EP1991224A2 - Use of piperacillin in topical intravaginal preparations for the treatment of vaginal bacterial infections - Google Patents

Use of piperacillin in topical intravaginal preparations for the treatment of vaginal bacterial infections

Info

Publication number
EP1991224A2
EP1991224A2 EP07713470A EP07713470A EP1991224A2 EP 1991224 A2 EP1991224 A2 EP 1991224A2 EP 07713470 A EP07713470 A EP 07713470A EP 07713470 A EP07713470 A EP 07713470A EP 1991224 A2 EP1991224 A2 EP 1991224A2
Authority
EP
European Patent Office
Prior art keywords
piperacillin
topical
gram
use according
vaginal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07713470A
Other languages
German (de)
English (en)
French (fr)
Inventor
Enrico Boldrini
Giulia Falcone
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Opocrin SpA
Original Assignee
Opocrin SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Opocrin SpA filed Critical Opocrin SpA
Publication of EP1991224A2 publication Critical patent/EP1991224A2/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina

Definitions

  • the present invention concerns the use of piperacillin in topical intrav- aginal preparations for the treatment of gynaecological and obstetric bacterial vaginal infections. More specifically, the invention concerns the use of a broad-range semi-synthetic ⁇ -lactamic antibiotic, piperacillin, for the production of bactericide preparations effective on pathogens responsible for vaginal ecosystem alterations and which lend themselves to the treatment and pre- vention of gynaecological and obstetric bacterial infections via topical vaginal application.
  • Bacterial vaginosis previously known as "aspecific vaginitis", was recognised at the end of the nineteenth century and then more clearly identified in the 1950s as a bacterial syndrome characterised by the depletion of the micro-organisms in the normal vaginal flora, and particularly the lactobacilli, with a simultaneous increase, up to 100-1,000 times the normal quantities, of the pathogenic vaginal anaerobic bacteria, including Gardnerella vaginalis, Mobiluncus spp., Prevotella spp., Mycoplasma spp. and, in particular, Mycoplasma hominis, and Bactericides spp..
  • vaginal pathology not classifiable as specific vaginitis or as bacterial vaginosis, characterised by a pH above 5, by yellowish and malodorous secretions (but negative in the "fish odour test” or "whiff test"), inflammatory manifestations and disparheunia.
  • vaginal lactate As in bacterial vaginosis, the concentration of vaginal lactate is depressed also in aerobic vaginitis, but unlike patients with bacterial vaginosis, the vaginal succinate is not produced in the aerobic pathology. A further difference is that aerobic vaginitis causes an immune response in the host; this mostly leads to a high production of interleukin-6 with interleukin 1-b.
  • the treatment regimen for bacterial vaginosis consist of 500 mg of metronidazole or 300 mg of clindamycin for oral therapy twice a day for seven days. These doses turned out to be equivalent to topical treatment with clindamycin in the form of 2% vaginal cream or with metronidazole in vaginal gel, administered daily in 5 g doses, respectively once a day for seven days, or twice a day for five days.
  • the literature shows that there is no general consensus as regards screening and pharma- cological treatment.
  • the treatment regimens recommended by the Centres for Diseases Control and Prevention for pregnant women include 250 mg of metronidazole for oral administration three times a day for seven days or 300 mg of clindamycin for oral administration twice a day for seven days (Centres for Diseases Control and Prevention, Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC, Morb. Mortal. WkIy. Rep., 2002, 51 : 1-22).
  • the antibiotics in use have so far not been seen to appreciably reduce adverse obstetric outcomes such as premature membrane rupture, corionamnionitis, premature delivery, endometritis and neonatal complications.
  • adverse obstetric outcomes such as premature membrane rupture, corionamnionitis, premature delivery, endometritis and neonatal complications.
  • this is due to the fact that the pathogenic micro-organisms to be controlled and eradicated in pregnancy are not so much the anaerobic ones typical of bacterial vaginosis, but the aerobic ones which have been recognised as etiological agents of anaerobic vaginitis.
  • SGB Group B Streptococcus
  • a micro-organism belonging to vaginal pathogenic flora of aerobic vaginitis It is a facultative aerobic Gram-positive coccus of about 2.0 ⁇ m, whose colonisation causes complications not just limited to the neonatal period.
  • SGB colonisation during pregnancy increases the risk of miscarriage and affects the pathogenesis of premature rupture of foetal mem- branes, of preterm delivery and of the low body weight of the newborn at birth.
  • the protocols envisage the intravenous administration of ⁇ -lactamic antibiotics during child delivery.
  • antibiotics widely used against SGB are penicillin G and ampicillin, but penicillin G continues to be the preferred antibiotic for intrapartum prophylaxis of colonised mothers, due to its effective transplacental passage, its low cost, but especially its broad range of action even against Gram-positive cocci, with a lower probability of the emergence of resistant micro-organisms.
  • Erythromycin and clindamycin are considered acceptable alternatives for mothers who are allergic to penicillin, although the resistance to these antibiotics may be significant: the prevalence of the resistance may vary from 7% to 25% for erythromycin and from 3% to 15% for clindamycin.
