BRPI0804639A2 - A process for preparing a veterinary suspension formulation for administering a water-insoluble medicament by means of water delivery systems and their veterinary suspension formulation for administering a water-insoluble medicament - Google Patents

Abstract

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 an animal. and to a process for preparing said veterinary formulation. The present invention aims to overcome difficulties in the administration of drugs via drinking water and is an attractive alternative, provided that the treatment efficiency is linked to the following parameters: - maximum availability of the drug; - minimum segregation of active compound in the water system; - precise dosing and homogeneity in water distribution; - stability of the active ingredient in the water system, regardless of the quality of the water used.

Description

"PROCESS FOR PREPARING FORMULATION VETERINARY DISPOSAL FOR ADMINISTRATION WATER INSOLUBLE MEDICATION BY WATER DISTRIBUTION SYSTEMS AND RESPECTIVEVALFORMULATION FOR INSOLUBLE MEDICINE ADMINISTRATION".

The present invention relates to a homogeneously dispersible veterinary suspension formulation in water, containing a therapeutic and prophylactic medication, comprising an active compound, in this case a benzoimidazole anthelmintic, specifically flubenzol, suitable for administration to an animal and a process. of preparing said veterinary formulation.

The invention aims to obtain stable and effective aqueous formulations of flubendazole for distribution in a water distribution system by dispensing into water tanks, automatic dosing equipment or beverage tanks for controlled or non-animal dispensing.

Drinking water administration of drugs is intended as an attractive alternative to solve the administration of benzimidazole compounds to pigs and poultry, whose administration is generally limited orally, as a food cover or by mixing it.

However, this type of administration has the following disadvantages:

medicated feed may not be available when animals become ill - individual variable intake;

- possibility of cross contamination;

- sick animals have difficulty ingesting food, thus not ingesting the appropriate amount of food.

The present invention aims to overcome such difficulties by administering drugs via drinking water, being an attractive alternative, provided that the treatment efficiency is linked to the following parameters:

- maximum availability of the drug;

minimal segregation of the active compound in the water system;

- precise dosing and homogeneity in water distribution;

- stability of the active ingredient in the water system, regardless of the quality of the water used.

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 product, as described in US Patent 3,657,267.

Flubenzol, being water-insoluble, is generally in the form of tablets, granules, pills or chewable or palatable formulated compositions and mixed with feeds and is 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.

However, use in animal husbandry requires that it be administered in such a way as to enable the availability of the active ingredient and to remain stable in storage.

Additional features and advantages of the process according to the present invention will become clear from their comparison with the state of the art.

The oldest State of the art document on the subject, US4719239, owned by BERND W. MULLER, describes multi-component pharmaceutical formulations for various stable and well-available forms of drug application at room temperature, whether parenterally, either via the skin or in way debanos. The technology described in the paper seeks to solve homogenization problems and the availability of the drug by dissolving the active ingredient that is poorly or moderately soluble in liquid medium. Suggestion, 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 availability of the drug.

This document shows the use of humectants or lubricants selected from lignosulfonates or nonionic ethoxylates through the use of p-cyclodextrin derivatives, preferably p-cyclodextrin complexes to increase water solubility. Among the benzimidazole derivatives, flubendazole, in column 3, row 27. To prepare various forms of presentation, such as infusion, injections, drop solutions, or even medical baths, the method consists of dissolving the active ingredient in p-cyclodextrin ether, drying the dissolution at temperatures from 15 to 35 ° C. Stir the mixture with water containing a product of sodium or potassium chloride, glucose, mannitol, xylitol or solutions of phosphate, acetate or citrate buffers.

The state of the art shows the search for more storage stable aqueous solutions, that is, they do not agglomerate and no departmental changes occur, but remain in suspension after 24 hours, as described in patent BR9408023-2 (US5538989 / WO9523590), which shows the combination of therapeutically effective amount of febendazole, a preservative and a water soluble nonionic surfactant of the polyethylene sorbitan monooleate type, called Tweem 80, in any type of water. However, this patent does not prepare suspensions that remain active after prolonged use.

BRPI9506681 teaches the use of suspending emulsions, consisting of an oil-in-water emulsion comprising 0.01-50% by weight of the total preparation, preferably 0.1-10%, of a lipid gallate material as an emulsifier. The lipid gallate material consists of at least 50% digalactosyl diacyl glycerols, the remainder being other polar lipids, capable of therapeutically effective use of veterinary medicines in aqueous medium, among other applications, with excellent stability when stored at low and high temperatures for a long period of time. excellent dispersibility and diffusibility on the water surface and in the water.

