Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to a prolonged-release pharmaceutical composition of furazidin for oral administration, which can be used for treating urinary tract infections (UTI).
• UTI urinary tract infections
• Urinary tract infections are the most common condition requiring medical consultation and care in outpatients. UTIs account for approx. 10-20% of all community- acquired infections and for approx. 40-50% of nosocomial infections. Approx. 80% of all UTIs occur in women. According to epidemiological studies, bacteriuria occurs at least once in a lifetime of approx. 10% of female population and in 1-2% of male population, with asymptomatic UTIs in women probably occurring twice as frequently.
• UTI urinary tract infection
• cUTI complex UTI
• 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.
• uncomplicated UTI include:
• AUC Acute uncomplicated cystitis
• Acute uncomplicated pyelonephritis An upper UTI (pyelonephritis) ought to be assumed if, in the case of acute symptoms, flank pain, pain on palpation of the flank, and/or fever (>38°C) persist.
• Asymptomatic bacteriuria Clinically symptomatic UTI is distinguished from asymptomatic bacteriuria. The term ‘asymptomatic UTI’ ought not to be used.
• Recurrent uncomplicated UTIs A recurrent UTI is assumed if relapse rates of >2 symptomatic episodes occur within 6 months or >3 symptomatic episodes within 12 months.
• 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.
• 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.
• Recurrent UTIs are defined as infections characterised by at least 3 episodes within one year or 2 episodes within 6 months. Infection recurrence is understood as a repeated UTI episode caused by the same micro-organism, i.e. by its endospores, within 3 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 14 days after sterilisation of urine. In the population of young, healthy and sexually active women, 10% experience at least one UTI episode a year, and the risk of recurrent UTIs is approx. 0.5- 0.7/person/year.
• 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.
• 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 (70-95% of cases), is susceptible to furazidin at a constant level of approx.
• furazidin upon oral administration, furazidin has a very short half-life (below 1 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 50 or 100 mg of furazidin. Due to the unfavourable pharmacokinetics, furazidin must be administered 3 to 4 times daily (each time 100 mg or 2 x 50 mg of furazidin) in order to maintain an effective concentration of furazidin in the plasma.
• IR immediate release
• furazidin is quickly absorbed in the gastrointestinal tract, reaching high blood concentrations. During this time, intensive liver metabolism occurs, causing exacerbation of adverse effects.
• the present invention relates to the following aspects:
• 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.
• composition according to (1) or (2) wherein the pharmaceutical composition is a single dosage form in the form of a 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.
• the tablet is a bilayer tablet.
• the immediate release component a) and/or the modified- release component b) also contain an extragranular fraction, for example, comprising one or more of a lubricant, a filler, an absorbent and a glidant.
• the immediate release component a) has a furazidin content of 32 to 50 wt.%, preferably 41 to 50 wt.%, more preferably 45 to 46 wt.%, such as 45.45 wt.%, based on the total weight of the immediate release component a); furthermore, the modified release component b) has a furazidin content of 40 to 60 wt.%, preferably 52 to 56 wt.%, more preferably 54 to 55 wt.%, such as 53.57 wt.%, based on the total weight of the modified-release component b).
• modified-release component b) comprises 10 to 40 wt.% of the controlled-release agent, preferably 10 to 35 wt.% and more preferably 20 to 30 wt.% of the controlled-release agent, based on the total weight of the modified-release component b).
• the controlled-release agent comprises at least one pH- independent polymer.
• the matrix is formed by the pH-independent polymer, or by the pH-independent polymer and a binder.
• 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 1.1 to 1.8, preferably 1.3 to 1.6, at each pH of 1.2, 4.5, 6.8 and 7.4, wherein the swollen state is obtained by immersing the dry modified release component b) in 30 to 35 mL of a solution contained in a beaker for 2 h, the beaker being placed in a wiggled, heated bath at 37°C, the solution being a phosphate buffer of pH 4.5, 6.8 or 7.4 or aqueous HC1 of pH 1.2.
• HPMC hydroxypropylmethylcellulose
• HEC hydroxyethylcellulose
• MC methylcellulose
• xanthan gum sodium carboxymethylcellulose
• copovidone vinylpyrrolidone-vinyl acetate copolymer
• Preferred examples of hydroxypropylmethylcellulose (HPMC) have a weight average molecular weight (Mw) of 70,000 to 1,000,000, preferably 70,000 to 600,000, more preferably 70,000 to 170,000.
• Preferred examples of carboxymethylcellulose (CMC) have a weight average molecular weight of 200,000 to 500,000, preferably 350,000 to 450,000, more preferably 370,000 to 400,000.
• Preferred examples of hydroxyethylcellulose (HEC) have a weight average molecular weight of 50,000 to 200,000, preferably 80,000 to 150,000, more preferably 80,000 to 100,000.
• methylcellulose have a weight average molecular weight of 12,000 to 280,000, preferably 10,000 to 220,000, more preferably 370,000 to 400,000.
• Preferred examples of copovidone have a weight average molecular weight of 50,000 to 100,000, preferably 45,000 to 70,000.
