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WO2002039992A2 - Composes d'addition d'agents antibacteriens quinoloniques avec des polymeres de polysaccharides naturels - Google Patents

Composes d'addition d'agents antibacteriens quinoloniques avec des polymeres de polysaccharides naturels Download PDF

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Publication number
WO2002039992A2
WO2002039992A2 PCT/IB2001/002171 IB0102171W WO0239992A2 WO 2002039992 A2 WO2002039992 A2 WO 2002039992A2 IB 0102171 W IB0102171 W IB 0102171W WO 0239992 A2 WO0239992 A2 WO 0239992A2
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WO
WIPO (PCT)
Prior art keywords
adduct
aqueous solution
weight
solution
water
Prior art date
Application number
PCT/IB2001/002171
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English (en)
Other versions
WO2002039992A3 (fr
Inventor
Piergiorgio Anzaghi
Rosanna Stefli
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Pharma Biotech Limited
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Filing date
Publication date
Application filed by Pharma Biotech Limited filed Critical Pharma Biotech Limited
Priority to AU2002212631A priority Critical patent/AU2002212631A1/en
Publication of WO2002039992A2 publication Critical patent/WO2002039992A2/fr
Publication of WO2002039992A3 publication Critical patent/WO2002039992A3/fr

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention concerns adducts of natural polysaccharide polymers with active ingredients belonging to the class of quinolonic drugs with improved therapeutic activity.
  • the polymer conjugated with the antibiotic can be active as such or, if the "linker” is biodegradable, it behaves as a prodrug that afterwards is bioactivated in vivo, releasing the antibiotic.
  • this approach is expensive and complicated since it is necessary to chemically characterize the compound, in so far as it proves to be a new chemical product and therefore study once again its pharmacptoxicology, pharmacokinetics and clinical efficacy.
  • SUMMARY OF THE INVENTION The Applicant has now surprisingly found some adducts of quinolonic antibacterial agents, characterized in that the percentage of said active ingredient is between 40 and 80% by weight calculated on the total weight of the adduct.
  • the adducts according to the present invention are in powder form or in the form of an aqueous solution that preferably contains them in a concentration of between 0.1 and 1% by weight calculated on the total weight of the aqueous solution.
  • the present invention further relates to the process for preparing the aforesaid adducts which, in particular, comprises the following steps: a) preparing the solution of the polysaccharide polymer in water in a percentage of ingredient of between 20 and 60% by weight on the total weight of the adduct and adding the active ingredient, thereby obtaining a concentration of the adduct being preferably comprised in the aforesaid intervals, b) filtering the aqueous solution thus obtained, in case the adduct in aqueous solution form is achieved, c) removing water thereby obtaining the adduct according to the present invention in powder form.
  • the present invention further relates to pharmaceutical compositions containing the adducts according to the present invention in association with suitable ex
  • the present invention represents an optimum form for administering both orally and parenterally quinolonic antibacterial drugs to be used in the treatment of infections caused by Gram-negative and Gram-positive bacteria.
  • the present invention concerns adducts between an active ingredient, belonging to the class of Quinolones, and a natural biocompatible polysaccharide, able to interact without forming covalent and ionic bonds.
  • the adducts can be administered both orally and parenterally, depending on the physical-chemical characteristics and the pharmacodynamic and pharmacokinetic profile of the active ingredient.
  • the active ingredients used in the adducts according to the present invention are preferably nalidixic acid, pipemidic acid, cinoxacin, norfloxacin, cyprofloxacin, pefloxacin, enoxacin, ofloxacin and the levo form thereof levofloxacin. These are mainly used in the treatment of infections caused by Gram-negative and positive bacteria and their action mechanism consists in blocking DNA synthesis by inhibiting the DNA enzyme gyrase. More in detail, norfloxacin is effective in urinary, enteric and gonorrhea infections, at a dosage of 800-1200 mg/die through oral administration.
