Kurzzeitüberhitzung und schnelle Trocknung
KR20130043174A (ko) 타크로리무스를 함유하는 수중유형 크림상 조성물
US20200206139A1 (en) Compositions for the improved delivery of drugs
EP1214052B1 (fr) Produit veterinaire utilise pour l'administration d'un medicament insoluble dans l'eau a un animal cible, au moyen d'un systeme de distribution d'eau
CN101106976A (zh) 用于输送活性成分的新型药物体系，其制备方法和用途
Elema et al. Bioavailability of flumequine after oral administration to Atlantic salmon (Salmo salar L.)
CN102657610A (zh) 3,5-二羟基-4-异丙基二苯乙烯微乳剂及其制备方法
WO2010045700A1 (fr) Procédé de préparation d'une formulation de suspension vétérinaire pour l'administration d'un médicament insoluble dans l'eau
CN105939713A (zh) 格拉匹纶组合物及其使用方法
CN100502850C (zh) 辣椒总碱类化合物与β-环糊精或β-环糊精衍生物的药用组合物
RU2627429C2 (ru) Составы с контролируемым высвобождением и способы их использования
TW200808373A (en) Liquid drug formulation
US20220331238A1 (en) Oil-in-water emulsion of mometasone
CN107405503A (zh) 鞣花酸二水合物在药物制剂中调节血糖水平的用途
CN108210452B (zh) 一种兽用喹赛多纳米混悬液及其制备方法
DE60120630T2 (de) Pharmazeutische Zusammensetzung enthaltend Xanthangummi
WO2021070066A1 (fr) Composition topique améliorée de colchicine
CN115518039B (zh) 一种兽用托芬那酸固体脂质纳米混悬液及其制备方法
US20190021992A1 (en) New improved composition comprising at least one cadotril
JPS6383022A (ja) 獣医用治療剤
BRPI0712734A2 (pt) composição farmacéutica, uso da composição, e, métodos para preparar uma composição farmacêutica, e para proteger um animal de uma infeção parasìtica
CN115518039A (zh) 一种兽用托芬那酸固体脂质纳米混悬液及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09821453

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09821453

Country of ref document: EP

Kind code of ref document: A1