The object of the invention is a furazidine liquid dosage form and the method for the preparation thereof. The invention is applicable in medicine.

Solid dosage forms containing furazidine in the form of a tablet containing lactose, potato starch, sucrose, stearic acid and polysorbate (Teva, US Pharmacia) , or potato starch, sucrose, colloidal silicon dioxide, stearic acid (Adamed) , or lactose monohydrate, silicified microcrystalline cellulose with the following composition: 98% of microcrystalline cellulose and 2% colloidal anhydrous silica, magnesium stearate, colloidal anhydrous silica, sodium carboxymethyl starch type A (Adamed) as auxiliary substances are known. None of the above tablets are suitable for precise dose measurement, especially of paediatric doses. Some of the above are not suitable for lactose-intolerant individuals. Russian patent RU2221575 relates to the administration of antibiotics and furazidine in tablets together with mineral water to small children. This method requires the administration of difficult-to-split solid tablets to small children. Therefore, there is still a need to provide the furazidine liquid dosage form which is also suitable for precise dosing in young patients, with an active substance having high stability, without the necessity to use buffer substances, and which is easy to ingest without any unpleasant taste sensations when swallowing, as well as suitable for lactose-intolerant individuals, and the preparation thereof. Surprisingly, the present invention meets the above mentioned needs.

The first object of the invention is the furazidine liquid dosage form characterised in that it contains furazidine in the amount from 0.10 g/100 g to 5.04 g/100 g, a sweetening agent selected from a group of disaccharides , a suspension stabilising agent, preservatives, suspension stabilising and viscosity controlling agents, a suspension stabilising and surface-active agent, a bitter taste masking agent and purified water as a solvent. Preferably, the sweetening agent according to the invention is sucrose. Still preferably, the suspension stabilising agent is selected from a group comprising polyhydric alcohols or mixtures thereof, preferably, these are glycerol, propylene glycol, sorbitol. More preferably, preservatives according to the invention are substances selected from a group of parahydroxybenzoic acid esters and mixtures thereof, preferably, methyl parahydroxybenzoate, most preferably these are methyl parahydroxybenzoate, propyl parahydroxybenzoate, or acids and salts thereof, most conveniently sorbic acid and potassium sorbate, or benzoic acid and sodium benzoate. In another preferred embodiment of the invention, suspension stabilising and viscosity controlling agents are selected from a group of natural polysaccharides, comprising xanthan gums, and/or from a group of cellulose derivatives, preferably these are hydroxypropyl celluloses, hypromellose . Still it is preferable that the suspension stabilising and surface-active agent according to the invention is selected from a group comprising ethers of higher fatty alcohols with polyoxyethylated glycols, including macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably these are polysorbates . In further equally convenient embodiment of the invention, the bitter taste masking agent is a natural orange flavour. Most preferably, the form according to the invention contains furazidine, sucrose, glycerol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, macrogolglycerol ricinoleate, hydroxypropylcellulose, xanthan gum, natural orange flavour, and purified water.

The second object of the invention is a method for the preparation of furazidine fluid dosage form characterised in that it includes: a) preparing a solution containing suspension stabilising and viscosity controlling agents are selected from a group of natural polysaccharides and/or from a group of cellulose derivatives ;

b) preparing a solution containing the sweetening agent and preservatives selected from a group of parahydroxybenzoic acid esters and mixtures thereof, or acids and salts thereof, dissolved in heated purified water, preferably subsequently cooling the prepared solution; c) preparing a solution by mixing a wetting agent from a group of polyhydric alcohols or mixtures thereof, suspension stabilising and surface-active agents, bitter taste masking agents, preferably a natural orange flavour, and furazidine with purified water, and, subsequently, preparing a suspension by combining the solution from step a) , the filtered solution from step b) and the solution from step c) , wherein more preferably the suspension is formed by mixing the solution from step a) and a solution of mixed substances from steps b) and c) , most preferably the suspension is formed by mixing the substances from steps a) , b) , and c) . Preferably, the method according to the invention is characterised by that the suspension stabilising and viscosity controlling agent is xanthan gum, hydroxypropyl celluloses or hypromellose . In another preferred embodiment of the invention, the sweetening agent is sucrose, and the preservative are parahydroxybenzoic acid esters, preferably methyl parahydroxybenzoate and propyl parahydroxybenzoate, most preferably sorbic acid and potassium sorbate, benzoic acid and salts thereof. Most preferably, the method according to the invention is characterised by that the wetting agent is selected from a group of polyhydric alcohols, glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, preferably macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, preferably polysorbates .