• hydroxypropylmethylcellulose KI 5M a combination of hydroxypropylmethylcellulose KI 5M and copovidone (e.g. Kollidon VA 64 and/or Plasdone S 630).
• the pH-independent polymer is a combination of hydroxypropylmethylcellulose K4M and hydroxy ethylcellulose.
• the immediate release component a) comprises, as the at least one excipient, at least one of a filler, a disintegrant, a binder, a lubricant, a glidant and any combination thereof.
• the immediate release component a) comprises a filler, a disintegrant, a glidant, a lubricant, and, optionally, a binder.
• the immediate release component a) contains a binder in addition to the filler, the disintegrant, the glidant and the lubricant.
• modified-release component b) comprises, as the at least one excipient, at least one of a filler, a disintegrant, a binder, a lubricant, a glidant and any combination thereof.
• the modified-release component b) comprises a filler, a disintegrant, a binder, a lubricant, and, optionally, a glidant. More preferably, the modified-release component b) contains no glidant.
• the filler is at least one 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, and more preferably the filler is at least one selected from the group consisting of lactose monohydrate, microcrystalline cellulose, or a combination thereof.
• the binder is at least one 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, and more preferably the binder is polyvinylpyrrolidone.
• the disintegrant is at least one 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 lubricant is at least one independently selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerol tri stearate, palm oil derivatives such as palmitic acid or hydrogenated palm oil, 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 immediate release component a) but not the modified-release component b) comprises a glidant.
• the glidant is at least one 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 immediate release component a) comprises 10 to 50 wt.%, preferably 10 to 30 wt.%, of a filler, 0.5 to 6 wt.%, preferably 2 to 6 wt.%, of a disintegrant, 1.4 to 1.7 wt.%, preferably 1.6 wt.%, of a glidant, 2 to 4 wt.%, preferably 2.3 wt.%, of a lubricant, based on the total weight of the immediate release component a).
• the modified-release component b) comprises 10 to 40 wt.%, preferably 10 to 35 wt.%, more preferably 20 to 30 wt.%, of the controlled-release agent, 10 to 45 wt.%, preferably 10 to 30 wt.%, of a filler, 0.3 to 5 wt.%, preferably 2 to 5 wt.%, more preferably 3 wt.%, of a disintegrant, 0.4 to 5 wt.%, preferably 0.9 wt.%, of a binder, 0.5 to 2 wt.%, preferably 1 wt.%, of a lubricant, and, optionally, up to 1.3 wt.% of a glidant and preferably no glidant, based on the total weight of the modified-release component b).
• the immediate release component a) contains 45.5 wt.% of furazidin, 29.5 wt.% of microcrystalline cellulose, 5.0 wt.% of sodium starch glycolate, 15.6 wt.% of maize starch, 1.6 wt.% of colloidal anhydrous silica, 2.3 wt.% of stearic acid and 0.5 wt.% of polyvinylpyrrolidone, based on the total weight of the immediate release component a).
• modified-release component b) contains 53.6 wt.% of furazidin, 13.6 wt.% of lactose monohydrate, 19.7 wt.% of hydroxypropylmethylcellulose K4M, 8.2 wt.% of hydroxy ethylcellulose, 3 wt.% of croscarmellose sodium, 1.0 wt.% of magnesium stearate and 0.9 wt.% of polyvinylpyrrolidone, based on the total weight of the immediate release component b).
• composition according to any one of (1) to (36), wherein the pharmaceutical composition is a single dosage form and configured to provide, after oral administration, a maximum plasma concentration of furazidin (Cmax) of 353.1 ⁇ 122.5 ng/mL after tmax of 2.5 ⁇ 0.5 hours after administration, and an area under the plasma concentrationtime curve from time zero to 24 hours (AUC0-24) of 1404.1 ⁇ 392.8 ng h/mL, as determined by human PK studies.
• Cmax maximum plasma concentration of furazidin
• AUC0-24 area under the plasma concentrationtime curve from time zero to 24 hours
• composition according to any one of (1) to (37), wherein the pharmaceutical composition is configured to provide, after oral administration of a single dosage form of the pharmaceutical composition twice a day and 12 hours apart for 3 days, a maximum plasma concentration in steady state (C ma x,ss) of furazidin of 516.4 ⁇ 149.3 ng/mL and an area under the plasma concentration-time curve from time zero to 24 hours in steady state (AUCO-24,SS) of 3498.1 ⁇ 932.2 ng h/mL, as determined by human PK studies.
• C ma x,ss maximum plasma concentration in steady state
• AUCO-24,SS area under the plasma concentration-time curve from time zero to 24 hours in steady state
• CTAB hexadecyltrimethylammonium bromide
• the present invention relates to a pharmaceutical composition as defined in any one of (1) to (39) for use in a method of treatment of a urinary tract infection.
• the pharmaceutical composition for use according to (40), wherein the urinary tract infection is an acute or recurrent uncomplicated urinary tract infection, such as infections in women caused by Escherichia coli.
