Patent Description:
Urinary tract infections (UTI) are the most common condition requiring medical consultation and care in outpatients. UTIs account for approx. <NUM>-<NUM>% of all community-acquired infections and for approx. <NUM>-<NUM>% of nosocomial infections. <NUM>% of all UTIs occur in women. According to epidemiological studies, bacteriuria occurs at least once in a lifetime of approx. <NUM>% of female population and in <NUM>-<NUM>% of male population, with asymptomatic UTIs in women probably occurring twice as frequently.

An uncomplicated urinary tract infection (uUTI) is a clinical syndrome characterized by pyuria and a documented microbial pathogen on urine culture, accompanied by local signs and symptoms such as urinary frequency, urinary urgency, dysuria, and suprapubic pain. Uncomplicated UTIs (uUTI), often also referred to as acute cystitis, occur in females with normal anatomy of the urinary tract and are not accompanied by systemic signs or symptoms, such as fever higher than <NUM> degrees Celsius or costovertebral angle pain. Urinary tract infections in males are characterized as complicated UTI (cUTI) because these infections occur in association with urologic abnormalities such as instrumentation or bladder outlet obstruction (e.g., benign prostatic hypertrophy).

A UTI is classified as uncomplicated if there are no relevant functional or anatomical anomalies in the urinary tract, no relevant renal functional impairment and no relevant concomitant disease that would promote the UTI, or the risk of developing serious complications. Examples of uncomplicated UTI include:.

UTIs are a significant clinical problem due to their serious sequelae, such as septic conditions, urolithiasis, renal failure, hypertension or occurrence of these complications during pregnancy. Community-acquired infections most often occur as a result of ascending invasion of native bacterial flora coming from the gastrointestinal tract. In typical cases, the first stage of infection is colonisation of the urinary meatus (in males; in females, the vestibule of the vagina), followed by urinary bladder invasion through the urethra. In women, because of the close proximity of the vagina, rectum and urinary meatus, shortness of the urethra as well as mechanical introduction of microorganisms into the urethra during sexual intercourse, the risk of infections is higher than in men.

Recurrent UTIs are defined as infections characterised by at least <NUM> episodes within one year or <NUM> episodes within <NUM> months. Infection recurrence is understood as a repeated UTI episode caused by the same micro-organism, i.e. by its endospores, within <NUM> weeks of the end of treatment. Such recurrences are often asymptomatic. Reinfections are repeated infections occurring after the urinary tract has been sterilised using antibacterial agents, but caused by a different bacterial strain, occurring up to <NUM> days after sterilisation of urine. In the population of young, healthy and sexually active women, <NUM>% experience at least one UTI episode a year, and the risk of recurrent UTIs is approx. <NUM>- <NUM>/person/year.

Despite of the severe course and the recurrent nature of UTI, its treatment is still initiated empirically (without bacteriological assessment of urine). This means that, in a considerable proportion of patients treated with quinolines or trimethoprim/sulfamethoxazole (being a standard), this treatment might be unsuccessful due to increased antibiotic resistance to these products that has been witnessed in the recent years. In view of the epidemic of UTIs and the increasing drug resistance of bacterial strains, a need arises for an efficacious drug characterised by favourable safety, efficacy and patient acceptance profile.

Despite the growing microbial resistance, furazidin is efficient in the treatment of different forms of UTI. It is also safe, exhibiting less side effects, comparing to other antimicrobial agents and may be administered to children as well. The efficacy results from the high sensitivity of micro-organisms to furazidin. Moreover, the low resistance of uropathogens to furazidin is virtually unchanging in time, contrary to what is observed in the case of other antibiotics or chemotherapeutic agents. Escherichia coli, the most frequent pathogen causing acute UTIs (<NUM>-<NUM>% of cases), is susceptible to furazidin at a constant level of approx. <NUM>%, which has not changed for several decades, with simultaneous increase observed in drug resistance to quinolines or trimethoprim/sulfamethoxazole and fosfomycin. The unchanging and high susceptibility of microbial strains to furazidin makes it a very suitable candidate for the first-choice oral drug in empiric therapy of UTIs.

However, upon oral administration, furazidin has a very short half-life (below <NUM> hour). Blood drug concentrations of furazidin decrease very quickly after administration, reaching levels lower than the minimum concentration for exhibiting therapeutic effects. This creates a necessity of frequent administration of furazidin, which is according to the prior art administered in the form of immediate release (IR) tablets, containing <NUM> or <NUM> of furazidin. Due to the unfavourable pharmacokinetics, furazidin must be administered <NUM> to <NUM> times daily (each time <NUM> or <NUM> x <NUM> of furazidin) in order to maintain an effective concentration of furazidin in the plasma. Patient's compliance is however difficult because patients are reluctant to take furazidin in constant intervals <NUM> or <NUM> times a day (up to <NUM> tablets), in particular, as furazidin should be taken with a meal. Thus, eating times need to be adjusted to the dosage regimen. Even under the assumption of patients' complete adherence to the dosing schedule, it is very difficult to maintain therapeutic concentrations plasma and urine throughout the day.

Another problem associated with the conventional furazidin treatment is the "first pass effect". Upon oral administration, furazidin is quickly absorbed in the gastrointestinal tract, reaching high blood concentrations. During this time, intensive liver metabolism occurs, causing exacerbation of adverse effects.

Furthermore, <CIT> is concerned with a pharmaceutical oral composition comprising furazidin in the form of powder, granules or minitablets, which comprises furazidin and at least one bulking agent chosen from the group consisting of starch, gelatinized starch, microcrystalline cellulose, lactose, glucose, mannitol, sorbitol, anhydrous colloidal silica, talc, dextrins or/and their mixture. The composition may be directly administered to a patient, it may be used for preparation of an oral suspension or a filling of a capsule.

<NPL>) report on a nitrofurantoin bilayer tablet, which comprises an immediate release layer and a sustained-release layer. The sustained-release layer contains Carbopol71G as the control releasing agent.

It is an object of the present invention to provide a pharmaceutical composition of furazidin that reduces or overcomes at least some of the above-mentioned problems.

The object is solved by the prolonged-release pharmaceutical composition and the pharmaceutical composition for use according to the appended claims.

In particular, the present invention relates to the following aspects:.

The prolonged-release pharmaceutical composition according to the present invention provides patients with an effective, safe and convenient therapy of UTI. Due to the prolonged release, the administration frequency of a single dosage form of the pharmaceutical composition can be reduced to two times a day (BID), for example, for <NUM> to <NUM> days such as <NUM> days. The pharmaceutical composition can be conveniently taken <NUM> to <NUM> hours, preferably <NUM> hours, apart and in combination with a meal, that is, shortly before, together with or shortly after a meal (in particular, breakfast and dinner). Here "shortly" means within <NUM> minutes. The meals can be consumed at regular times (for example, <NUM> a. and <NUM> p. ), without significantly adjusting the eating times to the dosage regimen.