Owing to the present invention, it is possible to obtain furazidine liquid dosage form which is characterised by high stability, is suitable for precise dose measurement, causes no unpleasant taste sensations, and can be ingested by lactose- intolerant individuals, and during the preparation thereof there is no need to use buffer substances which unfavourably affect the stability of the active substance.

Example 1. The method for preparing the suspension according to the invention The product being the object of the invention, the preferred embodiment of which is presented in Table 1, was prepared according to the following production technology which involves :

- preparing the solution I containing the suspension stabilising and viscosity controlling agents: from a group of natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g. hydroxypropyl celluloses, hypromellose;

- preparing the solution II containing: sucrose and preservatives selected from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, dissolved in heated purified water, and cooling the solution;

- preparing the solution III by mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, e.g. polysorbates, natural orange flavour and furazidine with purified water;

- preparing the suspension by combining the solution I, filtered solution II, and solution III; or preparing the solution · I containing the suspension stabilising and viscosity control 1ing agents: from a group of natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g. hydroxypropyl celluloses, hypromellose; preparing the solution II containing: sucrose and preservatives: from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, dissolved in heated purified water, mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, e.g. polysorbates, natural orange flavour and furazidine; preparing the suspension by combining the solution I, filtered solution II; or dissolving sucrose and preservatives: from a group of parahydroxybenzoic acid esters and mixtures thereof, e.g. methyl parahydroxybenzoate and propyl parahydroxybenzoate, or acids and salts thereof, e.g. sorbic acid and potassium sorbate, benzoic acid and sodium benzoate, in heated purified water, mixing the wetting agent from a group of polyhydric alcohols or mixtures thereof, e.g. glycerol, propylene glycol, sorbitol, suspension stabilising and surface-active agents from a group of ethers of higher fatty alcohols with polyoxyethylated glycols, e.g. macrogolglycerol ricinoleate, or from a group of polyoxyethylene sorbitan and higher fatty acids esters, or from a group of sorbitan and higher fatty acids esters, e.g. polysorbates, natural orange flavour and furazidine and solubilising ( suspension stabilising and viscosity controlling agents: from a group of natural polysaccharides, e.g. xanthan gums, and/or from a group of cellulose derivatives, e.g. hydroxypropyl celluloses, hypromellose) .

Requirements concerning the size of furazidine were as follows: 10÷150 μπι

Table 1 - Composition of the product being the object of the invention

Or Starting material Amount [g]

Solution I

Xanthan gum 0.34

Hypromellose 0.20

Purified water q.s.

Solution II

Sucrose 40.0

Potassium sorbate 0.20

Sorbitol 5.0

Polysorbate 80 0.10

Furazidine 0.84

Natural orange flavour 0.55

Purified water Ad 100 or

Starting material Amount [g]

Xanthan gum 0.34

Hydroxypropyl cellulose 0.20

Sucrose 40.0

Sodium benzoate 0.20

Propylene glycol 5.0

Macrogolglycerol ricinoleate 0.10

Furazidine 0.84

Natural orange flavour 0.55

Purified water Ad 100

A stable furazidine liquid dosage form was obtained (Example 2) which is suitable for precise dosing also in young patients, easy to ingest without any unpleasant taste sensations when swallowing (Example 3), suitable for lactose- intolerant individuals, the unique composition of all components of which (active substance and auxiliary substances) provides optimal pH for the stability of the active substance: furazidine, without using any pH control agents/pH buffer systems (Example 4) . Example 2. Physical stability of the liquid dosage form depending on the auxiliary substances used in stability tests

The disclosed composition of the invention provides the best stability for the liquid dosage form in stability tests due to optimal dispersion of the active substance, adequate size reduction of active substance particles, and proper viscosity of the dispersing phase, thereby lowering the tendency of the active substance to settle.

Mixtures of the active substance and auxiliary substances were prepared with compositions presented in Table 2.

Table 2 - Selection of auxiliary substances

Surprisingly, it has been found that only the use of as many as four auxiliary substances: hydroxypropyl cellulose, xanthan gum, macrogolglycerol ricinoleate, glycerol, in properly experimentally determined concentrations, resulted in the proper stability of the obtained suspension (Sample 5) . Also, only in this case the satisfactory viscosity of the drug liquid dosage form as well as the suitable redispersion time for the active substance were obtained.

