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
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

• the present invention relates to a gastric-retention sustained-release multi-layer Nitrofurantoin-based tablet .
• Nitrofurantoin is an antibacterial active ingredient of the nitrofuran class, mostly used for the treatment of urinary tract infections. It is an antibiotic molecule having bactericidal or bacteriostatic action, depending on the dose administered. In urinary tract infections, the dosage of the sustained-release form is 100 mg every 12 hours.
• a sustained-release reference product is commercially available. Such product, sold in capsule form, is formulated using two different forms of Nitrofurantoin : Nitrofurantoin macrocrystals (having greater transit rate in solution) and Ni trofurantoin monohydrate (having lower transit rate in solution) .
• Nitrofurantoin macrocrystals having greater transit rate in solution
• Ni trofurantoin monohydrate having lower transit rate in solution
• the commercially available capsule is a Nitrofurantoin-based formulation, which is prescribed to be taken on a full stomach.
• Data in the literature show that the absorption of the active ingredient occurs in a limited tract of the first portion of the small intestine, mainly in the duodenum, whereby the active ingredient needs to be released gradually from the stomach, so as not to cross the area of greatest absorption too quickly.
• Nitrofurantoin- based products should be administered on a full stomach, so as to increase gastric retention of the pharmaceutical form, with a sustained release of Nitrofurantoin over time.
• the use of two different types of Ni trofurantoin further complicates its formulation.
• Preoperative use in hospitals involves administration in the fasted state, a condition wherein the product does not have optimal absorption. This implies a need to increase the dosage, up to its doubling.
• absorption of the reference product by the body is about 40% lower on an empty stomach than on a full stomach.
• the pylorus is fully opened approximately every 2 hours, allowing the solid contents present having dimensions lower than about 15 mm to be emptied.
• the commercially available oral solid pharmaceutical forms may therefore remain there from 0 to about 2 hours. This constitutes a significant problem, since the current pharmaceutical forms are not capable of reproducing the absorption kinetics of nitrofurantoin which is specific of administration on a full stomach and needed for an appropriate pharmacological effect in the absence of overdosing.
• the technical problem addressed by the present invention is therefore that of improving the absorption kinetics of nitrofurantoin, also in the case wherein it is administered on an empty stomach, as is the case of preoperative administration.
• Nitrofurantoin- based preparations are used before certain surgical procedures, as prophylaxis for urinary tract infections. Since the patient must fast over the preceding 10/12 hours in surgical procedures requiring general anesthesia, Nitrofurantoin should be administered on an empty stomach.
• a further object of the invention is a formulation containing Nitrofurantoin having dimensions which are sufficiently small to be easily swallowed and, at the same time, sufficiently large after swelling, to be retained in the stomach for such a period allowing the complete release of the active ingredient Nitrofurantoin from a sustained-release pharmaceutical form useful for obtaining the desired plasma concentrations, on an empty stomach and on a full stomach.
• the object of the invention is a Nitrofurantoin-based tablet with heterogeneous compartments, as defined in the appended claims, the definitions of which form an integral part of the present description.
• Yet another object of the invention is a sustained- release swelling double-layered Nitrofurantoin-based pharmaceutical form.
• Yet another object of the invention is a sustained- release swelling three-layer Nitrofurantoin-based tablet .
• Yet another object of the invention is a swelling tablet, formed by a drug-free core and covered by a coating containing the sustained-release Nitrofurantoin- based active ingredient.
• Yet another object of the invention is a swelling tablet having different compartments, so as to be capable of modulating the release rate of the active ingredient, depending on the outer contact surface of the compartment containing the active ingredient.
• the above-mentioned forms may further comprise a polymer-based film capable of making elastic films, which allow the pharmaceutical form to swell.
• a polymer-based film capable of making elastic films, which allow the pharmaceutical form to swell.
• EUDRAGIT NE 30 D neutral ethyl acrylate- methyl methacrylate copolymer
• EUDRAGIT RL 100 copolymer of ethyl acrylate, methyl methacrylate and low content of methacrylic acid esters with quaternary ammonium groups
• EUDRAGIT RS 100 copolymer of ethyl acrylate, methyl methacrylate and low content of methacrylic acid esters with quaternary ammonium groups
• Kollicoat SR 30D polyvinyl acetate.
• a different object of the invention is furthermore a process for preparing the formulation of the invention as defined in claims 8 to 10.
• Figure 1 shows three different embodiments of double-layered tablets according to the invention
• Figure 2 shows a graph illustrating the dissolution profile of the tablets of Figure 1;
• Figures 3, 4 and 5 show the tablets of Figure 1 in a swelling condition.
• the present invention relates to a sustained-release double-layered Nitrofurantoin-based tablet.
• the double-layered tablet object of this invention comprises two layers of swelling polymers and other excipients suitable for pharmaceutical use, with one layer containing the active ingredient Nitrofurantoin, and the other one being inert, containing excipients only .
• Nitrofurantoin is an antibacterial active ingredient of the nitrofuran class, mostly used against urinary tract infections.
• the generally recommended daily dosage is 100 mg of Nitrofurantoin every 12 hours, for 5 days.
• the swelling polymers are hydrophilic polymers selected from carbopols, alginates, chitosans, hydroxypropyl methylcellulose and polyethylene oxides, more preferably hydroxypropyl methylcellulose or polyethylene oxides.