Patients using such a therapy would find it easier to take the drug regularly as scheduled, leading to an increase of the compliance. Furthermore, the prolonged release form of furazidin of the present invention provides more appropriate pharmacokinetic characteristics and, thus, improved efficacy compared to the immediate release tablets. The prolonged release form ensures maintaining a therapeutic level of the active substance over the time and, thus, enables twice a day (BID) administration. This is beneficial from both the clinical and the patient's perspective, since there is no need for continuous control of administration of subsequent drug doses. Constant therapeutic blood and urine concentrations of the furazidin are maintained during the treatment and, by consequence, increased treatment effectiveness, which may lead to decreased recurrence or complication rate, is observed. Additionally, the prolonged release dosage form prevents a rapid release of large quantities of furazidin and, thus, helps to minimise adverse effects such as the "first pass effect".

By deteriorating circumstances of UTI patients, the pharmaceutical composition of the present invention also increases the patients' quality of life. The present invention provides a prolonged-release pharmaceutical composition of furazidin, which provides better efficacy and safety profile than conventional immediate release furazidin tablets.

The efficacy and pharmacokinetics (PK) of the pharmaceutical composition according to the present invention have been confirmed in Phase I, pivotal, randomized, open-label, three-period, cross-over, food effect study under fasting and fed (high protein meal and high calorie/high fat meal) conditions and Phase I, pivotal, randomized, open-label, two-period, multiple dose, cross-over bioavailability study under fed conditions.

According to an aspect of the present invention, a prolonged-release pharmaceutical composition for oral administration is provided, the prolonged-release pharmaceutical composition comprising: a) an immediate release component, comprising furazidin and one or more pharmaceutically acceptable excipients; and b) a modified-release component, comprising furazidin, a controlled-release agent, and one or more pharmaceutically acceptable excipients.

An immediate release (IR) component releases furazidin with no special rate controlling features, whereas the modified-release (MR) component releases furazidin with a delay after its administration due to the controlled-release agent. The understanding of the terms correspond to common pharmaceutical handbook definitions. The immediate release component shows a release of the active substance, which is not deliberately modified by a special formulation and/or manufacturing method. The immediate-release (IR) component ensures that furazidin is available to the body without relevant impact of the dosage form. According to the present invention, the IR component achieves in vitro dissolution of at least <NUM> wt. % of the furazidin within <NUM> minutes, based on the total furazidin content of the IR component. The modified-release component releases the active ingredient at a controlled rate, in particular, a constant rate. Preferably, the release rate is independent from the pH, the ionic content, and other contents within the entire segment of the gastrointestinal tract, in particular the stomach and the small intestine. According to the present invention, the modified-release component has an in vitro dissolution rate of <NUM> to <NUM> wt. % of furazidin within <NUM>, based on the total furazidin content of the MR component. The <NUM>-h time point of the dissolution profile has been chosen as representative for the correlation and referent for the prediction of the required full dissolution profile (up to release of the total amount of the API). The aforementioned in vitro dissolution rates are determined by using European Pharmacopoeia edition <NUM> Apparatus Baskets "<NUM>" in <NUM> volume of phosphate buffer solution of pH=<NUM> with the addition of <NUM>% CTAB (hexadecyltrimethylammonium bromide) at <NUM>±<NUM> and <NUM> rpm.

The combination of IR component and MR component according to the present invention provides a prolonged-release pharmaceutical composition. The prolonged-release dosage form shows a sustained release of furazidin compared to that of prior art immediate release dosage forms administered by the same route. The prolonged-release pharmaceutical composition achieves in vitro dissolution rates of furazidin of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> %, within <NUM>, <NUM> to <NUM> wt. % within <NUM> and above <NUM> wt. % within <NUM>, based on the total furazidin content of a single dosage form of the pharmaceutical composition. The in vitro dissolution rates are determined by using European Pharmacopoeia edition <NUM> Apparatus Baskets "<NUM>" in <NUM> volume of phosphate buffer solution of pH=<NUM> with the addition of <NUM>% CTAB (hexadecyltrimethylammonium bromide) at <NUM>±<NUM> and <NUM> rpm.

The inventors have found that a prolonged, in particular more constant, release of furazidin can be achieved by the combination of IR component and MR component, as the immediate release is combined with a modified, controlled release. In other words, a component having a high release rate is combined with a component having a prolonged release rate as reflected by the in vitro dissolution rates of furazidin of the IR and MR components. More precisely, the prolonged-release pharmaceutical composition according to the invention may be understood as a biphasic release dosage form, in which the first phase of drug release is determined by a fast release dose fraction (immediate release component) providing a therapeutic drug level shortly after administration. The second extended release phase provides the dose fraction required to maintain an effective therapeutic level for a prolonged period. The pharmacokinetics of the pharmaceutical composition of the present invention thus differ fundamentally from the pharmacokinetics of prior art furazidin compositions for the treatment of UTI.

The inventors have surprisingly found that, due to the combination of IR component and MR component, having different furazidin release properties, the dosage frequency can be reduced to <NUM> times daily (BID), whereas prior art furazidin dosage forms require regular administration <NUM> or <NUM> times a day. Moreover, the pharmaceutical composition can be conveniently administered in combination with a meal (that is, shortly before, together with or shortly after the meal), for example breakfast and dinner, without significantly adjusting the times when the meal is taken or which food is consumed. Furazidin compositions of the prior art require adjusting the eating times to the dosage regimen (e.g. <NUM> hours apart) and the intake of protein-rich food to improve the furazidin availability. Thus, the pharmaceutical composition of the present invention enhances the patients' compliance as the pharmaceutical composition needs to be administered less often and the therapy is more convenient.

Since furazidin is released in a controlled, in particular, constant manner, therapeutic plasma and urine concentrations of furazidin can be achieved more easily, which improves the therapeutic effect. In particular, the furazidin concentration can be maintained above the MIC values. Since only a part of the furazidin is released immediately from the pharmaceutical composition and then small doses are released from the modified-release component, the release of large furazidin quantities is avoided. The release of small quantities of furazidin minimizes adverse effects, such as the "first pass effect".

In conclusion, the pharmaceutical composition of the present invention enables an effective, safe and convenient therapy of UTI. Compliance and efficacy are improved, and side-effects are reduced in comparison to furazidin compositions of the prior art.

In the pharmaceutical composition, furazidin may be contained as the free base or as a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts are the sodium or the potassium salts of furazidin. Since the salts have a higher solubility, it is preferred that the MR component contains furazidin as the free base. More preferably, the pharmaceutical composition contains furazidin as the free base and no salts of furazidin.

The pharmaceutical composition is a single dosage form in the form of a bilayer tablet. In the tablet, the immediate release component a) forms a first layer, the modified-release component b) forms a second layer, and the first layer at least partially covers the surface of the second layer. The tablet is a bilayer tablet, which means that the first layer is arranged on one side (i.e. one of the two faces) of the second layer and, typically, covers this side completely. Such a tablet can be produced economically.

The tablet may be uncoated or coated. The coating may, for example, be a film-coating. The tablet may have any suitable coating, e.g. functional coating. Such coatings can be found in the "<NPL>. Preferably, the tablet is uncoated.