  • Cyprofloxacin is suitable for urinary, respiratory, gastrointestinal and cutaneous infections and in osteomyelitis, since it is effective against Gram-negative organisms (E. Coli, Klebsiella, Salmonella typhi, Neisseria gonorrhoea et meningitidis, Haemophilus influentiae), Gram-positive (Staph. aureus et epidermidis, listeria) and Mycobacterium tubercolosis. It can be orally administered in the corresponding hydrochloride salt with daily doses of 500-1000 mg or, in more serious cases, intravenously in amount of 800-1200 mg/die in the corresponding lactate salt (A. Kucers et. N.Mck Bennett, The use of Antibiotics, 4 th ed., Heinemann Medical Books, 1989).
  • the percentage of the quinolonic antibacterial agent calculated on the total weight of the adduct is 60%.
  • the natural polysaccharide polymers dextrans are preferred, inulin and, for oral preparations, maltodextrins of pharmaceutical grade.
  • Dextrans are polymers formed by linear chains of molecules of ⁇ -D- glucose and may exhibit very different molecular weights, ranging from 1000 Dalton (dextran 1 ) to 110000 Dalton (dextran 110) and do not undergo enzymatic degradation. Hydrophilia and therefore the solubility in water decreases with the increase of molecular weight.
  • the dextrans with molecular weights lower than 4000 are completely excreted with urine within 48 hours, while those having higher molecular weights remain in circulation for longer periods of time.
  • Preferred in the present invention are 4-70 dextrans.
  • the maltodextrins consist of a branched polymer of maltose and dextrins in which the D-glucose units are mainly linked by ⁇ bond (1-4), but also (1-6) in the branched portions. They show a molecular weights ranging from 900 to 9000 Dalton. Also inulin is a natural polysaccharide linear structure constituted by fructose molecules with a molecular weight of 5000, it does not undergo enzymatic degradation and is excreted with urine, so that it is used in the medical field as a diagnostic means of renal functionality.
  • the selected natural polysaccharides are biocompatible and inert and therefore their quinolones adducts do not present problems with quinolones insofar as it concerns toxicity and also from an immunological stand point.
  • the preparation of the adducts envisages the solution of the polymer in water, in a percentage that may vary between 20 and 60% in weight, and the subsequent addition of the active ingredient, allowing the hydrophilic interaction of carboxylic and aminic groups of the antibacterial agent with those of the polymer. Weak hydrogen type bonds are thus formed with lower interaction forces if compared to covalent or ionic type bonds (Remington's Pharmaceutical Science 18 th ed. p. 186).
  • the polymer and the drug are dissolved in distilled water (optionally with buffers and preservatives), filtering is performed to obtain a clear solution.
  • filtering is performed to obtain a clear solution.
  • the solvent is removed from the adduct through a process of freeze-drying or nebulization (spray drying) thereby obtaining the adduct in solid form.
  • depyrogenated and sterile (w.f.p.) distilled water is used and the solution is filtered, with filters of from 0.1 to 0.2 ⁇ m porosity, then placed in depyrogenated and sterilized phialoids in a sterile environment, and preferably freeze-dried.
  • the solution can be readily reconstituted by adding an aqueous solvent such as w.f.p. water or a physiological solution.
  • Distilled water is used for the preparation of oral forms and the solution is filtered on filters of 0.45 ⁇ m porosity.
  • the solvent is removed preferably through nebulization, and a solid porous adduct is obtained suitable for the preparation of pharmaceutical forms for oral use, such as tablets, capsules and granules.
  • the titre of the active ingredient in the adduct was detected by HPLC, using a Perkin-Elmer LC75 chromatograph with an LC Pump 414-T Karitron Analytical injector, Waters detector-integrator and a Lichrosorb column RP18.
  • an adduct with a polysaccharide of low molecular weight can increase the solubility of a poorly soluble antibacterial agent and accordingly, if orally administered the same adduct can increase its bioavailibility.
  • an adduct with a high molecular weight polysaccharide can prolong the time the drug remains in circulation and therefore the same can prolong its effect.
  • the presence of reduced active ingredient doses lowers the toxicity with equal antibacterial activity.
  • the adducts in the form of aqueous solutions according to the present invention can be prepared with a process that in particular comprises the following steps: a') dissolving the active ingredient in distilled water, b') filtering the aqueous solution coming from the previous step, c') removing water, preferably by freeze-drying, from the product coming from in the previous step, d') reconstituting the aqueous solution by addition of water or other w.f.p. solvent, in which the polysaccharide polymer is dissolved, thereby obtaining a concentration of the adduct in said aqueous solution preferably comprised between 0.1 and 1% in weight.