• the further pharmaceutically acceptable excipients are selected, for example, from a diluent, a flowability agent, a lubricant, other polymers imparting swelling, or mixtures thereof.
• the formulation comprises the following percentage composition by weight:
• the double-layered tablets of the invention comprise a filming layer comprising an elastic, permeable polymeric film, preferably selected from EUDRAGIT NE 30 D (neutral ethyl acrylate-methyl methacrylate copolymer) , EUDRAGIT RL 100 (copolymer of ethyl acrylate, methyl methacrylate and low content of methacrylic acid esters with quaternary ammonium groups), EUDRAGIT RS 100 (copolymer of ethyl acrylate, methyl methacrylate and low content of methacrylic acid esters with quaternary ammonium groups), Kollicoat SR 30D, polyvinyl acetate.
• EUDRAGIT NE 30 D neutral ethyl acrylate-methyl methacrylate copolymer
• EUDRAGIT RL 100 copolymer of ethyl acrylate, methyl methacrylate and low content of methacrylic acid esters with quaternary ammonium groups
• the total height of the tablets is from 8.2 to 8.4 mm, wherein the height of the layer containing the active ingredient Nitrofurantoin is from 0.5 to 2 mm.
• Nitrofurantoin For the layer containing the active ingredient Nitrofurantoin, about 150 mg of granules containing Nitrofurantoin and Hydroxypropyl methylcellulose 2208 were used, in a % by weight ratio of 70:30 (Table 2) .
• Eudragit RL:Triethyl citrate:Talc in a weight ratio of 10:1:5 in a mixture of acetone : isopropanol : water in a ratio of 8:12:1.
• the formulation of the invention may furthermore comprise further excipients, such as for example a diluent, a flowability agent, a lubricant and/or other polymers which impart swelling.
• a technical problem inherent in the production of tablets is related to the availability of powders with high compaction and flowability characteristics.
• the powders that make up the mixture to be compacted are subjected to a granulation process.
• a granulate Compared to the powder from which it derives, a granulate has a set of characteristics that make it optimal for certain types of processing. Greater particle size improves its flowability and compaction properties and the aggregation of a powder in granules prevents typical phenomena of segregation and dispersion of fine powders. Furthermore, a granulate is less susceptible to changes due to ambient humidity than a powder, thus simplifying shipping and storage of the material. All these characteristics favor the industrialization of the production process of double layered Nitrofurantoin tablets.
• NM DG batch dry granulation
• NM H 2 O WG batch wet granulation with water
• NM E50 WG batch wet granulation with water and Hydroxypropyl methylcellulose 2910
• NM DG batch Using the rotary tablet press equipped with concave circular punches having a diameter of 8 mm, compacts were prepared, filling the die with Nitrofurantoin monohydrate, applying compression forces from 4 to 8 kN. The compacts obtained are ground in a mortar with the aid of a pestle. The product passing through a 1000 mm mesh sieve is collected and referred to as the NM DG batch .
• NM E50 WG About 35 g exactly weighed of Nitrofurantoin monohydrate and about 15 g exactly weighed of Hydroxypropyl methylcellulose 2208 are wet with 12.3 g of solution of Hydroxypropyl methylcellulose 2910 in demineralized water (4%, w:w) in a mortar and, with the aid of a pestle, a paste is produced which is passed through a 1000 mm-sided mesh web thanks to a granulator with rocker arms. The product is dried overnight in a stove at 40 °C and then passed again through a 1000 mm- sided mesh sieve. The batch is referred to as NM E50 WG.
• the total height of the tablets is from about 8.2 to 8.4 mm.
• the layer containing the active ingredient Nitrofurantoin has a height from about 0.5 to 2 mm.
• Figure 1 shows the images of the three batches of double-layered tablets resulting from the different types of granulation.
• Another problem addressed in the implementation of the present invention is that of obtaining a double layered tablet with sufficiently high bioavailability, in particular as regards the release of the active ingredient Nitrofurantoin .
• the dissolution profile may be easily modulated based on the surface of the compartment containing the active ingredient. Therefore, if we introduce two compartments containing the active ingredient around the same bulk (three-layer tablet) , we will have a proportionally increased release. Likewise, the drug-free compartment may be covered with a coating containing the active ingredient. This may be achieved with different techniques, such as for example double compression, or covering the cores in a fluid bed. The coated tablet shows an even faster dissolution profile.
• Table 7 lists the results obtained for each of the three batches produced and the single drug-free layer.
• FIGS 3, 4 and 5 show the swelling of the three batches of double-layered tablets produced.
• the three batches of double-layered tablets produced according to the invention have high bioavailability, a high degree of swelling and therefore improved release even on an empty stomach, with a consequent improvement in the treatment of urinary tract infections, compared to prior art formulations.
• the dimensional swelling is:
• the formulation may be administered on an empty stomach and may be used by patients in a preoperative condition.
• the process of the invention has furthermore allowed obtaining a sustained-release Nitrofurantoin formulation, capable of being retained at the gastric level, favoring the sustained release of the active ingredient, by using only one form of Nitrofurantoin (monohydrate, macrocrystals or anhydrous) .

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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• Bioinformatics & Cheminformatics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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Citations (4)

• 2019
  • 2019-01-22 IT IT102019000000897A patent/IT201900000897A1/it unknown
• 2020
  • 2020-01-21 WO PCT/IB2020/050444 patent/WO2020152581A1/en active Application Filing

Patent Citations (4)

Non-Patent Citations (1)

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