Also EP0760648, the corresponding Brazilian document PI9507637, belonging to Janssen Pharmaceutical Company, shows the use of emulsifiers in the formulation, such as polyethylene glycol, hydrogenated vegetable oil, sodium stearyl fumarate or magnesium stearate, in amounts of 0.1 to 1.5% by weight. , along with flavoring.

Another document, EP427582, corresponding to US5169846, also mixes the reactive ingredient with a co-solvent chosen from DMSO, NMP, tetraglycol, or propylene glycol and

Adding to another natural emulsifier, which may be a castor oil or other fatty acid polyethoxylate, controlled stirring or heating so as not to compromise the active ingredient stability in the formulation at temperatures ranging from 25 ° C to 50 ° C. Stresses the importance of agitation.

BRPI 9408023, corresponding to WO9513065, describes stable aqueous suspensions of flubenzol by the use of a surfactant and water, the surfactant being a water-soluble nonionic product selected from complex esters and ether-esters derived from hexahydric alcohols, alkylene oxides and fatty acids. by adding polyethylene chains and sorbitole hydroxyls hexitrol anhydrides derived from sorbitol esterified with fatty acids, lauric, palmitic or stearic acids, called Tween 80.

Document BRPI9507637-9, corresponding to US 5824336, which shows an alternative for improving the taste of granular medicament formulations, without destroying their effectiveness by mixing in pharmaceutically acceptable excipient compositions as fillers, lubricants, wetting agents and large amounts Autolysis and Yeast Hydrolysis Product Yield and Beer • Among the selected lubricants are polyethylene glycol and hydrogenated vegetable oil, among others. As has been shown, antihelmintics, notably benzimidazoles, are difficult to dissolve except in appropriate solvents, which makes them unfeasible for dilution in drinking water uniformly and long enough for correct dosing. Attempts to use special formulations, which have been demonstrated above, are economically unviable and provide segregation of the active ingredient in the dispensing water.

All of these technologies have not been found to provide adequate use in water distribution systems, which require control of the availability of the active ingredient, and to prevent segregation in the water distribution system.

The technology described in the publication WO0117504, is an exception in relation to the described technologies, however, to be applied in the field, it needs de-sophisticated industrial equipment. Such suspension methods, although feasible, are extremely complicated and require sophisticated installation by formulators, as noted below.

This publication WO0117504, which corresponds to document PI0013754-5, belongs to Janssen Pharmacistia, proposes a solution to problems with the stable veterinary formulation in which weakly or water-insoluble ingredient dissolution occurs in non-water miscible, generally vegetable oil, between they are sunflower oil, having a density close to that of water, to decrease the thickness or precipitation of the activating compound during storage, and suspending the mixture in an aqueous liquid, a formulation prepared with the following constituents: citric acid (1% by weight), potassium sorbate (0.1 wt.%), sodium benzoate (0.1 wt.%), EDTA (0.01 wt.%) and NaOH2M solution, the pH being adjusted to 5. aqueous gum arabic phase and xanthan gum, the mixture being added to the oil phase containing the active ingredient in a 10% wt / volume ether. This formulation is administered via drinking water, water dispensing systems.

In order to meet the objectives, this emulsion needs further homogenization under high pressure in three cycles to complete mixing.

However, as can be seen, such a formulation has a complex constitution and requires long and very specific homogenization procedures, such as high pressure homogenizers, to obtain the final suspension.

In order to achieve better homogenization and stability, simplicity and rapidity in obtaining the final suspension, as well as control of the required dosage of the reactive ingredient, guaranteed by the formulation against the above described technologies, the present invention proposes the suspension of flubendazole in miscible liquids, with certain granulometry, which is subsequently It is added to another aqueous solution, with stirring and temperature control, so that the desired suspension occurs without the use of high pressure homogenizers.