In the pharmaceutical composition, the IR component a) and the MR component b) may be compressed together, for example, by using a bilayer-tableting machine. The IR component and the MR component may also be granulated and then be compressed to a tablet, for example, by using a bilayer-tableting machine. Preferably, the immediate release component a) is contained as granulates, and the modified-release component b) is contained as granulates, in the pharmaceutical composition. The granulates may be obtained by common dry or wet granulation techniques, preferably by wet granulation. In addition to granulates, the immediate release component a) and/or the modified-release component b) may also contain an extragranular fraction, for example, comprising one or more of a lubricant, a filler, an absorbent and a glidant. The components of an extragranular fraction are added after formation of the granulates.

According to an embodiment, the pharmaceutical composition comprises, in total, <NUM> to <NUM> of furazidin, preferably <NUM> to <NUM> of furazidin, and more preferably <NUM> of furazidin. Thus, a single dosage form has a higher furazidin content than a furazidin composition according to the prior art (<NUM> or <NUM>). In the pharmaceutical composition, the immediate release component a) may contain <NUM> to <NUM> of furazidin, and the modified-release component b) may contain <NUM> to <NUM> of furazidin. Preferably, the immediate release component a) contains <NUM> to <NUM> of furazidin, and the modified-release component b) contains <NUM> to <NUM> of furazidin. More preferably, the immediate release component a) contains <NUM> of furazidin, and the modified-release component b) comprises <NUM> of furazidin. The pharmaceutical composition according to this embodiment is particularly suitable for a dosage regimen, where a single dosage form is administered two times daily, preferably, <NUM> to <NUM> hours, more preferably <NUM> hours apart. It allows for particularly constant, therapeutic plasma and blood concentrations of furazidin, which improves the efficacy of the treatment of UCI and reduces adverse side-effects.

In the aforementioned embodiment, the immediate release component a) has, in particular, a furazidin content of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. %, such as <NUM> wt. %, based on the total weight of the immediate release component a). Furthermore, the modified release component b) has, in particular, a furazidin content of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. %, such as <NUM> wt. %, based on the total weight of the modified-release component b).

In the pharmaceutical composition, the modified-release component b) contains a controlled-release agent in order to modify and sustain the release of furazidin from the MR component. Due to the controlled-release agent, the MR component has the above in vitro release values. The immediate release component a) has no modified or prolonged release of furazidin as noted above. In the pharmaceutical composition, the controlled-release agent may be used in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. %, based on the total mass of the composition. The modified-release component b) may comprise <NUM> to <NUM> wt. % of the controlled-release agent, preferably <NUM> to <NUM> wt. % and more preferably <NUM> to <NUM> wt. % of the controlled-release agent, based on the total weight of the modified-release component b).

The controlled-release agent is contained in a matrix of the modified-release component b). The matrix of the modified-release component b) may be formed by the controlled-release agent or the controlled-release agent and a binder. The controlled-release agent is at least one pH-independent polymer. Hence, the matrix of the MR component is preferably formed by the pH-independent polymer or the pH-independent polymer and a binder. In the MR component, furazidin is preferably dispersed or suspended in the matrix, such that the release is modified and prolonged.

The term "pH-independent polymer" means that the polymer matrix exhibits pH-independent drug permeability and pH-independent swelling and, thus, enables modified release of the active ingredient by pH-independent swelling and erosion. Thus, the release of furazidin from such a polymer matrix is independent from the pH environment and the modified release according to the above in vitro dissolution values is fulfilled irrespective of the pH. "pH-independent" means independent from the pH value in the gastrointestinal tract, which is usually between <NUM> and <NUM> (stomach and small intestine). More preferably, a thickness ratio of the thickness of the matrix of the pH-independent polymer in a swollen state to the thickness of the dry matrix of the pH-independent polymer before swelling is in the range of <NUM> to <NUM>, preferably <NUM> to <NUM>, wherein the swollen state is obtained by immersing the dry modified-release component b) in <NUM> to <NUM> of phosphate buffer of pH=<NUM> contained in beaker for <NUM>, the beaker being placed in a wiggled, heated bath at <NUM>.

The pH-independent polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose, xanthan gum, sodium carboxymethylcellulose, non-ionic poly(ethylene oxide), and any combination thereof. More preferably, the pH-independent polymer has a weight average molecular weight (Mw) of <NUM>,<NUM> to <NUM>,<NUM>,<NUM>, preferably <NUM>,<NUM> to <NUM>,<NUM>. Preferred examples of hydroxypropylmethylcellulose (HPMC) have a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>,<NUM>, preferably <NUM>,<NUM> to <NUM>,<NUM>, more preferably <NUM>,<NUM> to <NUM>,<NUM>. Preferred examples of carboxymethylcellulose (CMC) have a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, preferably <NUM>,<NUM> to <NUM>,<NUM>, more preferably <NUM>,<NUM> to <NUM>,<NUM>. Preferred examples of hydroxyethylcellulose (HEC) have a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, preferably <NUM>,<NUM> to <NUM>,<NUM>, more preferably <NUM>,<NUM> to <NUM>,<NUM>. The weight average molecular weights are measured by GPC/SEC according to EU Pharmacopoeia <NUM> method <NUM>. In the modified-release component b), it is even more preferred if the pH-independent polymer is a combination of hydroxypropylmethylcellulose K4M and hydroxyethylcellulose such as Natrosol, a combination of hydroxypropylmethylcellulose K4M and non-ionic poly(ethylene oxide) such as Polyox <NUM><NUM><NUM>, a combination of hydroxypropylmethylcellulose K4M and hydroxypropylmethylcellulose K100LV (Mw = <NUM>,<NUM> to <NUM>,<NUM>, such as <NUM>,<NUM>), a combination of hydroxypropylmethylcellulose K4M and hydroxypropylcellulose such as Klucel LF, a combination of hydroxypropylmethylcellulose K15M and xanthan gum such as Xantural <NUM>, or a combination of hydroxypropylmethylcellulose K15M and sodium carboxymethylcellulose such as Blanose 7M31F. Combinations of two pH-independent polymers are preferred for more adequately sustaining and controlling the furazidin release. Most preferably, a combination of hydroxypropylmethylcellulose K4M and hydroxyethylcellulose is used as the pH-independent polymer.

In the pharmaceutical composition, the immediate release component a) and the modified-release component b) each comprise at least one excipient. As the at least one excipient, the immediate release component a) may comprise at least one of a filler, a disintegrant, a binder, a lubricant, a glidant and any combination thereof. Preferably, the immediate release component a) comprises a filler, a disintegrant, a glidant, a lubricant, and, optionally, a binder. The immediate release component a) preferably consists of furazidin and a filler, a disintegrant, a glidant, a lubricant, and, optionally, a binder. Preferably, a binder is also present in the immediate-release component a).

The modified-release component b) may comprise, as the at least one excipient, at least one of a filler, a disintegrant, a binder, a lubricant, a glidant and any combination thereof, preferably the modified-release component b) comprises a filler, a disintegrant, a binder, a lubricant, and, optionally, a glidant. The modified-release component b) preferably consists of furazidin, a controlled-release agent, a filler, a disintegrant, a binder, a lubricant, and, optionally, a glidant. More preferably, the MR component does not contain a glidant.