• composition for use according to any one of (40) to (42), wherein the pharmaceutical composition is a single dosage form, which is administered orally within an interval of from 30 min before a meal and 30 min after a meal, preferably between at a meal and 30 min after a meal.
• composition for use according to any one of (40) to (44), wherein oral administration of one single dosage form of the pharmaceutical composition provides a maximum plasma concentration of furazidin (Cmax) of 353.1 ⁇ 122.5 ng/mL after tmax of 2.5 ⁇ 0.5 hours after administration, and an area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24) of 1404.1 ⁇ 392.8 ng h/mL, as determined by human PK studies.
• Cmax maximum plasma concentration of furazidin
• AUC0-24 area under the plasma concentration-time curve from time zero to 24 hours
• the prolonged-release pharmaceutical composition for oral administration has the features according to the above (1) and (3).
• a the prolonged-release pharmaceutical composition for oral administration which comprises: 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.
• the pharmaceutical composition for oral administration according to this aspect may be further characterized according to any one of the above (2) and (4) to (39).
• the said pharmaceutical composition is for use in a method of treatment of a urinary tract infection.
• the pharmaceutical composition for use may be further characterized according to any one of the above (41) to (46).
• the prolonged-release pharmaceutical composition for oral administration has the features of the above (1) and (6).
• a prolonged-release pharmaceutical composition for oral administration which comprises: 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 comprising, in total, 150 to 250 mg of furazidin.
• the pharmaceutical composition for oral administration according to this aspect may be further characterized according to any one of the above (2) to (39).
• said pharmaceutical is for use in a method of treatment of a urinary tract infection.
• the pharmaceutical composition for use may be further characterized according to any one of the above (41) to (46).
• the prolonged-release pharmaceutical composition for oral administration has the features according to the above (1) and (37).
• a prolonged-release pharmaceutical composition for oral administration which comprises: 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 and configured to provide, after oral administration, a maximum plasma concentration of furazidin (Cmax) of 353.1 ⁇ 122.5 ng/mL after tmax of 2.5 ⁇ 0.5 hours after administration, and an area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24) of 1404.1 ⁇ 392.8 ng h/mL, as determined by human PK studies.
• Cmax maximum plasma concentration of furazidin
• AUC0-24 area under the plasma concentration-time curve from time zero to 24 hours
• the pharmaceutical composition for oral administration according to this aspect may be further characterized according to any one of the above (2) to (36), (38) and (39).
• said pharmaceutical is for use in a method of treatment of a urinary tract infection.
• the pharmaceutical composition for use may be further characterized according to any one of the above (41) to (44) and (46).
• 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, in particular a tablet, of the pharmaceutical composition can be reduced to two times a day (BID), for example, for 5 to 8 days such as 7 days.
• BID two times a day
• the pharmaceutical composition can be conveniently taken 11 to 13 hours, preferably 12 hours, apart and in combination with a meal, that is, shortly before, together with or shortly after a meal (in particular, breakfast and dinner).
• “shortly” means within 30 minutes.
• the meals can be consumed at regular times (for example, 7 a.m. and 7 p.m.), without significantly adjusting the eating times to the dosage regimen.
• 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.
• 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”.
• 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.
• PK pharmacokinetics
• 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.
• An immediate release (IR) component releases furazidin with no special rate controlling features
• 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.
• the IR component achieves in vitro dissolution of at least 80 wt.% of the furazidin within 45 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.
• 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.
• the modified-release component has an in vitro dissolution rate of 5 to 15 wt.% of furazidin within 2 h, based on the total furazidin content of the MR component.
• the 2-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).
• CTAB hexadecyltrimethylammonium bromide
• 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 10 to 40 wt.%, preferably 10 to 30 %, within 1 h, 40 to 65 wt.% within 6 h and above 80 wt.% within 14 h, based on the total furazidin content of a single dosage form of the pharmaceutical composition.
• CTAB hexadecyltrimethylammonium bromide
• 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 dosage frequency can be reduced to 2 times daily (BID), whereas prior art furazidin dosage forms require regular administration 3 or 4 times a day.
• 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. 8 hours apart) and the intake of protein-rich food to improve the furazidin availability.
• 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.
• 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.
• 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”.
• the pharmaceutical composition of the present invention enables an effective, safe and convenient therapy of UTI. Compliance and efficacy are improved, and sideeffects are reduced in comparison to furazidin compositions of the prior art.
• furazidin may be contained as the free base or as a pharmaceutically acceptable salt thereof.
• 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 tablet.
• the immediate release component a) forms a first layer
• the modified-release component b) forms a second layer
• the first layer at least partially covers the surface of the second layer.
• the second layer may be completely surrounded by the first.
• 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 “Pharmaceutical Manufacturing Handbook" edited by Shayne Cox Gad, published by John Wiley & Sons, Inc., Hoboken, New Jersey, March 2008. Preferably, the tablet is uncoated.
• 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.
• the immediate release component a) is contained as granulates
• the modified-release component b) is contained as granulates, in the pharmaceutical composition, in particular, when the pharmaceutical composition is a bilayer tablet as the single dosage form.