  • the adducts of the present invention were obtained with simple, quick and economic processes if compared to the traditional synthetic approaches, which envisage the formation of a covalent or saline bond between the antibacterial agent and the polymer, therefore resulting less expensive.
  • 1.51 g of ivory coloured adduct are obtained in granular powder form, soluble in water and with a norfloxacin titre of 59.5% by weight.
  • the adduct is suitable to be formulated in capsules, sachets, and after being compressed in tablets.
  • EXAMPLE 2 Preparation of the solid adduct: 50% dextran - 50% norfloxacin 1 g of dextran 5 is dissolved in 1 L of distilled water and 1 g of norfloxacin is added to the solution, bringing the pH to the value of 4.8 by the addition of 1N HCI. The solution is filtered with a filter of 0.45 ⁇ m porosity and the solvent is removed by spraydrying as described in example 1. 1.87 g of whitish coloured adduct are obtained in the form of a light powder, with a norfloxacin titre of 49% in weight. The powder added with suitable excipients can be placed in sachets or formulated into capsules or directly compressed.
  • the freezer-dryer is programmed to perform the freeze- drying cycle at the following temperatures: -35°C for prefreezing, -10°C during freeze-drying, +10°C for primary drying and +35°C for secondary drying, while maintaining the vacuum at 2.2 0 "2 mbar.
  • 1.6 g of dextran 5 are dissolved in a volume of 800 ml of w.f.p. water under magnetic stirring 3.1 g of cyprofloxacin lactate equal to 2.43 g of cyprofloxacin are then added, while adjusting the pH with 1 N HCI until complete solution.
  • the solution is brought to 1.5 L with w.f.p. water, filtered with a sterilizing filter with 0.2 ⁇ m porosity and placed in depyrogenated and sterilized vials, in a ratio of 37.5 ml/vial.
  • the cyprofloxacin titre in the solution is 60.5%.
  • EXAMPLE 6 PREPARATION OF THE SOLID ADDUCT: 40% DEXTRAN - 60% CYPROFLOXACIN
  • the adduct solutions of example 5 are subjected to freeze-drying following the same cycle described in example 4.
  • the freeze-dried substance obtained is compact with a cyprofloxacin titre of 60.4% by weight. It can be readily reconstituted by slow infusion with the addition of 30 ml of physiological solution.
  • EXAMPLE 7 Preparation of the solution of the adduct: 40% inulin - 60% cyprofloxacin
  • the inhibition halos were obtained with the diffusion method (FUI X ed., p. 135), using a Mueller-Hinton Medium Difco culture medium (with low thymine and thymidine content) conforming to the MG-P standards of the NCCLS in 9 cm diameter sterile Petri dishes and Tryptic soy broth (Difco).
  • Small discs of filter paper were prepared for the sensitivity test, by soaking them in a quinolonic antibacterial agent at defined concentrations, and the corresponding adduct small discs were prepared, in which the total dose is the same, but the active ingredient content by weight is lower.
  • Broth cultures were prepared placing a bacterial patina loop of a culture in agar of 12 h in a test tube containing 5 ml of Sterile Tryptic Soy Broth and then incubated at 37° C for 4 h. If necessary, the suspensions were diluted with sterile water to obtain a similar turbidity to the reference standard (0.5 Mc Fariand).
  • EXAMPLE 9 Determination of the in vitro minimum inhibiting concentration (MIC)
  • the MIC values were calculated with the method of dilutions in liquid medium (F. Pasquinelli, Manual for laboratory technicians, vol. II, pp. 1286-89, 1968), using a Mueller-Hinton broth at pH 7.4, sterilized at 120°C for 20 minutes.
  • a series of test tubes containing a fixed medium volume of medium scalar concentrations by doubling the concentration of the active ingredient were added, from 0.1 ⁇ g/ml to 10 ⁇ g/ml.
  • the same procedure was also followed for the adducts.
  • a drop of 1 :10 dilution of the broth culture was added to all the test tubes and were incubated at 37°C for 18-24 hours. After this time, the test tube with the highest dilution in which turbidity was not observed was considered as the one containing the minimum inhibiting concentration.
  • Table II The results obtained are contained in Table II.
  • adducts of the present invention of quinolonic antibacterial agents and natural polysaccharide polymers show, in the in vitro and in vivo tests of antimicrobial activity in mice, a comparable activity or slightly higher than that of the active ingredient alone, although they contain it in lower amounts, thus reducing the cost of the therapy.
  • these adducts are obtained with a quick, economic process which is suitable for the subsequent preparation of parenteral forms and, if combined with suitable excipients for the preparation, of oral forms for the treatment of infections due to Gram-positive and Gram-negative bacteria in animals and humans.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Abstract