Example 3. Providing an acceptable taste of the liquid dosage form containing furazidine

The disclosed composition according to the invention provides an acceptable taste of the liquid form of the drug. Considering the fact that said drug will be intended mainly for children and the elderly, the main idea behind this part of experimental testing was to introduce as few artificial taste improving agents as possible. In the earlier steps of the formulation development, the sucrose was used which mainly functions as a density regulator as well as taste regulator, and because of that the masking of the active substance bitter taste it gives is insufficient to enable the use of the formulation (Sample 5) as a final drug form. Tests with the variant use of different flavours were conducted. Exemplary formulations from this testing step are shown in Table No. 3.

Table 3 - Bitter taste masking, technological trials

No. Amount [g]

Starting material

Sample 6 Sample 7 Sample 8

1. Furazidine 0.84 0.84 0.84

2. Sucrose 40.0 40.0 40.0

3. Glycerol 5.0 5.0 5.0

4. Macrogolglycerol ricinoleate

0.10 0.10 0.10

5. Xanthan gum

0.34 0.34 0.34

6. Hydroxypropyl cellulose

0.20 0.20 0.20 raspberry 0.55 - -

7. Flavour: strawberry - 0.55 - orange - - 0.55

8. Purified water

ad. 100 ad. 100 ad 100

Surprisingly, it has been found that the use of natural orange flavour only in combination with sucrose already present in the formulation masked the bitter taste of the active substances without the necessity to use additional sweeteners and other taste improving agents. It is worth highlighting that other flavours were unsuccessful; moreover, the addition of natural orange flavour to the formulation had no negative effect on the stability of the suspension which was the object of earlier series of experiments.

Example 4. Providing proper environment for the stability of the active substance in liquid dosage form

Prior art formulations with furazidine available on the market contain no liquid auxiliary substances. As it is known, aqueous environment has an undesirable effect on the stability of therapeutic substances and it is necessary to provide suitable conditions, mainly pH, for the chemical stability of the active substance. The developmental work in this step was started with the determination in what pH range furazidine in aqueous environment is chemically stable. To achieve that, furazidine was combined with aqueous solutions of different pH and contaminations resulting from the active substance degradation were tested (Table 4).

Table No. 4 - Stability of furazidine in aqueous environment depending on pH

It has been found that furazidine in combination with water shows the best stability in a pH range of 1-2 which is too low for the final drug form. Based on the data presented above, the liquid drug form, for which the main solvent is water, has the final pH in a range of 1-2 which renders the oral application of such a dosage form impossible due to the risk of irreversible lesions in upper alimentary organs during the application. Nevertheless, it was decided to verify whether it is possible to determine a composition of auxiliary substances such that the furazidine stability is ensured at a different, more neutral pH, which would allowed the use of such a drug form in therapeutic practice.

In order to confirm the above observations, the product was made with different pH and contaminations resulting from the active substance degradation were tested in the final product. In Table 5, the results for the obtained product are presented : Table 5. The effect of product pH on the active substance stability

Based on the conducted experiments, no increase in the contamination level was observed at the tested pH range (2.0 - 6.5) of the product.

Subsequently, the furazidine stability in the product was verified with pH control agents/buffer systems typically used in such types of a drug form. To achieve that a series of technological samples was prepared, some of which are shown in Table 6

Table 6 - Furazidine stability in a liquid drug form depending on the pH control agent/buffer system used