• the granulates may be obtained by common dry or wet granulation techniques, preferably by wet granulation.
• 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.
• 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.
• the pharmaceutical composition is a single dosage form, in particular a bilayer tablet as described above, and comprises, in total, 150 to 250 mg of furazidin, preferably 180 to 220 mg of furazidin, and more preferably 200 mg of furazidin.
• a single dosage form has a higher furazidin content than a furazidin composition according to the prior art (100 mg or 50 mg).
• the immediate release component a) may contain 35 to 55 mg of furazidin
• the modified-release component b) may contain 145 to 165 mg of furazidin.
• the immediate release component a) contains 45 to 55 mg of furazidin, and the modified-release component b) contains 145 to 155 mg of furazidin. More preferably, the immediate release component a) contains 50 mg of furazidin, and the modified-release component b) comprises 150 mg 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, 11 to 13 hours, more preferably 12 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.
• the immediate release component a) has, in particular, a furazidin content of 32 to 50 wt.%, preferably 41 to 50 wt.%, more preferably 45 to 46 wt.%, such as 45.45 wt.%, based on the total weight of the immediate release component a).
• the modified release component b) has, in particular, a furazidin content of 40 to 60 wt.%, preferably 52 to 56 wt.%, more preferably 54 to 55 wt.%, such as 53.57 wt.%, based on the total weight of the modified-release component b).
• 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.
• the controlled-release agent may be used in an amount of 4 to 35 wt.%, preferably 9 to 30 wt.%, more preferably 15 to 25 wt.%, based on the total mass of the composition.
• the modified-release component b) may comprise 10 to 40 wt.% of the controlled-release agent, preferably 10 to 35 wt.% and more preferably 20 to 30 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.
• the matrix of the MR component is preferably formed by the pH-independent polymer or the pH- independent polymer and a binder (herein also denoted as “matrix of the pH-independent polymer”).
• furazidin is preferably dispersed or suspended in the matrix, such that the release is modified and prolonged.
• 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.
• 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.
• 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-independenf means independent from the pH value in the gastrointestinal tract, which is usually between 1.5 and 8.5 (stomach and small intestine).
• 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 1.1 to 1.8, preferably 1.3 to 1.6, at each pH of 1.2, 4.5, 6.8 and 7.4, wherein the swollen state is obtained by immersing the dry modified release component b) in 30 to 35 mL of a solution contained in a beaker for 2 h, the beaker being placed in a wiggled, heated bath at 37°C, the solution being a phosphate buffer of pH 4.5, 6.8 or 7.4 or aqueous HC1 of pH 1.2.
• This allows for pH-independent drug permeability and pH-independent drug release from the MR component.
• the modified-release component has, in particular, an in vitro dissolution rate of 5 to 15 wt.% of furazidin within 2 h, based on the total furazidin content of the MR component.
• CTAB hexadecyltrimethylammonium bromide
• the pH-independent polymer provides a MR component having an in vitro dissolution rate at each pH of 1.2, 4.5 and 7.4, which is within a range of ⁇ 10% of the respective in vitro dissolution rate at a pH of 6.8.
• the drug release from the MR component is thus pH-independent.
• the pH-independent polymer is at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose, methylcellulose (MC), xanthan gum, sodium carboxymethylcellulose, non-ionic poly(ethylene oxide), copovidone (vinylpyrrolidone-vinyl acetate copolymer), and any combination thereof. More preferably, the pH-independent polymer has a weight average molecular weight (Mw) of 50,000 to 7,000,000, preferably 350,000 to 800,000.
• Mw weight average molecular weight
• HPMC hydroxypropylmethylcellulose
• CMC carboxymethylcellulose
• HEC hydroxy ethylcellulose
• MC methylcellulose
• copovidone have a weight average molecular weight of 50,000 to 100,000, preferably 45,000 to 70,000.
• the weight average molecular weights are measured by GPC/SEC according to EU Pharmacopoeia 5.0 method 2.2.30.
• Kollidon VA 64 and/or Plasdone S 630 or a combination of hydroxypropylmethylcellulose K15M and copovidone (e.g. Kollidon VA 64 and/or Plasdone S 630).
• Combinations of two pH- independent polymers are preferred for more adequately sustaining and controlling the furazidin release.
• pH-independent polymers can also serve as binders.
• such a compound can be used as both controlled-release agent and binder in the same pharmaceutical composition.
• the immediate release component a) and the modified-release component b) each comprise 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.
• 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.
• 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.
• the immediate release component a) and/or, preferably and, the prolonged-release component b) comprise a filler.
• a filler means at least one filler.
• 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.
• 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.
• 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 10 to 50 wt.%, preferably 10 to 30 wt.%, based on the weight of the immediate release component a).
• the modified-release component b) contains the filler in an amount of 10 to 45 wt.%, preferably 10 to 30 wt.%, based on the weight of the modified-release component b).
• the immediate release component a) and/or the modified-release component b) comprise a binder.
