WO2017103631A1

WO2017103631A1 - Oral pharmaceutical composition in the form of granules comprising metronidazole or derivatives thereof and a taste-masking agent

Info

Publication number: WO2017103631A1
Application number: PCT/GR2016/000068
Authority: WO
Inventors: Christos Koutsodimos; Georgios Motsios
Original assignee: Verisfield (Uk) Ltd, Greek Branch
Priority date: 2015-12-17
Filing date: 2016-12-16
Publication date: 2017-06-22
Also published as: GR1008992B

Abstract

The present invention relates to an oral pharmaceutical composition in the form of granules, in addition to a method for the production thereof. The granules comprise a core comprising metronidazole or derivatives thereof, and a coating comprising a polymer with taste-masking properties, wherein said polymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1. The granules have a pleasant taste and can be easily swallowed with a liquid such as water. The granules can be used by all categories of patients including children, elderly and adults with swallowing problems, for the treatment of various infections caused by microorganisms susceptible to metronidazole.

Description

Oral pharmaceutical composition in the form of granules comprising metronidazole or derivatives thereof and a taste-masking agent

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition in the form of granules for oral use, comprising metronidazole or derivatives thereof. The composition also comprises a taste-masking agent and is suitable for administration to all categories of patients, including children, elderly and adults with swallowing problems.

BACKGROUND OF THE INVENTION

Metronidazole (a-hydroxyethyl-2-methyl-5-nitroimidazole) is a 5-nitroimidazole, a heterocyclic compound with a nitro group on the fifth position of an imidazole ring. It is derived from the Streptomyces antibiotic azomycin. Developed in 1959, it was used against trichomoniasis in the early 1960s and was the first drug to have a cure rate approaching 100% with systemic treatment. It is the 5-nitro group that, when reduced to a nitro radical within the Trichomonas vaginalis parasite, is responsible for the antiprotozoal activity.

Metronidazole is an antimicrobial agent that has been used in clinical medicine for more than 45 years. It was originally indicated for the management of infection caused by 7. vaginalis, but was later shown to be effective against other protozoal infections, such as amebiasis and giardiasis. The first report on the efficacy of metronidazole in the management of anaerobic infections was published in 1962. In that investigation, acute ulcerative gingivitis was successfully treated by using metronidazole therapy. However, major advances were made about 10 years later in the 1970s, when it was shown that metronidazole is useful in the treatment of systemic anaerobic infections, including those caused by Bacteroides fragilis. Later metronidazole was introduced for the management of Clostridium difficile infections and is still recommended as an alternative to vancomycin for the treatment of such infections. Treatment regimens for the eradication of Helicobacter pylori still include metronidazole in combination with other agents. Metronidazole is also indicated for the treatment of bacterial vaginosis caused by Gardnerella vaginalis. After 45 years of extensive use, metronidazole remains the criterion standard for the management and prophylaxis of anaerobic infections. Metronidazole is highly active against gram-negative anaerobic bacteria, such as B. fragilis, and gram-positive anaerobic bacteria, such as C. difficile. The pharmacokinetic and pharmacodynamic properties of the drug are favourable. After oral administration, metronidazole is well absorbed, and its peak plasma concentrations occur 1-2 h after administration. Metronidazole is the major component in the plasma, but lower amounts of active metabolites are also present. Protein binding is low; less than 20% of the circulating metronidazole is bound to plasma proteins.

The concentrations of metronidazole in cerebrospinal fluid and saliva are similar to those found in plasma.

Metronidazole is effective for the management of anaerobic infections, such as intraabdominal infections, gynecologic infections, septicemia, endocarditis, bone and joint infections, central nervous system infections, respiratory tract infections, skin and skin- structure infections, and oral and dental infections. It is also used prophylactically before abdominal and gynecological surgical procedures to reduce the risk of postoperative anaerobic infection. Metronidazole also produces good clinical results when it is used for the treatment of giardiasis, trichomoniasis, and amoebiasis, and it is recommended for the treatment of patients with bacterial vaginosis or nonspecific vaginitis caused by G. vaginalis.