The suspensions of the present invention obtained by simple and rapid process are suitable for use in water distribution systems, where maximum availability of the drug, in precise and homogeneous dosage, with active ingredient stability, regardless of the water used, occurs. It is therefore a process for preparing an anthelmintic veterinary formulation, and suitable to provide the desired solubility.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention consists of the steps of:

1 - Prepare a first suspension, by micronization of the active principle, in particles ranging from 1 to 15 microns, consisting of a benzoimidazole class anthelmintic, preferably flubendazole, to obtain a better particle size distribution;

2 - Homogenizing the 8% Flubendazole suspension with a water-soluble emulsifier chosen from alkaneglycols or polyalcanoglycols, preferably propylene glycol, with a temperature ranging from 50 to 55 ° C;

- After complete mixing and homogenization, add a water-soluble nonionic surfactant, which allows the emulsification of oil in water of the polyethylene sorbitan monooleate type, preferably Berafood EH800, in a proportion of 1 to 5% by weight, stirring at a temperature of 50 ° C. at 55 ° C, preferably at 50 ° C;

- In a second reactor, prepare a second aqueous solution by mixing a commercially available emulsifier co-ownership, with interlactose, sucrose, mannitol, starch being chosen, preferably xanthan gum, in the ratio of 0.1 to 0, 3%, and promoting dispersion at a temperature of about 60 ° C, then adding 0.1 to 0.5% by weight of a bactericidal preservative, chosen from hydroxybenzoic acid esters, such as Nipagin, Nipasol; Benzalkonium Chloride or Potassium Sorbate, preferably potassium sorbate, in the ratio (range) 0.1 to 0.5% by weight, stirring being maintained at a constant temperature around 60 ° C until complete homogenization;

The final suspension is prepared by adding the second aqueous solution obtained on first solution, maintaining the temperature ranging from 40 to 60 ° C, preferably at 50 ° C, cooling to 20-25 ° C under stirring.

The active surfactant is preferably a non-ionic, water soluble surfactant consisting of fatty acid esters containing radicals, preferably Barafood 80.

Preferably the present invention is a process of preparing veterinary suspensions formulations by preparing a first solution by micronizing doflubendazole to a smaller size and adding 5 wt.% Depropylene glycol for homogenization at about 50 ° C. ° C and after complete mixing, add the product Berafood EH800 at a rate of 0.5% by weight, under stirring, at a temperature of 50 ° C; in a second reactor, a second aqueous suspension is prepared by mixing an emulsifier, xanthan gum at a rate of 0.3%, and promoting dispersion 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 to a 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 following is an example of the preparation of a Fluvermazole formulation, specialty of the company's Flubendazole (4%), object of the invention, and afterwards its demonstration of uniformity of distribution characteristics.

However, such an example is not limiting to the subject matter of the present invention.

Example 1

Preparation of the formulation "Fluverm Suspension 4%": Firstly the Organic Suspension is prepared.

A: In a vitrified vessel, 240 kg of Propylene Glycol is charged and heated to 55 ° C. Then add 20 kg of Flubendazole with a 100% particle size less than 15 microns and stir for 30 minutes at 55 ° C for complete product distribution.

Then add 2.5 kg of Berafood EH80 (Tween 80) and stir for a further 20 minutes.

Preparation of Aqueous Solution B: 235 kg of demineralized water is charged to another vasovrifiable at 20 ° C, 1.75 kg of an emulsifier, Xanthan Gum is added and stirred for 20 minutes for complete dispersion and warmed. add 60 kg of Potassium Sorbate and leave for 10 minutes while stirring at 60 ° C for complete dissolution.

Formulation of the final suspension: After complete mixing of solution B, it is poured over suspension A and allowed to stir for 10 minutes at temperatures ranging from 55-60 ° C. It is then cooled to 25 ° C, thus preparing the final solution.

The following information will be shown to confirm the homogeneity of the formulations and their distribution in water after a period of storage prepared according to the above examples.

Flubendazole principle water stability evaluation in veterinary formulationFluverm Suspension 4%, in which the method is used, in which the active will be quantified by reading the absorbance in UV / Vis spectrophotometer.

In order to determine the stability of the active ingredient, Flubendazole, of the 4% Fluorescent Suspension formulation, the experiment was designed in which the formulation was diluted in water to be administered to animals. The amount of active ingredient was measured at 3 points, which correspond to the period indicated for the consumption of this drug dissolved in water. The points adopted for the collected sample are:

- 0 minutes

- 60 minutes

- 120 minutes

The dosage was calculated based on the estimated weight of the whole batch to be treated as follows: 4.0 mg Flubendazole per kg body weight for 10 days.

Dilutions were prepared with the volume of water to be consumed by the flock during the first two hours of the day. A total of 141L of 4% Fluverm Suspension was used in the study for two groups of birds. 1500 L of water containing the active ingredient was administered to each of the treated poultry groups.