• 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.
• a binder means at least one binder.
• 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.
• 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 0.4 to 5 wt.%, preferably 0.8 to 3 wt.%, more preferably 0.8 wt.%, based on the total mass of the composition.
• the immediate release component a) may contain the binder in an amount of 0.4 to 5 wt.%, preferably 0.4 to 3 wt.%, more preferably 0.5 wt.%, based on the weight of the immediate release component a).
• the modified-release component b) may contain the binder in an amount of 0.4 to 5 wt.%, preferably 0.4 to 3 wt.%, more preferably 0.9 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.
• the immediate release component a) and/or, preferably and, the modified-release component b) comprise a disintegrant.
• a disintegrant means at least one disintegrant.
• 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.
• 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 0.3 to 5 wt.%, preferably 1 to 4.5 wt.%, more preferably 3.6 wt.%, based on the total mass of the composition.
• the immediate release component a) may contain the disintegrant in an amount of 0.5 to 6 wt.%, preferably 2 to 6 wt.%, more preferably 5 wt.%, based on the weight of the immediate release component a).
• the modified-release component b) may contain the disintegrant in an amount of 0.3 to 5 wt.%, preferably 2 to 5 wt.%, more preferably 3 wt.%, based on the weight of the modified-release component b).
• the immediate release component a) and/or, preferably and, the modified-release component b) comprise a lubricant.
• a lubricant means at least one lubricant.
• 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 154, hydrogenated vegetable oil, such as hydrogenated castor oil, and any combination thereof.
• the lubricant is at least one independently selected from magnesium stearate and stearic acid.
• the lubricant may be used in an amount of 1 to 10 wt.%, preferably 2 to 4 wt.%, more preferably 1.3 to 1.4 wt.% such as 1.35 wt.%, based on the total mass of the composition.
• the immediate release component a) may contain the lubricant in an amount of 2 to 4 wt.%, preferably 2.3 wt.%, based on the weight of the immediate release component a).
• the modified-release component b) may contain the lubricant in an amount of 0.5 to 2 wt.%, preferably 1 wt.%, based on the weight of the modified-release component b).
• 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.
• 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 0.3 to 3 wt.%, preferably 0.4 to 2 wt.%, more preferably 0.46 wt.%, based on the total mass of the composition.
• the immediate release component a) may contain the glidant in an amount of 1.4 to 1.7 wt.%, preferably 1.6 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 1.3 wt.%, based on the weight of the modified-release component b).
• 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.
• 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.
• compositions of the present invention are obtained by combining preferred embodiments such as preferred contents and preferred components.
• 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.
• the single dosage form of the pharmaceutical composition contains 150 to 250 mg of furazidin, preferably 180 to 220 mg of furazidin, and more preferably 200 mg of furazidin.
• the immediate release component a) comprises 35 to 55 mg, preferably 45 to 55 mg, more preferably 50 mg, of furazidin
• the modified-release component b) comprises 145 to 165 mg, preferably 145 to 155 mg, more preferably 150 mg, of furazidin.
• the modified-release component b) comprises 10 to 40 wt.%, preferably 10 to 35 wt.%, more preferably 20 to 30 wt.%, of a pH-independent polymer as the controlled-release agent, the pH-independent polymer being at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose, methylcellulose (MC), xanthan gum, sodium carboxymethylcellulose, non-ionic poly(ethylene oxide), copovidone (vinylpyrrolidone-vinyl acetate copolymer), and any combination thereof.
• HPMC hydroxypropylmethylcellulose
• HEC hydroxyethylcellulose
• MC methylcellulose
• xanthan gum sodium carboxymethylcellulose
• copovidone vinylpyrrolidone-vinyl acetate copolymer
• the immediate release component a) comprises 10 to 50 wt.%, preferably 10 to 30 wt.%, of a filler, 0.5 to 6 wt.%, preferably 2 to 6 wt.%, of a disintegrant, 1.4 to 1.7 wt.%, preferably 1.6 wt.%, of a glidant, 2 to
• the immediate release component a) may comprise 0.4 to 5 wt.%, preferably 0.4 to 3 wt.%, more preferably 0.5 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 32 to 50 wt.%, preferably 41 to 50 wt.%, more preferably 45 to 46 wt.%, such as 45.45 wt.%, of furazidin and can consist of furazidin and the aforementioned excipients in the indicated amounts.
• the immediate release component a) contains or consist of 45.5 wt.% of furazidin, 29.5 wt.% of microcrystalline cellulose, 5.0 wt.% of sodium starch glycolate, 15.6 wt.% of maize starch, 1.6 wt.% of colloidal anhydrous silica, 2.3 wt.% of stearic acid and 0.5 wt.% of polyvinylpyrrolidone, based on the total weight of the immediate release component a).