Cette invention se rapporte à des composés d'addition de polymères de polysaccharides naturels avec des agents antibactériens quinoloniques, se présentant sous la forme de solutions aqueuses ou de poudres solides et qui possèdent une efficacité thérapeutique identique comparée à celle du principe actif correspondant seul, utilisé aux mêmes doses. Ils possèdent par conséquent une toxicité inférieure avec une activité antimicrobienne égale.
PCT/IB2001/002171 2000-11-17 2001-11-16 Composes d'addition d'agents antibacteriens quinoloniques avec des polymeres de polysaccharides naturels WO2002039992A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002212631A AU2002212631A1 (en) 2000-11-17 2001-11-16 Adducts of quinolonic agents with natural polysaccharide polymers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2000A002476 2000-11-17
IT2000MI002476A IT1319664B1 (it) 2000-11-17 2000-11-17 Addotti di antibatterici chinolonici con polimeri polisaccaridicinaturali.

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WO2002039992A2 true WO2002039992A2 (fr) 2002-05-23
WO2002039992A3 WO2002039992A3 (fr) 2002-08-01

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1459739A1 (fr) * 2003-03-19 2004-09-22 The Jordanian Pharmaceutical Manufacturing Co. Ltd. Non hygroscopique Compositions pharmaceutiques contenant non-hydrate Quinilone acide carboxylique
EP1930006A4 (fr) * 2005-09-28 2010-10-13 Daiichi Sankyo Co Ltd Procédé de production de préparation lyophilisée contenant de la quinolone
CN102824319A (zh) * 2012-09-27 2012-12-19 西南大学 增效氧氟沙星冻干粉针剂及其制备方法
JP2013523676A (ja) * 2010-03-29 2013-06-17 フェリング ベスローテン フェンノートシャップ 速溶解性医薬組成物
JP2014526483A (ja) * 2011-09-16 2014-10-06 フェリング ベスローテン フェンノートシャップ 速溶性医薬組成物
CN110755374A (zh) * 2019-11-22 2020-02-07 南京知和医药科技有限公司 一种左氧氟沙星注射液及制备工艺

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL80459A (en) * 1986-10-30 1991-04-15 Abic Ltd Water-soluble adduct of norfloxacin and nicotinic acid
IT1312110B1 (it) * 1999-05-18 2002-04-04 Istituto Biochimico Pavese Pha Addotti antibiotico-polimero polisaccaridico naturale

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1459739A1 (fr) * 2003-03-19 2004-09-22 The Jordanian Pharmaceutical Manufacturing Co. Ltd. Non hygroscopique Compositions pharmaceutiques contenant non-hydrate Quinilone acide carboxylique
EP1930006A4 (fr) * 2005-09-28 2010-10-13 Daiichi Sankyo Co Ltd Procédé de production de préparation lyophilisée contenant de la quinolone
US8129533B2 (en) 2005-09-28 2012-03-06 Dalichi Sankyo Company, Limited Method for production of quinolone-containing lyophilized preparation
JP2013523676A (ja) * 2010-03-29 2013-06-17 フェリング ベスローテン フェンノートシャップ 速溶解性医薬組成物
JP2014526483A (ja) * 2011-09-16 2014-10-06 フェリング ベスローテン フェンノートシャップ 速溶性医薬組成物
US9731018B2 (en) 2011-09-16 2017-08-15 Ferring B.V. Fast dissolving pharmaceutical composition
CN102824319A (zh) * 2012-09-27 2012-12-19 西南大学 增效氧氟沙星冻干粉针剂及其制备方法
CN110755374A (zh) * 2019-11-22 2020-02-07 南京知和医药科技有限公司 一种左氧氟沙星注射液及制备工艺

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ITMI20002476A1 (it) 2002-05-17
AU2002212631A1 (en) 2002-05-27
WO2002039992A3 (fr) 2002-08-01
IT1319664B1 (it) 2003-10-23

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