Metronidazole is available in oral, intravenous, vaginal, and topical formulations. The oral forms available are tablets in various strengths (200mg, 250mg, 400mg and 500mg) and also oral suspension in strengths of 125mg/5ml and 200mg/5ml under the brand name FLAGYL^®. Many generic products are also available but not all the aforementioned strengths are available in all countries.

Metronidazole remains a widely used antibiotic, especially in its oral forms. However, metronidazole and its derivatives are extremely bitter drugs with unpleasant metallic taste. The main disadvantage of the oral suspension is that it has a very unpleasant taste despite the use of sweeteners and flavouring agents. As far as tablets are concerned, even though the patient cannot feel the bitter-metallic taste of the drug after they are coated they still have an unpleasant aftertaste. The unpleasant taste and/or aftertaste of the available oral formulations containing metronidazole or derivatives thereof, remain over 45 years their main drawback. However, metronidazole still remains a first choice antibiotic for the treatment of various bacterial infections and it is challenging to design a specific composition containing metronidazole and/or derivatives thereof that would have a pleasant taste and would be suitable for the treatment of all infections caused by microorganisms susceptible to metronidazole. There is still a need to mask the taste of metronidazole sufficiently to ensure patient compliance during therapy.

From the point of view of patient compliance it is also important to note that many patients, including children and elderly experience difficulty in swallowing tablets, especially if the tablets have an unpleasant aftertaste. It is estimated that 50% of the population experience such difficulty in swallowing, which may potentially lead to the drug not being taken as prescribed by patients which in turn would have a major impact on the efficacy of the proposed treatment.

It is thus even more challenging to design an oral formulation containing metronidazole or derivatives thereof which would have a pleasant taste and also be easily administered to all categories of patients such as children, elderly and patients having swallowing problems, thus leading to better compliance with the prescribed therapy and a consequential enhancement of the drug's efficacy rate. Many techniques have been proposed for the taste masking of products with bitter and/or metallic taste such as metronidazole, in orally administered pharmaceutical forms.

US 2007/0167380 discloses a pharmaceutical composition that contains erythromycin A or a derivative thereof and alginic acid. The composition may also include one or more active ingredients such as metronidazole. The pharmaceutical composition may be formulated as a dry syrup, suspension, conventional, chewable or dispersible tablet. When blended with erythromycin A, the alginic acid is effective in masking the bitter taste of the active ingredient. The preparation steps include mixing of erythromycin A or a derivative thereof with alginic acid and other pharmaceutically acceptable excipients and either granulating the mixture in an aqueous solvent/medium or dispersing the mixture in an aqueous solvent with subsequent layering on inert cores such as nonpareil seeds, microcrystalline cellulose spheres etc. In the latter process, the drug- polymer mixture, together with the other pharmaceutically acceptable excipients is loaded onto the inert core using a fluid bed processor. The granules obtained through either process are dried. The process further includes coating with a coating material. To further reduce the dissolution or release of the active ingredient in the mouth where it can be perceived by the taste buds, the granules may be coated with a polymer such as Eudragit^® E100, S100 and L-100, available from Rohm and Haas Company. pH- sensitive coatings such as Eudragit^®, are particularly advantageous for use with specific active ingredients such as clarithromycin, which is acid labile, or in oral formulations that need to remain intact in the stomach and release the active ingredient in other locations, like the intestine. US 2002/0061333 discloses formulations containing macrolide compounds as active ingredients on their own or in combination with other active ingredients such as metronidazole. The invention relates to dispersible tablets that are capable of complete disintegration in less than 3 minutes when they are placed in a liquid such as water, thus leading to an oral suspension that can be easily made homogeneous by stirring with a teaspoon. Such tablets may, however, be also swallowed directly with a quantity of liquid capable of facilitating their deglutition. The formulations disclosed can be easily administered to children, elderly and patients with swallowing problems. The formulations further comprise other pharmaceutically acceptable excipients such as a disintegrating agent, sweetener, diluents(s), surfactant, lubricant(s), glidants and flavourings. In spite of the absence of sugars and in particular of sucrose, the tablets in accordance with the invention surprisingly have a markedly more pleasant taste than that associated with dispersible powders and granules provided up until the time of filing of US 2002/0061333 for the bitter macrolides, even when they contain high quantities of macrolide.