• the modified-release component b) comprises 10 to 40 wt.%, preferably 10 to 35 wt.%, more preferably 20 to 30 wt.%, of the controlled-release agent, 10 to 45 wt.%, preferably 10 to 30 wt.%, of a filler, 0.3 to
• a disintegrant preferably 2 to 5 wt.%, more preferably 3 wt.%, of a disintegrant, 0.4 to 5 wt.%, preferably 0.9 wt.%, of a binder, 0.5 to 2 wt.%, preferably 1 wt.%, of a lubricant, and, optionally, up to 1.3 wt.% of a glidant, based on the total weight of the modified-release component b).
• 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 40 to 60 wt.%, preferably 52 to 56 wt.%, more preferably 54 to 55 wt.%, such as 53.57 wt.%, of furazidin and can consist of furazidin and the consist of furazidin and the aforementioned excipients in the indicated amounts.
• the modified-release component b) contains or consists of 53.6 wt.% of furazidin, 13.6 wt.% of lactose monohydrate, 19.7 wt.% of hydroxypropylmethylcellulose K4M, 8.2 wt.% of hydroxy ethylcellulose, 3 wt.% of croscarmellose sodium, 1.0 wt.% of magnesium stearate and 0.9 wt.% of polyvinylpyrrolidone, based on the total weight of the immediate release component b).
• the IR component and MR component form a bilayer tablet and the MR component contains pH-independent polymer matrix allowing for the modified release of furazidin.
• 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.
• 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 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.
• the dry modified-release component Before swelling, has a thickness in the range of 3.0 to 5.0 mm, preferably 3.5 - 4.0 mm.
• 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 1.1 to 1.8, preferably 1.3 to 1.6.
• 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.
• the pharmaceutical composition is a single dosage form, in particular in the form of a bilayer tablet, and configured to provide, after oral administration, a maximum plasma concentration of furazidin (Cmax) of 353.1 ⁇ 122.5 ng/mL after tmax of 2.5 ⁇ 0.5 hours after administration, and an area under the plasma concentrationtime curve from time zero to 24 hours (AUC0-24) of 1404.1 ⁇ 392.8 ng h/mL, as determined by human PK studies.
• Cmax maximum plasma concentration of furazidin
• AUC0-24 area under the plasma concentrationtime curve from time zero to 24 hours
• the pharmaceutical composition may be configured to provide, after oral administration of a single dosage form, in particular in the form of a bilayer tablet, of the pharmaceutical composition twice a day and 12 hours apart for 3 days, a maximum plasma concentration in steady state (C ma x,ss) of furazidin of 516.4 ⁇ 149.3 ng/mL and an area under the plasma concentration-time curve from time zero to 24 hours in steady state (AUCo-24,ss) of 3498.1 ⁇ 932.2 ng h/mL, as determined by human PK studies.
• C ma x,ss maximum plasma concentration in steady state
• AUCo-24,ss area under the plasma concentration-time curve from time zero to 24 hours in steady state
• CTAB hexadecyltrimethylammonium bromide
• the invention relates to the method of manufacturing the prolonged- release pharmaceutical composition.
• the method 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 particular 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).
• 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).
• no coating is formed, that is, step (d) is preferably not carried out.
• 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 theticianHandbook of Pharmaceutical Excipients" edited by R. C. Rowe, P. J. Sheskey, and S. Owen, Pharmaceutical Press, edition VII.
• 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 “Pharmaceutical Manufacturing Handbook” edited by Shayne Cox Gad, published by John Wiley & Sons, Inc., Hoboken, New Jersey.
• 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.
• 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.
• the IR component a) and/or the MR component b) are prepared using dry granulation (steps (a) and (b)).
• 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) breakingdown the resulting slugs or sheets using a milling technique to produce granules; V) adding the remaining part of lubricant and subsequent blending.
• the primary powder blend particles are aggregated under high pressure using one of two main dry granulation processes: either roller-compaction or slugging.
• 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.
• 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).
• the IR component a) and/or the MR component b) are prepared using wet granulation (steps (a) and (b)).
• 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.
• 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.
• 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.
• 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.
• the prolonged-release pharmaceutical composition is prepared by using a bilayer tableting technology in step (c).
• the present invention provides a method of treating UTI using a pharmaceutical composition as described herein above.
• 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 coH. such as recurrent uncomplicated urinary tract infection in women caused by Escherichia coli.
• the pharmaceutical composition is a single dosage form, such as a bilayer tablet, which is administered orally two times daily, preferably 11 to 13 hours apart, more preferably 12 hours apart.
• the pharmaceutical composition is administered for 5 to 8 days, preferably 7 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.
• the high dosages of furazidin require large dosage forms, with the necessity of taking 2 or 4 tablets, depending on the available presentation, at once 3 or 4 times daily for 7 up to 10 days.
• the pharmaceutical composition is administered in combination with a meal, as absorption of furazidin is improved.
• combination with a meal means that the pharmaceutical composition is taken shortly before, together with or after the meal.
• the pharmaceutical composition is a single dosage form, which is administered orally within an interval of from 30 min before a meal and 30 min after a meal.
• the pharmaceutical composition is administered between at a meal and 30 min after a meal, and more preferably, right after the meal, that is, within 5 min after a meal.