In the pharmaceutical composition, the immediate release component a) and/or, preferably and, the prolonged-release component b) comprise a filler. Herein, a filler means at least one filler. Accordingly, the filler may be at least one filler independently selected from the group consisting of anhydrous or monohydrate lactose, sucrose, microcrystalline cellulose, starch such as maize starch, pregelatinized starch, microcrystalline cellulose coated with colloidal silica, mannitol and any combination thereof. Preferably, the filler is at least one independently selected from the group consisting of anhydrous or monohydrate lactose, mannitol, microcrystalline cellulose, maize starch, saccharose and any combination thereof. More preferably, the filler is at least one selected from the group consisting of lactose monohydrate, microcrystalline cellulose, or a combination thereof. The immediate release component a) may contain the filler in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, based on the weight of the immediate release component a). The modified-release component b) contains the filler in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, based on the weight of the modified-release component b).

In the pharmaceutical composition, the immediate release component a) and/or the modified-release component b) comprise a binder. Preferably the immediate release component a) and the modified-release component b) comprise a binder, the binder being contained in addition to the controlled-release agent. Herein, a binder means at least one binder. Accordingly, the binder may, for example, be at least one binder independently selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, hydroxycellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, copovidone, pregelatinized starch, gelatine and any combination thereof. Preferably, the binder is at least one independently selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone and any combination thereof. More preferably the binder is polyvinylpyrrolidone. The binder may be used in an amount equal to <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, based on the total mass of the composition. The immediate release component a) may contain the binder in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, based on the weight of the immediate release component a). The modified-release component b) may contain the binder in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, based on the weight of the modified-release component b). A binder is not required if the respective component is produced by dry granulation or direct compacting. It is however preferred to use wet granulation in the preparation of the components, where a binder is commonly used as described in more detail below.

In the pharmaceutical composition, the immediate release component a) and/or, preferably and, the modified-release component b) comprise a disintegrant. Herein, a disintegrant means at least one disintegrant. Accordingly, the disintegrant may, for example, be at least one disintegrant independently selected from the group consisting of carboxymethylcellulose sodium salt, sodium croscarmellose, microcrystalline cellulose, crospovidone, sodium starch glycolate, maize starch, and any combination thereof. Preferably, the disintegrant is at least one independently selected from the group consisting of sodium starch glycolate, sodium croscarmellose, maize starch and any combination thereof. More preferably, the disintegrant is sodium croscarmellose or sodium starch glycolate. The disintegrant may be used in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, based on the total mass of the composition. The immediate release component a) may contain the disintegrant in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, based on the weight of the immediate release component a). The modified-release component b) may contain the disintegrant in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, based on the weight of the modified-release component b).

In the pharmaceutical composition, the immediate release component a) and/or, preferably and, the modified-release component b) comprise a lubricant. Herein, a lubricant means at least one lubricant. Accordingly, the lubricant may, for example, be at least one lubricant independently selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerol tristearate, palm oil derivatives such as palmitic acid or hydrogenated palm oil, especially Softisan <NUM>, hydrogenated vegetable oil, such as hydrogenated castor oil, and any combination thereof. Preferably, the lubricant is at least one independently selected from magnesium stearate and stearic acid. The lubricant may be used in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. % such as <NUM> wt. %, based on the total mass of the composition. The immediate release component a) may contain the lubricant in an amount of <NUM> to <NUM> wt. %, preferably <NUM> wt. %, based on the weight of the immediate release component a). The modified-release component b) may contain the lubricant in an amount of <NUM> to <NUM> wt. %, preferably <NUM> wt. %, based on the weight of the modified-release component b).

In the pharmaceutical composition, the immediate release component a) and/or the modified-release component b) may comprise a glidant. It is preferred that the immediate release component a) but not the modified-release component b) comprises a glidant. Herein, a glidant means at least one glidant. Accordingly, the glidant may, for example, be at least one glidant independently selected from the group consisting of fumed silica (colloidal silicon dioxide), such as colloidal anhydrous silica, starch, talc and any combination thereof. Preferably, the glidant is colloidal anhydrous silica. The glidant may be used in an amount of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, based on the total mass of the composition. The immediate release component a) may contain the glidant in an amount of <NUM> to <NUM> wt. %, preferably <NUM> wt. %, based on the weight of the immediate release component a). The modified-release component b) may contain the glidant in an amount of up to <NUM> wt. %, based on the weight of the modified-release component b).

According to a further embodiment of the pharmaceutical composition, the immediate release component a) and/or the modified-release component b) comprise at least one absorbent as an excipient. An absorbent may, for example, be added to the granulate of the IR component or the MR component or the extragranular fraction in order to stabilize moisture level and, thus, to improve the quality of the physical properties of the granulate and facilitate subsequent compression of the granulate to form a tablet. The absorbent provides stabilisation of moisture level and pH of the granulate and of the final composition. The absorbent is preferably pH-neutral. The absorbent may, for example, be selected from magnesium aluminometasilicates. Preferably, the absorbent is selected from one of the Neusilin grades, such as Neusilin US2® from Fuji Chemicals. In general, an absorbent is not required in the pharmaceutical composition.

Particularly preferred pharmaceutical compositions of the present invention are obtained by combining preferred embodiments such as preferred contents and preferred components.

For example, according to a particularly preferred embodiment, the single dosage form of the pharmaceutical composition contains <NUM> to <NUM> of furazidin, preferably <NUM> to <NUM> of furazidin, and more preferably <NUM> of furazidin. The immediate release component a) comprises <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM>, of furazidin, and the modified-release component b) comprises <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM>, of furazidin. In the matrix of the modified-release component b), the modified-release component b) comprises <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. %, of the pH-independent polymer as the controlled-release agent.

According to another particularly preferred embodiment, the immediate release component a) comprises <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, of a filler, <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, of a disintegrant, <NUM> to <NUM> wt. %, preferably <NUM> wt. %, of a glidant, <NUM> to <NUM> wt. %, preferably <NUM> wt. %, of a lubricant and, optionally, <NUM> to <NUM> wt. % of a binder, based on the total weight of the immediate release component a). The immediate release component a) may comprise <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, of a binder, based on the total weight of the immediate release component a). The filler, the disintegrant, the lubricant, the glidant and the binder are preferably selected from the above-mentioned compounds. The immediate release component a) may further contain <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. %, such as <NUM> wt. %, of furazidin and can consist of furazidin and the aforementioned excipients in the indicated amounts. Even more preferably, the immediate release component a) contains or consist of <NUM> wt. % of furazidin, <NUM> wt. % of microcrystalline cellulose, <NUM> wt. % of sodium starch glycolate, <NUM> wt. % of maize starch, <NUM> wt. % of colloidal anhydrous silica, <NUM> wt. % of stearic acid and <NUM> wt. % of polyvinylpyrrolidone, based on the total weight of the immediate release component a).