Calculation of Theoretical Concentration of Flubendazole in Drinking Water administered:

In the drinking water of the two groups of birds to be treated was added 7 liters of the 4% Fluverm Suspension compound and diluted in 1500 L of drinking water.

Amount of Fluubendazole in FluvermSuspension: 4%

1 L of Fluverm Suspension has 40 g of Fluendazole.

7 L of Fluverm Suspension has 280 g of Fluendazole.

- Amount of Flubendazole in drinking water:

280 g Flubendazole in 1500 L of water.

0.19 g Flubendazole per liter of water.

0.19 mg Flubendazole per mL of water.

The concentration of Flubendazole in Drinking Water administered is 0.19 mg / mL.

Therefore, in the 10 days the studies were performed, the concentration of Flubendazole in the water samples was approximately 0.19 mg / mL.- Calculation of Actual Flubendazole Concentration in Drinking Water administered

Having determined which concentration of Flubendazole should be present in the water samples, we proceeded to quantify the analytical in the samples.

Initially, a sample of Standard Flubendazole with a concentration of 0.2 mg / mL was prepared, and the absorbance of this sample was 0.497.

The results obtained for Flendendazole quantification in the water samples are summarized in Tables 1 and 2.

Table 1. Concentration of Flubendazole presents drinking water given to Group A birds during 10 days.

<table> table see original document page 14 </column> </row> <table> Result: Through the analysis of Table 1, it is possible to observe the great variability of the results obtained to determine the amount of Fluverm Suspension in water. Since in certain cases, as indicated on days 7 and 10, the sample collected after two hours has a concentration close to or greater than the initial one, it can be inferred that the variation in the results obtained is due to problems in the collection of the sample. Thus it is not possible to state that the product degrades in the water to be administered.

In order to determine whether or not the product remains stable in drinking water, a new analysis of the samples collected on the tenth day of treatment was performed 24 hours after the first analysis. The results obtained are described in Table 2.

In this study, one should analyze whether the concentration of Flubendazole in water does not vary as a function of time.

Table 2

Analysis of samples collected on the tenth day after 14 hours after the first analysis.

<table> table see original document page 15 </column> </row> <table>

It can be observed that the absorbances and concentrations obtained are practically identical to those obtained in the first analysis. This fact, proven that the product does not degrade in drinking water to which it was added.

This same variation in the analytical results was observed in the samples collected from water administered to Group B birds. The results obtained for determining the amount of Flubendazole in water are summarized in Table 3. It was observed that on day 5 of the study constant concentrations of Flubendazole were obtained in the drinking water administered to the birds. This would indicate that variations in analytical results are again the result of problems with sample collection.

In order to prove this possibility the samples collected on the fifth day of the experiment were subjected to a new analysis and it was observed that there were no appreciable changes in the analytical concentration, as can be seen in table 4.

Table 3

Concentration of Flubendazole present in water given to Group B of birds during the 10-day period.

<table> table see original document page 16 </column> </row> <table> Table 4

Analysis of samples collected on the tenth day of treatment 14 hours after the first analysis.

<table> table see original document page 17 </column> </row> <table>

In order to prove the stability of Flubendazole in drinking water during the administration period (2 hours), a new study has now been proposed on a small scale.

The stability evaluation of the formulation was conducted as follows:

7 mL of 4% Fluverm Suspension in 1.5 liters of drinking water was added. This dilution is the same as that used in the field test. Addition was performed using two lots of different 4% Fluorescent Suspension.

The mixture was manually stirred and Flubendazole concentration was determined. After one hour, the mixture was again analyzed for Flubendazole quantification. At the end of another hour, a new analysis was performed to determine the concentration of the sample.

For the quantification of Flubendazole in this study the same methodology described above was used.

It should be noted that regardless of the concentration values obtained in this study, it is important to check whether the amount of

Flubendazole does not decrease with time.

The results obtained are described in table 5. Table 5

Flubendazole stability evaluation in drinking water.

<table> table see original document page 18 </column> </row> <table>

From the analysis of Table 5 it can be observed that there was no degradation of Flubendazole in drinking water during the recommended period for administration.

Flubendazole concentration in water is practically 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.

Thus, it can be concluded that the active ingredient Flubendazole present in the formulation FluvermSuspension 4% does not degrade in the drinking water in which it was administered.