• a single dosage form of the pharmaceutical composition usually contains 150 to 250 mg of furazidin, preferably 180 to 220 mg of furazidin, and more preferably 200 mg of furazidin.
• the immediate release component a) comprises 35 to 55 mg, preferably 45 to 55 mg, more preferably 50 mg, of furazidin
• the modified-release component b) comprises 145 to 165 mg, preferably 145 to 155 mg, more preferably 150 mg, of furazidin.
• 200 mg of furazidin formulated as a fixed dose comprising 50 mg of furazidin in IR component and 150 mg of furazidin in MR component is administered, 2 times daily, for example, for 7 days.
• 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 method of treatment according to the present invention thus provides favourable furazidin pharmacokinetics, which are not obtained by prior art furazidin compositions.
• oral administration of one single dosage form of the pharmaceutical composition provides a maximum plasma concentration of furazidin (Cmax) of 353.1 ⁇ 122.5 ng/mL after tmax of 2.5 ⁇ 0.5 hours after administration, and an area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24) of 1404.1 ⁇ 392.8 ng h/mL, as determined by human PK studies described below.
• oral administration of a single dosage form of the pharmaceutical composition twice a day and 12 hours apart provides after 3 days a maximum plasma concentration in steady state (C ma x,ss) of furazidin of 516.4 ⁇ 149.3 ng/mL and an area under the plasma concentration-time curve from time zero to 24 hours in steady state (AUCo-24,ss) of 3498.1 ⁇ 932.2 ng h/mL, as determined by human PK studies as described below.
• Fig. 1 shows the pharmacokinetic profiles of means in plasma of the food effect study of Example 5.
• Fig. 2 shows the pharmacokinetic profiles of means in urine of the food effect study of Example 5.
• Fig. 3 shows the pharmacokinetic profile of means in plasma of the multiple-dose study of Example 6.
• Fig. 4 shows the pharmacokinetic profile of means in urine of the multiple-dose study of Example 6.
• IR components IR/1 to IR/4
• MR components MR/1 to MR/15
• Table 1 Compositions of exemplary IR components
• IR/1 and IR/2 are prepared as follows:
• step 7 Blending the granulate obtained in step 7 with the part of maize starch, colloidal anhydrous silica (i.e. filler, glidant) after sizing.
• colloidal anhydrous silica i.e. filler, glidant
• IR/3 and IR/4 are prepared as follows:
• step 2 Blending all the components from step 1 except of the lubricant.
• the MR components MR/1 to MR/15 are prepared as follows:
• furazidin lactose monohydrate, hypromellose K4M, hydroxyethylcellulose 250L, croscarmellose sodium or the corresponding compounds (i.e. furazidin, filler, control release agent and disintegrant) in a high shear granulator.
• 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 3).
• a bilayer tablet having the composition of IR/l+MR/1 in total 200 mg 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 6 tablets are indicated in Table 4.
• Table 5-1 shows dissolution results of selected MR components at a pH of 6.8.
• the MR components were pressed to tablets and subjected to a dissolution test using the above conditions.
• the sampling times are indicated in Tables 5-1 to 5-4.
• the mean value calculated from 6 samples is indicated. le 5-1.
• Dissolution data for exemplary MR components, pH 6.8
• Example 3 the swelling properties of the MR component having a pH-independent polymer matrix and the dissolution of furazidin from the MR component were investigated.
• 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 2 h mean retention time of the tested tablet in the stomach a after meal.
• Sample preparation Tablets, having the composition indicated in Tables 6-1 to 6-4 below, were produced as described above in Example 1.
• the beaker is placed in wiggled, heated bath at a temperature of 37°C.
• the tablets are incubated for 2 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).
• the swollen MR component i.e. the MR component is the swollen state
• 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 5 tablets was calculated.
• Table 6 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 2h 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 2h time point showed a release of furazidin on the level of about 20 to 30 wt.% (a range of 10 to 35 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 7 wt.% (a range of 5 to 15 wt.% was considered acceptable) for the MR component MR/3 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.
• the final composition was packed in blisters, SBC 180/aluminum foil, and stored at long term (25°C/60% RH), intermediate (30°C/65% RH) and accelerated (40°C/75% RH) conditions.
• the level of impurities and the content of active substance were determined by HPLC according to the method disclosed in Journal of Pharmaceutical and Biomedical Analysis, Vol. 129 (2016), 433-440. The results are presented in Tables 8, 9 and 10.
• the requirements for the parameters tested during the stability study were established according to guidelines CPMP/ICH/367/96 (ICH Q6A), and CPMP/ICH/2738/99 (ICH Q3B (R2)). Table 9.
• Example 5 Phase I Clinical Trial Pivotal food effect study FUR-PK-03-19 (755/19) Study title: Randomized, open-label, three-period, cross-over, food effect pharmacokinetic study comparing bioavailability of furazidin, prolonged-release tablets, 200 mg having a composition of IR/l+MR/1 according to Example 1 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.