According to another particularly preferred embodiment, the modified-release component b) comprises <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. %, of the controlled-release agent, <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, of a filler, <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> wt. %, of a disintegrant, <NUM> to <NUM> wt. %, preferably <NUM> wt. %, of a binder, <NUM> to <NUM> wt. %, preferably <NUM> wt. %, of a lubricant, and, optionally, up to <NUM> wt. % of a glidant, based on the total weight of the modified-release component b). Preferably, it does not contain a glidant. The controlled-release agent, the filler, the disintegrant, the lubricant, the glidant and the binder are preferably selected from the above-mentioned compounds. The modified release component b) may further contain <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> wt. %, more preferably <NUM> to <NUM> wt. %, such as <NUM> wt. %, of furazidin and can consist of furazidin and the consist of furazidin and the aforementioned excipients in the indicated amounts. Even more preferably, the modified-release component b) contains or consists of <NUM> wt. % of furazidin, <NUM> wt. % of lactose monohydrate, <NUM> wt. % of hydroxypropylmethylcellulose K4M, <NUM> wt. % of hydroxyethylcellulose, <NUM> wt. % of croscarmellose sodium, <NUM> wt. % of magnesium stearate and <NUM> wt. % of polyvinylpyrrolidone, based on the total weight of the immediate release component b).

In a preferred variant of the pharmaceutical composition, the modified release of furazidin may be further characterized by the thickness of the pH-independent-polymer matrix after swelling, i.e. in the swollen state. After immersing the modified-release component b) in <NUM> to <NUM> of phosphate buffer of pH=<NUM> for <NUM> hours, the buffer being contained in a beaker, heated by a wiggled, heated bath at <NUM>, the matrix of the modified-release component b) is in a swollen state and has a thickness in the range of <NUM> to <NUM>, preferably <NUM> to <NUM>. The thickness measurements are performed on the MR component, swollen in a medium resembling fed conditions in vivo. Such a thickness of the swollen MR component is favourable for obtaining a controlled release of furazidin from the pH-independent polymer matrix and absorption in the upper part of the small intestine in order to obtain a desirable time/concentration profile of furazidin. Pharmacokinetics studies (PK phase I studies) showed that furazidin in form of a prolonged release composition according to the present invention is mainly absorbed in the upper part of the small intestine. Before swelling, the dry modified-release component has a thickness in the range of <NUM> to <NUM>, preferably <NUM> - <NUM>. The thickness ratio of the thickness of the modified-release component b) in the swollen state to the thickness of the dry modified-release component b) before swelling is in the range of <NUM> to <NUM>, preferably <NUM> to <NUM>.

As outlined above, the pharmaceutical composition of the present invention provides preferable pharmacokinetics as a controlled, preferably constant, release of furazidin is achieved. The pharmacokinetics obtained with the pharmaceutical composition of the present invention differ fundamentally from prior art furazidin compositions for the treatment of UTI, which basically show an immediate release of furazidin. The preferable pharmacokinetics allow for reducing the dosage frequency in the treatment of UTI, thus improving patients' compliance and convenience and ensuring a better therapeutic efficacy.

According to a preferred embodiment, the pharmaceutical composition is configured to provide, after oral administration, a maximum plasma concentration of furazidin (Cmax) of <NUM>±<NUM> ng/mL after tmax of <NUM>±<NUM> hours after administration, and an area under the plasma concentration-time curve from time zero to <NUM> hours (AUC<NUM>-<NUM>) of <NUM>±<NUM> ng·h/mL, as determined by human PK studies. Furthermore, the pharmaceutical composition may be configured to provide, after oral administration of a single dosage form of the pharmaceutical composition twice a day and <NUM> hours apart for <NUM> days, a maximum plasma concentration in steady state (Cmax,ss) of furazidin of <NUM>±<NUM> ng/mL and an area under the plasma concentration-time curve from time zero to <NUM> hours in steady state (AUC<NUM>-<NUM>,ss) of <NUM>±<NUM> ng·h/mL, as determined by human PK studies.

The pharmaceutical composition of the present invention has an in vitro dissolution rate of furazidin of <NUM> to <NUM> wt. %, preferably <NUM> to <NUM> %, within <NUM>, <NUM> to <NUM> wt. % within <NUM> and above <NUM> wt. % within <NUM>, based on the total furazidin content of the single dosage form, as determined by using European Pharmacopoeia edition <NUM> Apparatus Baskets "<NUM>" in <NUM> volume of phosphate buffer solution of pH=<NUM> with the addition of <NUM>% CTAB (hexadecyltrimethylammonium bromide) at <NUM>±<NUM> and <NUM> rpm.

A method of manufacturing the prolonged-release pharmaceutical composition, which is not encompassed by the wording of the claims, enables the production of the pharmaceutical composition using conventional tools and well-known pharmaceutical technologies, while significantly simplifying the manufacturing process, and reducing its costs comparing to manufacturing standards known in the art. The pharmaceutical composition in the form of a bilayer tablet can be prepared by a method comprising direct compression, dry granulation or wet granulation for making the immediate-release component and the modified-release component b).

Thus, a method of manufacturing the prolonged-release pharmaceutical composition comprises (a) a step of preparing the immediate release component a); (b) a step of preparing the modified-release component b); (c) a step of combining the immediate release component a) and the modified-release component (b) to form a bilayer tablet, in which the immediate release component a) forms a first layer, the modified-release component (b) forms a second layer; and, optionally, (d) a step of forming a coating around the first and second layers obtained in step (c). Preferably, no coating is formed, that is, step (d) is preferably not carried out.

In step (a) and step (b), the IR component and MR component may be independently prepared using a dry or wet technology such as dry or wet granulation.

A dry-granulated IR component or MR component can be obtained using direct dry granulation of a powder mixture comprising furazidin or a pharmaceutically acceptable salt thereof, suitable excipients as described above and, in case of the MR component, a controlled-release agent, as described above, in particular at least one pH-independent polymer. Other excipients can be also included, if needed. Suitable excipients, used in pharmacy, can be found in the "<NPL>. The dry granulation method used to obtain the IR component (step (a)) or the MR component (step (b)) can be selected from roller compaction and slugging. Methods known to the skilled person and are described, for example, in the "<NPL>.

A wet-granulated IR component or MR component can be obtained using a suitable granulation method known in the art using powder mixtures comprising furazidin or a pharmaceutically acceptable salt thereof, suitable excipients as described above and, in case of the MR component, a controlled-release agent, as described above, in particular at least one pH-independent polymer. Other excipients can be also included, if needed. The wet granulation method used to obtain the IR component (step (a)) or the MR component (step (b)) can be selected from low shear, high shear, and fluid bed granulation. Preferably, the IR component and the MR component are obtained by wet granulation (steps (a) and (b)).

Blending operations can be performed in a suitable blender, preferably in a container blender.

According to an embodiment of the method, the IR component a) and/or the MR component b) are prepared using dry granulation (steps (a) and (b)). In such a variant, the method preferably comprises the following steps: (I) blending furazidin or a pharmaceutically acceptable salt thereof with all excipients except lubricant and, in case of the MR component, with the at least one controlled-release agent to homogeneity; II) adding a part of the lubricant and subsequent blending; III) dry granulation by roller-compaction or slugging; IV) breaking-down the resulting slugs or sheets using a milling technique to produce granules; V) adding the remaining part of lubricant and subsequent blending.