US 5618559, US 6103262 and WO 95/20383 disclose the preparation of modified- release tablets containing metronidazole that can be used as once daily for the treatment of various infections, including bacterial vaginosis. The disclosed composition of these modified-release tablets is capable of delivering acceptable metronidazole bioavailability for up to 24 hours in a single tablet that is suitable for oral administration. The disclosed formulation comprises metronidazole and a copolymer that is aqueous permeable, aqueous expandable and pH-independent. A suitable copolymer is commercially available under the name Eudragit^® NE30D. This copolymer is "pH-independent", which means that it is insoluble in gastric juices, intestinal juices and water. By the term "aqueous permeable" is meant that an aqueous solution can pass through pores in the structure of the copolymer. By the term "aqueous expandable" it is meant that the copolymer composition is capable of swelling in an aqueous solution. The disclosed formulation further comprises a detackifier, an aqueous soluble pharmaceutical diluent, a second aqueous soluble diluent that can be the same or different from the first one and also a glidant and a lubricant.

Poly(meth)acrylates are well known copolymers under the trade name Eudragit^®. These polymers are derived from esters of acrylic and methacrylic acid, whose physicochemical properties are determined by functional groups (R). Eudragit^® polymers are available in a wide range of different physical forms (aqueous dispersion, organic solution, granules and powders). The various polymers can be flexibly combined, enabling the user to achieve the desired formulation properties in terms of drug release, protection from moisture, taste and odor masking in order to increase patient compliance with therapy.

US 6153220 discloses a taste-masked micromatrix formulation in the form of powder that can be further processed to final dosage forms such as sprinkles, suspensions, effervescent tablets, fast melt or chewable tablets. The composition comprises the use of a copolymer such as Eudragit^® E 100 in a taste-masked micromatrix powder, wherein the weight ratio of the cationic copolymer to the drug is greater than 2:1 , preferably greater than 4:1 and even more preferably greater than 6:1. The formulation may also contain a different type of Eudragit^® polymer based on the desired properties of the final drug in terms of dissolution and drug release.

US 6221402 discloses a pharmaceutical dosage form, which can be orally administered without a bitter taste, with improved drug release properties in the gastrointestinal tract. The formulation comprises an oral dosage form that includes at least three layers. The first layer, i.e. the core, includes the active ingredient and a low substituted hydroxypropyl cellulose and microcrystalline cellulose. The second layer, i.e. the inner coating layer, contains a water soluble polymer and the third layer, i.e. the outer coating layer, contains a saliva-insoluble polymer such as Eudragit^® E. The outer coating layer has a taste-masking effect to prevent the active ingredient from being released when a patient holds a coated drug in his mouth. The active ingredients used are usually of a bitter taste.

WO 01/80829 discloses a coating composition that masks the undesirable taste of an active ingredient that is consumed orally. The coating composition includes (a) polyvinyl acetate, (b) dimethylaminoethyl methacrylate and neutral methacrylic ester (Eudragit^® E100) and optionally (c) an alkaline modifier. The composition that includes the alkaline modifier has both taste-masking and enhanced-reiease properties, since it increases the speed of dissolution of the coating in the acidic environment of the stomach.

US 2004/0241235 discloses granules or coated granules that may be used to prepare dry syrups, tablets, sachets and suspensions. The formulations comprise a core containing at least one active ingredient in combination with at least one waxy compound and possibly at least one polymer and/or at least one binding agent, as well as at least three successive coating layers starting from the core. The three coatings layers described in the document are functional coatings, where the purpose is to provide the active ingredient with the desired release properties, such as delayed release by using polymers such as Eudragit^® L, S, FS301 , sustained release by using polymers such as Eudragit^® NE, RS, RL or immediate release by using polymers such as Eudragit^® E. The composition may further comprise additional coating layers identical to layers 1 and 3 as described above, as well as an outer coating aiming to mask the taste of the constituents of the preceding coating.