Starting material Sample 9 Sample 10

Furazidine 0.84 0.84

Sucrose 40.0 40.0

Glycerol 5.0 5.0 0.18 0.18

Methyl parahydroxybenzoate

Propyl 0.02 0.02 parahydroxybenzoate

Macrogolglycerol ricinoleate 0.10 0.10

Hydroxypropyl cellulose 0.34 0.34

Xanthan gum 0.20 0.20

Citric acid 0.5 -

Sodium citrate 1.73 -

Sodium hydrogen phosphate - 4.37

Sodium dihydrogen phosphate - 0.5

Natural orange flavour 0.55 0.55

Purified water ad 100 ad 100

5.08 5.12 start

pH

5.04 5.05

60°C 5 days

0.007 0.005 start

ACRO

0.09 <LOD

60°C 5 days

0.238 0.046 start

Cont. 1

0.141 0.330

60°C 5 days

<LOQ <LOQ start

Cont. 2

0.037 <LOQ

60°C 5 days

<LOQ <LOQ start

Cont. 3

<LOQ 0.136

60°C 5 days

start <LOQ <LOQ

Cont. 4

<LOQ 0.112

60°C 5 days

start 0.245 0.051

TOTAL

0.273 0.577

60°C 5 days Prepared formulations were tested in terms of the formation of contaminations resulting from the active substance degradation. Tests were performed immediately after the sample preparation and after the storage of samples in stress conditions (60°C, 5 days).

The test results show that the introduction of pH control agents/buffer systems to the composition of liquid drug form containing furazidine generates the increase in contaminations. Surprisingly, it has been found that in samples developed for the purpose of testing for the effectiveness of preservatives, in which no pH control agent/buffer system was used yet (it was not used, because simultaneously there were works on the selection of optimal pH regulators), Table 7, the contamination level during stress tests was in most cases below the detection level (LOQ) , indicating the furazidine was stable at pH between 4 - 6.5 despite the lack of pH stabilising substances.

Table 7 - Selection of a preservative

Starting material Sample 22

Furazidine 0.84

Sucrose 40.0

Glycerol 5.0

Methyl 0.18 parahydroxybenzoate

Propyl 0.02 parahydroxybenzoate

Macrogolglycerol ricinoleate 0.10

Hydroxypropyl cellulose 0.34

Xanthan gum 0.20

Natural orange flavour 0.55

Purified water ad 100

6.25 start

PH

5.40

60°C 5 days

<LOD start

ACRO

0.067

60°C 5 days

start <LOQ

Cont. 1

60°C 5 days <LOQ

<LOQ start

Cont. 2

0.135

60°C 5 days

<LOQ start

Cont. 3

<LOQ

60°C 5 days

<LOQ start

Cont. 4

<LOQ

60°C 5 days

<LOQ start

TOTAL

0.202

60°C 5 days Also, during the stability tests performed on the final drug form it has been found that, despite the lack of pH control agents/buffer systems, the active substance shows chemical stability and product pH does not go beyond set limits of deviations for the final drug form of 4 - 6.5. The results of stability tests on the liquid drug form are shown in Table 8.

Table 8 - Stability tests on the oral liquid drug form of the composition disclosed in the invention

Surprisingly, it has been found that in this case experimentally determined final formulation of auxiliary substances used has ensured the stability of the active substance despite the lack of pH control agents/buffer systems and, what is equally surprising, the chemical stability of furazidine has been obtained in a different more neutral pH range, enabling the formation of said liquid dosage form in contrast to conclusions drawn based on the pre-formulation tests in which the furazidine stability in combination with water at different pH was verified.

Example 4a. Determining the amount of active substance in a liquid drug form containing furazidine

According to the description of preparing the liquid dosage form containing furazidine disclosed in the essence of description, formulations were prepared with varying content of active substance, while other components were used in the amounts described in the essence of the invention. Limit amounts of active substance which give satisfactory results in terms of active substance stability are shown in Table 9.

Table 9 - Limit amounts of furazidine in the presented liquid dosage form

No. Amount [g]

Starting material

Sample 31 Sample 32 Sample 33

1. Furazidine 0.10 0.84 5.04

2. Sucrose 40.0 40.0 40.0

3. Glycerol 5.0 5.0 5.0

4. Macrogolglycerol ricinoleate

0.10 0.10 0.10

5. Xanthan gum 0.34 0.34 0.34

6. Hydroxypropyl cellulose

0.20 0.20 0.20

7. Natural orange flavour

0.55 0.55 0.55

8. Methyl

0.18 0.18 0.18 parahydroxybenzoate

9. Propyl

0.02 0.02 0.02 parahydroxybenzoate

10. Purified water

ad. 100 ad. 100 ad. 100

Form Light yellow Yellow Very yellow suspension suspension suspension

Time after which the furazidine

deposit occurred during After 30 minutes, no formation of deposit was observed centrifugation (3500 rpm) which would not redispersed The acceptance criterion for this part of experimental tests was to maintain the physical and chemical stability of the active substance as well as additionally the resistance to centrifugation which would result in the formation of a dense deposit of the active substance which did not redispersed.