In the dry methods of granulation, the primary powder blend particles are aggregated under high pressure using one of two main dry granulation processes: either roller-compaction or slugging. In both cases the intermediate products, slugs or sheets, are broken down using a suitable milling technique to produce granular material, which can be additionally sieved to separate the desired size fraction. Such a way of processing a furazidin powder blend is very advantageous for several reasons. It allows for the elimination of water, which may affect furazidin stability, and obtaining a granulate having grain sizes that are optimal for further processing (combination with the second component comprising furazidin and optional extragranular phase component without the effect of physical segregation). Additionally, a broad ratio (wt. %) of furazidin can be blended into the dry granulate intermediate, which is not possible in other dry pharmaceutical processes (e.g. direct compression).

According to another embodiment of the method, the IR component a) and/or the MR component b) are prepared using wet granulation (steps (a) and (b)). In such a variant, the method preferably comprises the following steps: I) mixing of furazidin or a pharmaceutically acceptable salt thereof with at least one filler, at least one disintegrant, optionally further excipients, and, in case of the MR component, at least one controlled-release agent in a high-shear granulator to homogeneity; II) granulating the mixture of step I) by addition of a binder solution in water or another processing agent, such as an alcohol, e.g. ethanol, or with a mixture thereof; III) drying and unifying the dried granule sizes by sieving or screening; and, optionally, IV) adding an extragranular phase comprising lubricant and/or a mixture of filler and glidant and/or an absorbent and a glidant.

Furazidin may be also subjected to a process of wet granulation (e.g. low shear, high shear or in a fluidized bed), to improve its solubility. Wet granulation facilitates obtaining the desired in vitro and in vivo release profiles. The resulting wet granulate is dried and, for example, screened to obtain a proper distribution of the particles, allowing a durable combination with the other component and additional excipients.

According to a preferred embodiment of the method, the IR component a) is prepared using dry granulation (step (a)), and the MR component b) is prepared using wet granulation (step (b)). It is also preferred to prepare the IR component (step (a) and the MR component (step (b)) by wet granulation.

In step (c) of the method, the resulting components a) and b) are combined together, and depending on the desired final form, for example, compressed into separate layers in a tablet, optionally followed by forming a coating in step (d), resulting in a single unit dosage form. Preferably, the prolonged-release pharmaceutical composition is prepared by using a bilayer tableting technology in step (c).

According to another aspect, the present invention provides a pharmaceutical composition as described herein above for use in a method of treatment of a urinary tract infection. The urinary tract infection is preferably an acute or recurrent uncomplicated urinary tract infection, for example caused by Escherichia coli, such as recurrent uncomplicated urinary tract infection in women caused by Escherichia coli.

According to an embodiment, the pharmaceutical composition is administered orally two times daily, preferably <NUM> to <NUM> hours apart, more preferably <NUM> hours apart. Typically, the pharmaceutical composition is administered for <NUM> to <NUM> days, preferably <NUM> days. This regimen has the advantage of better patients' compliance and improved quality of life during therapy in comparison to the treatment of UCI using a prior art furazidin composition. In conventional therapies, the high dosages of furazidin require large dosage forms, with the necessity of taking <NUM> or <NUM> tablets, depending on the available presentation, at once <NUM> or <NUM> times daily for <NUM> up to <NUM> days.

Typically, the pharmaceutical composition is administered in combination with a meal, as absorption of furazidin is improved. In combination with a meal means that the pharmaceutical composition is taken shortly before, together with or after the meal. It is thus preferred that the pharmaceutical composition is a single dosage form, which is administered orally within an interval of from <NUM> before a meal and <NUM> after a meal. Preferably, the pharmaceutical composition is administered between at a meal and <NUM> after a meal, and more preferably, right after the meal, that is, within <NUM> after a meal.

For oral administration two times a day, a single dosage form of the pharmaceutical composition usually contains <NUM> to <NUM> of furazidin, preferably <NUM> to <NUM> of furazidin, and more preferably <NUM> of furazidin. In particular, the immediate release component a) comprises <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM>, of furazidin, and the modified-release component b) comprises <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM>, of furazidin. In a particularly preferred variant, <NUM> of furazidin formulated as a fixed dose comprising <NUM> of furazidin in IR component and <NUM> of furazidin in MR component is administered, <NUM> times daily, for example, for <NUM> days.

It is an advantage of the present invention that the prolonged-release furazidin composition provides continuous furazidin effective concentration levels during the whole period of treatment, especially during the night. This effect could not be achieved with the use of a prior art immediate release formulation, which provides effective concentrations only during a short period of time after administration. Consequently, continuous bacteriostatic concentration in serum and urine could not be provided, which is however crucial for effective therapy.

The composition for use in the method of treatment according to the present invention thus provides favourable furazidin pharmacokinetics, which are not obtained by prior art furazidin compositions. Preferably, wherein oral administration of one single dosage form of the pharmaceutical composition provides a maximum plasma concentration of furazidin (Cmax) of <NUM>±<NUM> ng/mL after tmax of <NUM>±<NUM> hours after administration, and an area under the plasma concentration-time curve from time zero to <NUM> hours (AUC<NUM>-<NUM>) of <NUM>±<NUM> ng·h/mL, as determined by human PK studies described below. It is further preferred that oral administration of a single dosage form of the pharmaceutical composition twice a day and <NUM> hours apart provides after <NUM> days a maximum plasma concentration in steady state (Cmax,ss) of furazidin of <NUM>±<NUM> ng/mL and an area under the plasma concentration-time curve from time zero to <NUM> hours in steady state (AUC<NUM>-<NUM>,ss) of <NUM>±<NUM> ng·h/mL, as determined by human PK studies as described below.

Exemplary IR components (IR/<NUM> to IR/<NUM>) and MR components (MR/<NUM> to MR/<NUM>) according to the present invention are presented in the Tables <NUM> and <NUM> below.

In the following procedures, the amounts of the components were used as specified in Tables <NUM> and <NUM>.

The IR components IR/<NUM> and IR/<NUM> are prepared as follows:.

The MR components MR/<NUM> to MR/<NUM> are prepared as follows:.

The final blend granulates are compressed into bilayer-tablets with the aid of rotary press machine. During the compression process, the following requirements of the tablets should be satisfied (Table <NUM>).

For the pharmaceutical composition IR/<NUM>+MR/<NUM>, the above processes were used to prepare a batch of bilayer tablets using <NUM> of the granulate of the modified-release component and <NUM> of the granulate of immediate release component.

As prolonged-release pharmaceutical composition, a bilayer tablet having the composition of IR/<NUM>+MR/<NUM> (in total <NUM> furazidin) was used. Dissolution testing was performed using the following conditions:.

The quantities of drug substance released from the tested tablets are determined by HPLC. The mean value calculated from <NUM> tablets are indicated in Table <NUM>.

The following Table <NUM> shows dissolution results of selected MR components. The MR components were pressed to tablets and subjected to a dissolution test using the above conditions. The sampling times are indicated in Table <NUM>. The mean value calculated from <NUM> samples is indicated.

In Example <NUM>, the swelling properties of the MR component having a pH-independent polymer matrix and the dissolution of furazidin from the MR component were investigated. For the swelling test, the samples were prepared as follows. The test time and conditions are adjusted as to achieve complete dissolution of the IR layer and mimic the swelling characteristics of the MR component after <NUM> mean retention time of the tested tablet in the stomach a after meal.