WO 2008/015220 discloses the preparation of granules as well as orally disintegrating tablets that contain oxycodone and optionally acetaminophen. The described formulation is characterized in that the two active ingredients are not included in the same granule. The composition comprises oxycodone or a salt thereof, a binding agent and a subcoat comprising a compound that is soluble in gastric fluids. The subcoat is further coated with a taste-masking coating comprising a polymer such as Eudragit^® E100 or Eudragit^® E PO. The final formulation further comprises acetaminophen, at least one disintegrant and at least one soluble diluent.

In view of the prior art discussed above, it is still desirable to have a pharmaceutical composition containing metronidazole or derivatives thereof in a form for oral administration, which may be used by all categories of patients such as children, elderly and patients with swallowing problems and which has a pleasant taste and does not leave an aftertaste following its administration.

BRIEF DESCRIPTION OF THE INVENTION The subject of the present invention is therefore an oral pharmaceutical composition in the form of granules which comprise:

- a core comprising metronidazole or derivatives thereof, and

- a coating comprising a polymer with taste-masking properties,

wherein said polymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1.

The invention also relates to a method of manufacturing said oral granules.

The granules are insoluble in saliva and are easily swallowed with a liquid such as water. The granules in accordance with the present invention have a pleasant taste and can be used by all categories of patients including children, elderly and patients having problems with swallowing solid dosage forms such as tablets or capsules.

The granules are suitable for the treatment of all infections caused by microorganisms susceptible to metronidazole.

A detailed presentation of the invention is provided below. DETAILED DESCRIPTION OF THE INVENTION According to a first aspect of the invention, a pharmaceutical composition is provided in the form of granules for oral use which comprise:

- a core comprising metronidazole or derivatives thereof, and

- a coating comprising a polymer with taste-masking properties,

Preferably metronidazole benzoate is used as the active ingredient. The active ingredient is preferably included in the final granules at a proportion between 39.2% and 39.6% by weight, more preferably between 39.3% and 39.5%, even more preferably at a proportion of 39.4% of the total granules' weight.

Additional excipients which may be used for the granules are chosen from the group consisting of diluents, glidants, binders, anti-tacking agents, solubilizers, emulsifiers and sweeteners.

The oral granules contain in addition at least one flavouring agent, which imparts to the granules a taste favourable to patients.

The aforementioned excipients may be included in the layered structure of the granules as follows: The core of the granules comprises the active ingredient and preferably a diluent, a glidant and a binder. The core is coated with a coating comprising a polymer having taste-masking properties, namely poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1 , and preferably a solubility enhancer, an anti-tacking agent and an emulsifier. There may be a further, outer coating which comprises a sweetener and a flavouring agent.

According to another aspect of the present invention, a process for preparing the aforementioned oral granules is provided, which comprises the following steps:

- Preparing core granules comprising metronidazole or derivatives thereof,

- Coating of the core granules with a coating mixture comprising poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1 as a taste-masking agent.

The process preferably further comprises the application of a second, outer coating mixture with a sweetener and a flavouring agent to the granules.

The granules are preferably prepared and sprayed with the first, inner coating mixture and the second, outer coating mixture in a fluid bed dryer system.

With regard to the core of the granules, a diluent is used to achieve the desired flowability of the granules, while at the same time retaining moisture stability. The diluent may be selected from the group of microcrystalline cellulose, lactose, partially pregelatinised starch (starch 1500), maltodextrine, mannitol, sorbitol and xylitol.

Preferably partially pregelatinised starch (starch 1500) is used, at a proportion between 42.7% and 43.3% by weight, preferably between 42.9% and 43.1%, even more preferably at a proportion of 43% of the total granules' weight.

Furthermore, a glidant is preferably added, which may be selected from the group of calcium phosphate tribasic, colloid silicon dioxide, magnesium oxide, talc, magnesium silicate. Preferably talc is used at a proportion between 1.85% and 1.95% by weight, preferably between 1.88% and .92% by weight, even more preferably at a proportion of 1.90% of the total granules' weight.