• the pharmacokinetic data for plasma and urine were statistically analysed in 29 subjects. After single oral administration of furazidin, prolonged-release formulation, 200 mg to the healthy volunteers, peak plasma concentrations were reached at 2 hours (median) following administration under recommended fed conditions (high-protein meal). Cmax and AUCO-24 reached 353.1 ⁇ 122.5 ng/mL and 1404.1 ⁇ 392.8 ng*h/mL, respectively. Plasma concentrations of furazidin showed a mean terminal half-life of 1.0 hour in healthy subjects. The mean urine concentrations of furazidin under recommended fed conditions achieved 9971.867 ⁇ 3145.830 pg for Aeo-t and 1933.965 ⁇ 841.315 pg/h for Rmax. Peak urine concentrations were reached at 5 hours.
• AUC Total exposure
• AUC(6-24) Largest difference in exposure after meals versus fasting state is observed after 6 hours (AUC(6-24)), 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 6 to 24 hours about 5.6- 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 50 mg tablets).
• Aeo-t amount of unchanged drug excreted into the urine calculated as area under the urinary excretion rate curve from time zero to the last measurable rate
• Aeo-t amount of unchanged drug excreted into the urine calculated as area under the urinary excretion rate curve from time zero to the last measurable rate
• Aeo-t amount of unchanged drug excreted into the urine calculated as area under the urinary excretion rate curve from time zero to the last measurable rate
• Bioavailability was found to be 1.9-fold higher after high-protein meal and 2.5-fold higher after high-calorie/high-fat meal than under fasting conditions, (i.e. bioavailability after high- protein meal is about 25% lower than after high-calorie/high-fat meal).
• Peak plasma concentration was found to be 1.4-fold higher after high-protein meal and 1.7- fold higher after high calorie/high-fat meal than under fasting conditions, (i.e. peak plasma concentration after high-protein meal is about 19% lower than after high-calorie/high-fat meal).
• excreted amount of unchanged drug was found 1.9-fold higher after high-protein meal and 2.5-fold higher after high-calorie/high-fat meal than under fasting conditions, (i.e. excreted amount of unchanged drug after high-protein meal is about 25% lower than after high- calorie/high-fat meal).
• Urine excretion rate was found 1.4-fold higher after high-protein meal and 1.6-fold higher after high-calorie/high-fat meal than under fasting conditions, (i.e. urine excretion rate after high-protein meal is about 13% lower than after high-calorie/high-fat meal).
• the 90% confidence intervals for fedl*/fast, fed2*/fast and fedl*/fed2* ratios of LSM, based on In-transformed data of AUC(o-t) and Cmax were not found within the equivalence limits of 80.00-125.00 %. Hence, a significant food effect was confirmed.
• Furazidin administered orally should be taken at or after meals as this increases its bioavailability irrespective of the formulation or mechanisms of the drug release (MR or IR). Differences in concentrations after high-protein meal and after high-fat, high-calorie meal are statistically significant.
• 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.
• Test product 6 doses administered orally with 240 mL of water under fed (high-protein meal) conditions. Oral administration of one tablet given two times a day (12 hours interval apart). Total dose per day was 400 mg of furazidin. Dosing for 3 consecutive days (on Day 1, Day 2 and Day 3 twice a day). Multiple oral dose of Comparator product (9 doses) administered orally with 240 mL of water under fed (high- protein meal) conditions.
• the washout period was at least 7 days between the last dose in Period 1 and the first dose in Period 2. Blood samples were collected throughout a 76-hour period after the first IMP administration to characterize products absorption and elimination. Urine samples were collected over 24 hours post first dose on Day 1-Day 2 and over 28 hours post the first dose on Day 3 -Day 4.
• PK metrics AUC0-24, Cmax and AURC0-24
• PK metrics AUCo-24,ss (to reflect safety) and AURCo-24,Day3 (to reflect efficacy).
• 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 5 times the plasma elimination half-life. This is not unexpected as the elimination half-life is approximately 1 hr and so, by the 12-hour interval, more than 95% 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 12-hour dosage interval were essentially repeat single doses.
• the AUCo-24h, Cmax and AURCo-24h for Day 1 and AUCo -24h,ss and AURCo -24h,Day3 for Day 3 for furazidin were used to assess equivalence between both tested formulations.
• the results confirm that the 90% 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 80.00% to 125.00%.
• tmax ss The time of maximum plasma drug concentration (h)
• Furazidin is mainly absorbed in the upper part of the small intestine. Bioavailability was found 1.9-fold higher after high-protein meal than under fasting conditions.
• the peak serum concentration 353.1 ⁇ 122.5 ng/mL (Cmax) was reached within approx. 2.5 hour (tmax)
• AUCo-24 reached 1404.1 ⁇ 392.8 ng*h/mL.
• the maximum serum concentration 256.7 ⁇ 87.3 ng/mL (Cmax) was reached within 2 hours (tmax).
• furazidin prolonged-release tablet 200 mg to the healthy volunteers for 3 days (twice a day, 12 hours apart), peak plasma concentrations were reached at about 51 hours following administration under fed conditions (high-protein meal).

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