Sample preparation: Tablets, having the composition indicated in Table <NUM> below, were produced as described above in Example <NUM>. The tablets (n=<NUM>) were placed in beaker filled with <NUM> to <NUM> of phosphate buffer of pH=<NUM>. The beaker is placed in wiggled, heated bath at a temperature of <NUM>. The tablets are incubated for <NUM> hours.

The swollen samples were tested using a common texture analyser. Before testing, the probe of the texture analyser was calibrated against the testing platform (i.e. a blank slide).

After the IR component (if present) of the tablet was completely dissolved (completion after <NUM> incubation), the swollen MR component (i.e. the MR component is the swollen state) of the tablets was transferred from the beaker on slides and singly tested.

For the data analysis, the values of interest for a sample were obtained by a macro included in the software of the TA. XTplus Texture Analyser. The macro quantifies the measured gel thickness. The average of <NUM> tablets was calculated. The results are summarized in Table <NUM> indicating the thickness of the MR component before swelling, the thickness range of the individual results after swelling, the average thickness after swelling and the swelling ratio (thickness before swelling/thickness in the swollen state).

The dissolution amount of furazidin has been determined according to the dissolution test in Example <NUM>. The mean values for several tablets are indicated in Table <NUM>.

It was found that the thickness of the swollen MR component correlated with the dissolution profile of tablets composed of IR component and MR component as well as of the dissolution profile of the MR component alone.

The <NUM> time point has been chosen as representative for the correlation and referent for the prediction of the required full dissolution profile. The dissolution values at the representative <NUM> time point showed a release of furazidin on the level of about <NUM> to <NUM> wt. % (a range of <NUM> to <NUM> wt. % is acceptable for a prolonged-release composition) for the bilayer tablets composed of IR component and MR component and a release of furazidin on the level of about <NUM> wt. % (a range of <NUM> to <NUM> wt. % was considered acceptable) for the MR component MR/<NUM> when tested alone. It was found that the results are consistent with the expected levels of released furazidin over time to provide appropriate PK values in vivo.

Medicines must comply with the requirements of the chemical purity immediately after preparation (comply with the limits indicated in the release specification of the drug product), and within the period set by the relevant guidelines in time and storage conditions (comply with the limits indicated in the shelf-life specification of the drug product). The stability studies have been performed according to guideline CPMP/ICH/<NUM>/<NUM>-ICH Q1A (R2) Stability Testing of New Drug Substances and Products. The main impurity of furazidin is ACRO, i.e. (2E)-<NUM>-(<NUM>-nitro-<NUM>-furylo)acrylaldehyde.

The final composition was packed in blisters, SBC <NUM>/aluminum foil, and stored at long term (<NUM>/<NUM>% RH), intermediate (<NUM>/<NUM>% RH) and accelerated (<NUM>/<NUM>% RH) conditions. The level of impurities and the content of active substance were determined by HPLC according to the method disclosed in<NPL>. The results are presented in Tables <NUM>, <NUM> and <NUM>.

Study title: Randomized, open-label, three-period, cross-over, food effect pharmacokinetic study comparing bioavailability of furazidin, prolonged-release tablets, <NUM> having a composition of IR/<NUM>+MR/<NUM> according to Example <NUM> in healthy subjects in different fed conditions.

Aim of the study: The main study objective was to evaluate the pharmacokinetic properties and to compare the bioavailability of the Test product in healthy volunteers under different fed conditions.

Study conduct: In this bioavailability study, the pharmacokinetic profile was tested for the Test formulation (prolonged-release bilayer tablet, IR/<NUM>+MR/<NUM>) having a strength of <NUM> furazidin. The bioavailability study was carried out under different fed conditions (after a high-protein meal or after a high-fat, high-calorie meal) and in fasting state in <NUM> healthy subjects. On the day of dosing, the subjects received randomly after an overnight fast a single dose of the modified-release formulation, administered on empty stomach (fasting conditions, Treatment A) or after a high-protein meal (Treatment B) or after a high-fat, high-calorie meal (Treatment C), each time with <NUM> of water. For each subject, there were <NUM> dosing periods, separated by a washout period of <NUM> days. Blood and urine samples were collected over <NUM> hours (<NUM> blood samples and <NUM> urine samples). The results are shown in Tables <NUM> to <NUM> and <FIG> for the plasma analyses and in Tables <NUM> to <NUM> and <FIG> for the urine analyses.

The pharmacokinetic data for plasma and urine were statistically analysed in <NUM> subjects. After single oral administration of furazidin, prolonged-release formulation, <NUM> to the healthy volunteers, peak plasma concentrations were reached at <NUM> hours (median) following administration under recommended fed conditions (high-protein meal). Cmax and AUC<NUM>-<NUM> reached <NUM>±<NUM> ng/mL and <NUM>±<NUM> ng*h/mL, respectively. Plasma concentrations of furazidin showed a mean terminal half-life of <NUM> hour in healthy subjects. The mean urine concentrations of furazidin under recommended fed conditions achieved <NUM>± <NUM>µg for Ae<NUM>-t and <NUM>±<NUM>µg/h for Rmax. Peak urine concentrations were reached at <NUM> hours.

Total exposure (AUC) increases approximately <NUM> to <NUM>-fold after high-protein and after high-fat, high calorie meal respectively compared to the fasting state, while Cmax is increased to a lower extent. The exposure after a high fat, high calorie meal increases approximately <NUM>% compared to the exposure after high-protein meal. Largest difference in exposure after meals versus fasting state is observed after <NUM> hours (AUC(<NUM>-<NUM>)), which implies a difference in profile shape resulting from a much larger increase in exposure at later times post dosing. High-fat, high calorie meal increases the exposure from <NUM> to <NUM> hours about <NUM>-fold. Coadministration of the modified-release formulation with a high-protein meal increases overall plasma and urine levels in the same way as it was observed for the immediate release product (Furaginum Adamed <NUM> tablets). Higher exposures observed after a high-fat, high-calorie meal do not appear related to dose dumping. Dose dumping related to formulation failure would result in higher Cmax and exposures in the first four hours of the plasma concentration curves. Differences in profile shape between high-fat and high-protein administration are only observed in a subgroup of volunteers due to peaks occurring after <NUM> hours post dose, but it does not appear to be a formulation related issue because of the timing of differences.

Safety Results: Seven (<NUM>) subjects experienced a total of two (<NUM>) mild and seven (<NUM>) moderate adverse events (AE). In total, two adverse events were considered related to the oral administration of the Test product under fasting condition (Treatment A), i.e. one episode of mild nausea (and vomiting) and one episode of moderate pyrosis (heartburn). No adverse event was considered related to the oral administration of the Test product in fed condition, high-protein breakfast (Treatment B). One (<NUM>) adverse event was considered related to the oral administration of the Test product under fed condition, high-calorie/high-fat breakfast (Treatment C), i.e., one episode of moderate nausea (and vomiting). No serious adverse event (SAE) occurred during the Study.

<FIG> shows the pharmacokinetic profiles of means (N=<NUM>) in plasma under fasting conditions (Treatment A), under fed conditions of a high-protein breakfast (Treatment B) and under fed conditions of a high-calorie/high-fat breakfast (Treatment C).