A binder may further be used to maintain the balance between the binding and disintegrating properties of the granules. The binder may be selected from the group of povidone, gelatin, hydroxypropylmethyl cellulose, acacia gum, methyl cellulose and carboxymethyl cellulose sodium. Preferably povidone (e.g. Kollidon^® K30) is used due to its properties. Povidone's low viscosity in particular is a critical factor for the manufacturing process, because it makes the adopted technique of spraying in a fluidized bed dryer, easier to perform. Povidone (Kollidon^® K30) is used at a proportion between 2.2% and 2.8% by weight, preferably between 2.4% and 2.6% by weight, even more preferably at a proportion of 2.5% of the total granules' weight.

With regard to the inner coating of the granules, the main coating agent is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1 , which is a cationic polymer with excellent taste-masking properties. This polymer is available under the trade name Eudragit® and belongs in particular to the group of Eudragit® E (CAS Number 24938-16-7), which includes Eudragit® E PO (in powder form), Eudragit® E 00 (in the form of granules) and Eudragit® 12.5 (in the form of a 12.5% organic solution). Its film-forming and insulating properties are ideal in order to achieve a smooth coating of the granules using a fluid bed dryer system. The preferred polymer form, which is used in example 1 of the present invention, is Eudragit® E PO (powder), but the other forms, Eudragit® E100 and Eudragit® 12.5, may also be employed. Eudragit^® E PO is used at a proportion between 6.8% and 7.2% by weight, even more preferably at a proportion of 7.0% of the total granules' weight. Apart from its role as the main coating agent of the coating mixture, Eudragit® E PO also acts as an agent masking the unpleasant metallic taste of the active ingredient, which enhances patient compliance with the treatment with metronidazole granules of the present invention.

Eudragit^® E PO is insoluble in saliva and soluble in gastric fluids up to pH 5.0. The dissolution properties of Eudragit^® E PO, allow the final granules of the present invention to remain insoluble in saliva during administration of the granules, thus preventing the unpleasant metallic taste of the active ingredient to be perceived by the taste buds in the mouth during administration. The patient receiving the oral granules feels the pleasant taste of their flavouring, while the granules actually dissolve in the stomach. This advantageous feature of the present invention enhances patient compliance with metronidazole treatment in the form of granules.

Apart from Eudragit® E PO, the coating mixture for the granules may further comprise a solubility enhancer selected from the group of stearic acid or glycerin monostearate. Stearic acid is preferred and included at a proportion between 0.9% and 1.3% by weight, more preferably at a proportion of 1.1% of the total granules' weight. Stearic acid forms a salt with the copolymer Eudragit^® E PO which increases the workability of the coating mixture in the fluid bed dryer system, thereby facilitating the coating of the granules' core.

The inner coating mixture may further contain an anti-tacking agent selected from the group of calcium phosphate tribasic, colloid silicon dioxide, magnesium oxide, talc, magnesium silicate. Preferably talc is used at a proportion between 3.1% and 3.9% by weight, preferably between 3.3% and 3.7% by weight, even more preferably at a proportion of 3.5% of the total granules' weight.

The inner coating mixture may further comprise an emulsifier selected from the group of sodium lauryl sulphate, poloxamer 407 or poloxamer 188. Preferably sodium lauryl sulphate is used at a proportion between 0.65% and 0.75% by weight, more preferably at a proportion of 0.70% of the total granules' weight.

The coated granules may be further coated with an outer coating containing a sweetener and a flavouring agent.

The sweetener is selected from the group of aspartame, sucralose or saccharin sodium. Preferably sucralose is used at a proportion between 0.2% and 0.4% by weight, more preferably at a proportion of 0.3% of the total granules' weight.

The flavouring(s) may vary depending on the age of the patients (children, adults, elderly) for whom the granules are intended. The flavouring is preferably added at a proportion of 0.6% of the total granules' weight and may be for example strawberry, chocolate, vanilla, caramel, mint or mixtures thereof. The present invention will be more clearly understood by means of the examples that follow, which relate to exemplary embodiments of oral granules in accordance with the present invention and to the method for their manufacture.