It is shown that the final suspension formulation obtained in accordance with the present invention, with simplicity and speed, besides allowing the necessary dosage control of the active ingredient, attains the objectives of:

- maximum availability of the drug;

minimal segregation of the active compound in the water system;

- precise dosing and homogeneity in water distribution;

- stability of the active ingredient in the water system, regardless of the quality of the water used.

Claims (5)

1. "PROCESS FOR PREPARING FORMULATION VETERINARY SUSPENSION FOR ADMINISTRATION WATER INSOLUBLE DEMEDICATION THROUGH WATER DISTRIBUTION SYSTEMS characterized by the fact that it consists of the steps of: -1- Preparing a first suspension, through micronization of the active ingredient, in particular 1 to 15 microns, consisting of a benzoimidazole class anthelmintic, preferably flubendazole, to obtain a better particle size distribution; -2 - Homogenization of the suspension from 2 to 8% by weight of Flubendazole, with 1 to 5% by weight of an emulsifier, water soluble, chosen from entrealcanoglycols or polyalcanoglycols preferably propylene glycol, temperature ranging from 50 to 55 ° C; -3 - After complete mixing and homogenization, add a water-soluble non-ionic surfactant, which allows the emulsification of the oil in water, type m polyethylene sorbitan onooleate, preferably Berafood EH800, in a ratio of 1 to 5% by weight, stirring at temperatures ranging from 50 to 55 ° C, preferably at 50 ° C; -4 - In a second reactor, prepare a second aqueous solution, Mixing a commercially available emulsifier co-ownership, with interlactose, sucrose, mannitol, starch being chosen, preferably xanthan gum, in the proportion of 0.1 to 0.5%, and promoting dispersion at a temperature of about 60 ° C. Then add from 0,1 to 0,5% by weight of a bactericidal preservative, chosen from the esters of p-hydroxybenzoic acid, Nipagin or Nipasol, Benzalkonium Chloride or Potassium Sorbate, preferably potassium sorbate, (range) 0.1 to 0.5 wt%, stirring is maintained at a constant temperature around 60 ° C until complete homogenization The final suspension is prepared by adding the second aqueous solution obtained over the first solution and maintaining the temperature at 40 to 60 ° C, preferably at 50 ° C, cooling to 20-25 ° C. under agitation. 2. PROCESS FOR PREPARING FORMULATION VETERINARY SUSPENSION according to claim 1, characterized in that one of the preferred formulations consists of: - 1- The first solution is prepared by dichronization of flubendazole into particles, preferably less than 15 µm in size. microns to allow better particle size distribution - 2- Add 5% by weight of propylene glycol for homogenization at a temperature around 50 ° C - 3- After complete mixing add the product Berafood EH800 at a rate of 0.5% by weight. by weight, under stirring, at a preferred temperature of 50 ° C; 4- in a second reactor, a second aqueous suspension is prepared by mixing an emulsifier, xanthan gum in the ratio 0.1 to 0.3%, and promoting the dispersion at a temperature around 60 ° C; -5. Then 0.1 to 0.05% by weight of a bactericidal preservative, Potassium Sorbate is added. The stirring is maintained at a constant temperature at about 60 ° C until complete homogenization. Finally, the final formulation is obtained by adding the second aqueous solution obtained over the first suspension at a preferential temperature of 50 ° C. and cooling to 20-25 ° C under stirring. VETERINARY SUSPENSION FORMULATION FOR WATER INSOLUBLE MEDICINE ADMINISTRATION, obtained according to any one of claims 1 to 2, characterized in that it consists of: -1-2 to 8% of a classbenzoimidazole anthelmintic, preferably flubendazole; - 1 to 5% by weight of a water-soluble emulsifier, chosen from alkaneglycols or polyalcanoglycols, preferably propylene glycol, -3 to 1 to 5% by weight of a polyethylene sorbitan monooleate nonionic surfactant; 0.5% of a commercially available emulsifier may be selected from lactose, sucrose, mannitol, starch, preferably xanthan gum; 0.1 to 0.5% by weight of a bactericidal preservative chosen among hydroxybenzoic acid esters such as Nipagin, Nipasol; Benzalkonium Chloride or Potassium Sorbate. 4 FORMULATION according to claim 3, characterized in that the preferred formulation consists of 4% flubendazole; 5% by weight propylene glycol; Berafood EH800, in the proportion by 5% by weight; a goat xanthan emulsifier in the ratio of 0.3% and 0.1% by weight potassium desorbate.