<FIG> shows the pharmacokinetic profiles of means (N=<NUM>) in urine under fasting conditions (Treatment A), under fed conditions of a high-protein breakfast (Treatment B) and under fed conditions of a high-calorie/high-fat breakfast (Treatment C).

Study title: Randomized, open-label, two-period, multiple dose, cross-over, pivotal pharmacokinetic study comparing bioavailability of Furazidin, prolonged-release tablets, <NUM> of the composition IR/<NUM>+MR/<NUM> according to Example <NUM> and Furaginum Adamed <NUM>, tablets in healthy male and female subjects under fed (high-protein meal) conditions.

Aim of the study: The main study objective was to evaluate the pharmacokinetic properties and to compare the bioavailability of furazidin after multiple-dose administration of the Test product versus the Comparator product in healthy male and female volunteers under fed (high-protein meal) conditions.

Study conduct: Thirty (<NUM>) subjects were included into the study. The elimination half-life of prolonged-release furazidin is about <NUM> hour. The elimination half-life reported in literature for immediate-release furazidin is no longer than <NUM> hours. In plasma, steady-state can be achieved within <NUM> to <NUM> days of twice-daily dosing of <NUM> prolonged-release furazidin tablets according to the present invention and three times daily dosing of <NUM> immediate-release furazidin tablets, respectively, so as to demonstrate that steady state has been reached when five (<NUM>) doses of furazidin, prolonged-release tablet, <NUM> according to the present invention and seven (<NUM>) doses of Furaginum Adamed, <NUM>, tablets were administered orally on Day <NUM> through Day <NUM>. Dosing on Day <NUM> was continued up to <NUM> doses in total of prolonged-release tablets and, in total, <NUM> doses of immediate-release tablets to compare the total exposure after multiple dose administration.

Multiple oral doses of the Test product (<NUM> doses) administered orally with <NUM> of water under fed (high-protein meal) conditions. Oral administration of one tablet given two times a day (<NUM> hours interval apart). Total dose per day was <NUM> of furazidin. Dosing for <NUM> consecutive days (on Day <NUM>, Day <NUM> and Day <NUM> twice a day). Multiple oral dose of Comparator product (<NUM> doses) administered orally with <NUM> of water under fed (high-protein meal) conditions.

Oral administration of two tablets given at the same time (<NUM> x <NUM>) three times a day (<NUM> hours interval apart). Total dose per day was <NUM> of furazidin. Dosing for <NUM> consecutive days (on Day <NUM>, Day <NUM> and Day <NUM> three times a day).

The washout period was at least <NUM> days between the last dose in Period <NUM> and the first dose in Period <NUM>. Blood samples were collected throughout a <NUM>-hour period after the first IMP administration to characterize products absorption and elimination. Urine samples were collected over <NUM> hours post first dose on Day <NUM>-Day <NUM> and over <NUM> hours post the first dose on Day <NUM>-Day <NUM>.

Twenty-nine (<NUM>) subjects completed the study, and the data was used for the statistical analysis. Pharmacokinetic parameters were calculated from plasma and urine concentrations determined by a validated HPLC/MS/MS method for furazidin according to the method disclosed in <NPL>. Pharmacokinetic parameters of the Test and the Comparator products were compared. The <NUM>% confidence intervals for the Test to Comparator ratios were evaluated for the following pharmacokinetic parameters, which were considered as primary for bioavailability assessment:.

Concentration-time profiles of Cthrough concentrations were provided to assess reaching of steady-state. High Cthrough variability was observed as usual for very low plasma concentration levels at time points beyond <NUM> times the plasma elimination half-life. This is not unexpected as the elimination half-life is approximately <NUM> hr and so, by the <NUM>-hour interval, more than <NUM>% of the absorbed dose is eliminated. In fact, the majority of subjects showed Cthrough levels below the limit of quantitation. Hence, a steady state based on similar Cthrough levels cannot be established as the pharmacokinetics of the product at the <NUM>-hour dosage interval were essentially repeat single doses.

According to the Study Protocol, the AUC<NUM>-<NUM>, Cmax and AURC<NUM>-<NUM> for Day <NUM> and AUC<NUM>-<NUM>,ss and AURC<NUM>-<NUM>,Day3 for Day <NUM> for furazidin were used to assess equivalence between both tested formulations. The results confirm that the <NUM>% confidence intervals for Test to Comparator ratios of the geometric least squares means for above mentioned PK parameters were not within the bioequivalence acceptance range of <NUM>% to <NUM>%.

The results further confirmed that the exposure to the Test formulation was higher in terms of extent and intensity than exposure to the Comparator formulation both in plasma and urine.

Safety Results: Seven (<NUM>) subjects experienced a total of sixteen (<NUM>) moderate adverse events (AE). In total, four (<NUM>) adverse events were considered related to the oral administration of the Test product (i.e. the episodes of moderate headache), and six (<NUM>) adverse events (i.e. also episodes of moderate headache) were considered related to the oral administration of Comparator product.

<FIG> shows the pharmacokinetic profile of means (N=<NUM>) in plasma (A=Test product, B=Comparator).

<FIG> shows the pharmacokinetic profile of means (N=<NUM>) in urine (A=Test product, B=Comparator).

Conclusion: No accumulation was observed after multiple dosing and steady state was not confirmed for Test product after <NUM> days of dosing as expected by the short elimination half-life and the associated kinetics of repeat single doses. Bioavailability of Test product was higher after single and multiple dose administration compared to the Comparator product.

Claim 1:
A prolonged-release pharmaceutical composition for oral administration, comprising:
a) an immediate release component, comprising furazidin and one or more pharmaceutically acceptable excipients; and
b) a modified-release component, comprising furazidin, a controlled-release agent, and one or more pharmaceutically acceptable excipients,
wherein
the pharmaceutical composition is a single dosage form in the form of a bilayer tablet, in which the immediate release component a) forms a first layer, the modified-release component b) forms a second layer, and the first layer at least partially covers the surface of the second layer,
in a matrix of the modified-release component b), the controlled-release agent comprises at least one pH-independent polymer, which is at least one selected from the group consisting of hydroxypropylmethylcellulose (HMPC), hydroxyethylcellulose (HEC), hydroxypropylcellulose, xanthan gum, sodium carboxymethylcellulose, non-ionic poly(ethylene oxide), and any combination thereof,
the immediate-release component has an in vitro dissolution rate of at least <NUM> wt.% of the furazidin within <NUM> minutes, based on the total furazidin content of the immediate release component,
the modified-release component has an in vitro dissolution rate of <NUM> to <NUM> wt.% of furazidin within <NUM>, based on the total furazidin content of the modified-release component, and
the prolonged-release pharmaceutical composition has an in vitro dissolution rate of furazidin of <NUM> to <NUM> wt.% within <NUM>, <NUM> to <NUM> wt.% within <NUM> and above <NUM> wt.% within <NUM>, based on the total furazidin content of the single dosage form, and
the dissolution rates being determined by using European Pharmacopoeia edition <NUM> Apparatus Baskets "<NUM>" in <NUM> volume of phosphate buffer solution of pH=<NUM> with the addition of <NUM>% CTAB (hexadecyltrimethylammonium bromide) at <NUM>±<NUM> and <NUM> rpm.