EXAMPLE 1

Oral granules containing metronidazole base in the form of the salt metronidazole benzoate are prepared according to the manufacturing process described below and filled in sachets, having the following composition per sachet: TABLE 1

Ingredient Function Quantity Percentage

(mg) (%)

Core

Metronidazole benzoate Active ingredient 640 mg 39,4%

Equivalent to metronidazole 400 mg

Partially pregelatinised starch Diluent 700 mg 43,0%

(starch 1500)

Talc Glidant 30 mg 1 ,9%

Povidone (Kollidon^® 30) Binder 40 mg 2,5%

Inner coating

Eudragit^® E PO Taste masking 114,30 mg 7,0%

agent

Stearic acid Solubility enhancer 17,15 mg 1 , 1 %

Talc Anti-tacking agent 57,15 mg 3,5%

Sodium lauryl sulphate Emulsifier 11 ,45 mg 0,7%

Outer coatinq

Sucralose Sweetening agent 5 mg 0,3%

Strawberry flavor Flavoring agent 10 mg 0,6%

Therefore each sachet contains granules with a total weight of 1625.05 mg.

As far as the manufacturing process is concerned, the active ingredient, metronidazole benzoate, the partially pregelatinised starch (starch 1500) and 25% of the total amount of povidone (Kollidon^® 30) are inserted in a preheated fluid bed dryer system. When the temperature reaches 36°C-40°C, spraying of the binding material begins. Binding material consists of povidone in purified water at a ratio of 1 :13. Spraying parameters of the fluid bed were adjusted so as to achieve a smooth manufacturing process (no tacking of material, unhindered flow of material through the spraying nozzles). These parameters are presented in the following table 2:

TABLE 2

Spraying Parameters

Product temperature 36°C-40°C

Inlet air temperature 80°C

Incoming air speed (inlet airflow) 600-800 m³/h Spraying pressure 1.3 bar

Microclimate 0.5 bar

Flow of incoming material 500 g/min

Drying Parameters

Incoming air speed (inlet airflow) 600-800 m³/h

Incoming air temperature 36°C

Microclimate 0.5 bar

The core granules prepared by the process described above are coated with the inner coating mixture prepared as described below:

In a vessel containing purified water (equivalent to approximately 66% of the total coating mixture weight) the following ingredients are added in the order of mentioning: Eudragit^® E PO, talc, sodium lauryl sulphate and stearic acid. Homogenisation is performed for a total of 1 hour and the coating mixture is then sprayed on the core granules. The coating mixture is added to the fluid bed dryer under constant mild stirring, in order to prevent talc precipitation and foaming caused by sodium lauryl sulphate.

The coating mixture is sprayed on the core granules inside the fluid bed dryer system. Spraying parameters of the fluid bed dryer were adjusted so as to achieve a smooth manufacturing process (no tacking of material, unhindered flow of material through the spraying nozzles). The spraying parameters are defined in the following table 3:

TABLE 3

The coated granules are further coated with an outer coating containing a sweetener and flavouring(s). The coating mixture is prepared by mixing together the ingredients and is afterewards introduced into the fluid bed dryer system to form the final coating. Finally, the finished granules are filled in sachets.

EXAMPLE 2 The formulation described in the present invention comprises metronidazole or derivatives thereof in the form of granules for oral use, preferably metronidazole benzoate. It has a pleasant taste and can be used by all categories of patients for various infections caused by microorganisms susceptible to metronidzole. The dosage of metronidazole required varies depending on the type of infection and the age of the patient. The commonly used dosage scheme is 400mg given once, twice or three times per day. In order to further enhance patient compliance with metronidazole therapy the daily intake is preferably kept as low as possible. The preferred embodiment comprises metronidazole benzoate at a proportion of 39.4% of the total granules' weight. In the example below different strengths of metronidazole are described in order to achieve the required daily dose of metronidazole in a single dose, for most infections, and to minimize the daily doses for infections that require daily doses of more than 800 mg metronidazole, which are rather rare. TABLE 4

Ingredient Percentage Quantity Quantity Quantity Quantity

(%) (mg) (mg) (mg) (mg)

Core

Metronidazole benzoate 39.4% 320 mg 400 mg 800 mg 1280 mg equivalent to metronidazole 200 mg 250 mg 500 mg 800 mg

Partially Pregelatinised 43.0% 350 mg 436.73 mg 873.46 mg 1400 mg

Starch (Starch 1500)

Talc 1.9% 15 mg 19.30 mg 38.60 mg 60 mg

Povidone (Kollidon^® 30) 2.5% 20 mg 25.40 mg 50.80 mg 80 mg

Inner coating

Eudragit^® E PO 7.0% 57.15 mg 71.10 mg 142.20 mg 228.60 mg

Stearic acid 1.1 % 8.58 mg 11.17 mg 22.34 mg 34.30 mg

Talc 3.5% 28.58 mg 35.55 mg 71.10 mg 114.30 mg

Sodium lauryl sulphate 0.7% 5.72 mg 7.10 mg 14.20 mg 22.90 mg

Outer coatinq

Sucralose 0.3% 2.50 mg 3.05 mg 6.10 mg 10 mg

Strawberry flavor 0.6% 5 mg 6.10 mg 12.20 mg 20 mg

The compatibility of the excipients with the active ingredient described in examples 1-2 has been tested. The studies included the preparation of mixtures of the active ingredient, metronidazole benzoate with each of the excipients, in amounts proportionate to those of the proposed formulation of example 1. The mixtures have been placed in closed vials, stored for six months in normal conditions of 25°C, 60% RH and in accelerated conditions of 40°C, 75% RH and analysed by HPLC - for impurities.

The same mixtures of the active ingredient, metronidazole benzoate and each excipient have been also placed in open vials and stored for 30 days in forced conditions of 65°C and of 40°C, 75% RH and analysed by HPLC - for impurities.

The results of the HPLC analysis suggested no potential interaction between the active ingredient and the excipients. The oral granules described in the present invention are suitable for the treatment of all infections caused by microorganisms susceptible to metronidazole. In terms of mode of administration the oral granules of metronidazole, as described in the present invention, should be swallowed with a glass of water at least one hour before a meal. The granules contain a taste-masking agent insoluble in saliva, i.e. Eudragit^® E PO, which allows the patients to keep the pleasant taste of the flavouring in their mouth, while the granules are dissolved in the stomach by the gastric fluids. The dissolution profile of the oral granules prepared according to the formulation of example 1 has been tested in vitro, at a pH value of 1.2 which is within the range of the normal stomach pH values, i.e. between 1 and 2. The values given in table 5 below indicate that the formulation of the present invention is rapidly dissolved in the stomach.

TABLE 5

A bioequivalence study was conducted between the formulation of example 1 , where the granules in each sachet contain a total of 400mg of metronidazole base, and the oral suspension marketed under the trade name Flagyl^® 125mg/5ml containing 125mg of metronidazole base in every 5ml of suspension. The bioequivalence of the two products has been tested in a comparative, randomized single dose, two-way crossover, open label, clinical study performed on 20 healthy volunteers under fasting conditions. The dose given for both products was 400mg, which was either 1 sachet of the formulation of example 1 of the present invention or 16ml of oral suspension Flagyl^®, which is equivalent to 400mg of metronidazole base. According to the results of the clinical study the two products were proven to be non-bioequivalent, since the prescribed 90% confidence intervals for C_max and AUC₀._t were not within the range of 80.00%-125.00%. The oral granules of example 1 surprisingly resulted in a higher bioavailability of 20% and 30% compared to Flagyl^® oral suspension. Data are given in table 6 below:

TABLE 6

The pharmacokinetic parameters of both products tested are given in table 7 below:

TABLE 7

According to the results of table 7 above, the parameter C_max, which is defined as the maximum measured plasma concentration over the time span specified in the clinical trial protocol, is much higher for the formulation of the present invention compared to Flagyl^® oral suspension. The parameter AUC₀.t, which is defined as the area under the plasma concentration versus time curve, from time (0) to the last measurable concentration (t) is also grater for the formulation of the present invention compared to Flagyl^® oral suspension. These two parameters, which are the primary pharmacokinetic parameters, measured in the bioequivalence study performed; indicate the superiority of the formulation of the present invention in terms of bioavailability. The bioequivalence of the formulation of example 1 with the tablets marketed under the trade name Flagyl^® at the same strength of 400 mg/tab has also been tested. The bioequivalence study was conducted on 20 healthy volunteers under fasting conditions in a comparative randomized, single dose, two-way crossover, open label, clinical study. Bioequivalence was demonstrated for the two formulations within the prescribed 90% confidence interval of 80.00%-125.00% for C_max and AUC₀._t with respect to the parametric method on log-transformed data of metronidazole. Data are given in the table 8 below:

TABLE 8

The conclusion which can be drawn from the aforementioned bioequivalence studies is that the formulation of the present invention has advantageous pharmacokinetic properties compared to Flagyl^® oral suspension, while being bioequivalent with Flagyl^® tablets. This means that the oral granules of the present invention provide a novel formulation with a pleasant taste which can be easily administered to all categories of patients, including children, elderly, adults with swallowing problems and generally all patients who are unable to take metronidazole tablets, while at the same time showing superior pharmacokinetic properties in comparison with the oral suspension such patients might have to resort to until now. The higher bioavailability of the oral granules of the present invention reflects the improved absorption of metronidazole and means that said granules provide an alternative to the oral suspension which results in higher drug efficacy and a quicker therapeutic result.

The favourable pharmacokinetic properties of the formulation of the present invention compared to Flagyl^® oral suspension in combination with the pleasant taste of the oral granules of the present invention compared to marketed oral suspensions, result a new formulation that can substitute the use of oral suspensions for the treatment of infections caused by microorganisms susceptible to metronidazole due to the fact that the formulation of the present invention has a pleasant taste, it can be easily used by all categories of patients including children, elderly and adults with swallowing problems and at the same time having a higher bioavailability resulting in a better absorption and a quicker therapeutic result by using the oral granules of the present invention.

Claims

1. A pharmaceutical composition in the form of granules for oral use which comprise:

- a core comprising metronidazole or derivatives thereof, and

- a coating comprising a polymer with taste-masking properties,

wherein said polymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1.

2. A pharmaceutical composition according to claim 1 , wherein said granules comprise a second, outer coating which contains a sweetener and a flavouring agent.

3. A pharmaceutical composition according to claims 1 or 2, wherein said core comprises metronidazole benzoate. 4. A pharmaceutical composition according to claim 3, wherein metronidazole benzoate is comprised in the granules at an amount ranging between 39.2% and 39.6% of the total granules' weight, more preferably between 39.3% and 39.5%, and even more preferably at a proportion of 39.

4% of the total granules' weight.

5. A pharmaceutical composition according to any preceding claim, wherein said poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1 :2:1 is comprised in the granules at an amount ranging between 6.8% and 7.2% of the total granules' weight, more preferably at a proportion of 7.0% of the total granules' weight.

6. A pharmaceutical composition according to any preceding claim, wherein said core further comprises a diluent, a glidant and a binder.

7. A pharmaceutical composition according to any preceding claim, wherein said coating comprising poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co- methyl methacrylate) 1 :2:1 as a taste-masking agent further comprises a solubility enhancer, an anti-tacking agent and an emulsifier.

8. A process for preparing the pharmaceutical composition of claim 1 comprising the following steps: - Preparing core granules comprising metronidazole or derivatives thereof,

- Coating of the core granules with a coating mixture comprising poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1 as a taste-masking agent.

9. A process according to claim 8, wherein said poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1 is added to said coating mixture in powder form.

10. A process according to claims 8 or 9, wherein a second, outer coating mixture is applied to the coated granules, said outer coating mixture comprising a sweetener and a flavouring agent.

11. A process according to any preceding claim, wherein all the preparation steps are performed in a fluid bed dryer system.