  • a product of this kind should be able to eradicate vaginal bacterial infections - even recurring ones of the gynaecological and obstetric kind, which are probably correlated to the presence of bacterial biofilms adhering to the epithelium of the vaginal wall (Swidsinski et al., Adherent Biofilms in Bacterial Vaginosis, Obstet. Gynecol., 2005; 106(5): 1013-1023), with particular regard to vaginal colonisation by Streptococcus agalactiae, a micro-organism that causes serious pregnancy and neonatal complications.
  • Topical kanamicin and meclocyclin are active only on Gram-negative aerobic bacteria and thus effective in the treatment of aerobic vaginitis from E. coli.
  • a known antibiotic molecule, piperacillin formulated such that it can be used for topical vaginal administration, preferably with protracted release over time, has bacteri- cide activity against Gram-positive aerobic micro-organisms, Gram-negative aerobic micro-organisms, Gram-positive anaerobic micro-organisms and Gram-negative anaerobic micro-organisms present in the vaginal ecosystem of both pregnant and non-pregnant women.
  • piperacillin is a broad-range semi-synthetic ⁇ -lactamic antibiotic derived from D(-)- ⁇ - aminobenzylpenicillin, with the brute formula C 23 H 27 N5O 7 S and molecular weight of 517.56.
  • Its chemical name is (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo- i-piperazinecarboxamido ⁇ -phenylacetamidoJ-S.S-dimethyl ⁇ -oxo- ⁇ tia-i- azabiciclo[3.2.0]heptane-2-carboxylic acid, and it has the following structural formula:
  • piperacillin After parenteral administration, piperacillin is largely distributed in body tissues and fluids, including the bones, prostate gland and heart, and reaches high concentration in bile.
  • Sodium piperacillin, in the form for parenteral administration, is mainly used with the following indications:
  • piperacillin was also clinically experimented, but always exclusively for intravenous administration (Lockwood CJ. et al., Double-blind, placebo-controlled trial of piperacillin prophylaxis in preterm membrane rupture, 1993, 169(4): 970-6).
  • piperacillin has considerable bactericidal activity on micro-organisms deriving from vagi- nal fluid in pregnant and non-pregnant women diagnosed with bacterial vaginosis and aerobic vaginitis, and that this activity is advantageously carried out via topical intravaginal administration of the product, without the need to use parenteral administrations. Since piperacillin, even if for solely systemic use, has been known and used for some time, its clinical value and safety have been widely validated all over the world.
  • the present invention specifically provides the use of piperacillin or one of its pharmaceutically acceptable salts for the production of a topical intravaginal preparation for the treatment and prevention of gynaecological and obstetric bacterial vaginal infections.
  • this topical preparation is recommended for the treatment and prevention of both bacterial vaginosis and aerobic vaginitis.
  • the intravaginal topical preparation based on piperacillin according to the present invention is recommended for the treatment and prevention of aerobic vaginitis in pregnancy, with particular regard to aerobic vaginitis from Gram-positive aerobic germs such as Group B streptococci or Streptococcus agalactiae.
  • the topical intravaginal preparation contains between 0.005% and 5% weight of piperacillin or of one of its pharmaceutically acceptable salts.
  • the said pharmaceutically acceptable salt may be sodium salt, and the preparation may contain preferably between 0.03% and 5% weight of sodium piperacillin.
  • the topical formulations reported in the present invention are preferably prepared in order to allow a constant and protracted release of sodium pipercillin over time.
  • the piperacillin-based topical intravaginal drug may contain - besides the common excipients - also one or more bioad- hesive or mucoadhesive carriers in order to enhance the in-situ resistance time of the active ingredient.
  • the bioadhesive or mucoadhesive carrier may be an agent selected from the group consisting of hy- droxypropylcellulose, carbomers, alginates, pectin, xyloglucans, chitosan, xanthan gum and polycarbophil.
  • sodium piperacillin is conveyed in preparations containing xanthan gum as a bioadhesive or chitosan and/or alginates.
  • the topical intravaginal drug proposed may be presented in the form of ovules, vaginal tablets, cream, paste, emulsion, unguent, solution or suspension.
  • the preferred pharmaceutical form should enable the protracted release over time for a period up to 4 hours, in order to reduce the frequency of application. This possibility is guaranteed, in particular, by the formulation in vaginal tablets.
  • the said topical intravaginal drug is in the form of a coated vaginal tablet containing from 1 % to 2% weight of sodium piperacillin.
  • the topical intravaginal drug according to the present invention may be in the form of a gel containing between 0.2 and 2% weight of sodium piperacillin.
  • the piper- acillin-based topical preparation according to the present invention may include further optional ingredients, such as thickening agents, antioxidants, stabiliser, surfactants or other agents.
  • the preparation may contain preservatives or antimicrobial agents such as methyl-, propyl- or ethyl- paraben, benzoic acid, benzyl acid, as well as other substances convention- ally used in the pharmaceutical art such as excipients and carriers for preparations for topical administration.
  • Formulation 2 sodium piperacillin 0.035 % polycarbophil 0.5 % gelatine 27.0 %
  • PEG 300 30.30 % methylparaben 0.28 % ethylparaben 0.014 % water 42.105 %
  • Formulation 4 sodium piperacillin 1 .04 mg mannitol 17.9 mg pregelatinized com starch 8 .0 mg magnesium stearate 0.4 mg polycarbophil 57.7 mg
  • sodium piperacillin-based preparations in gel form were produced according to procedures commonly used in the pharmaceutical art, on the basis of the compositions reported below (where the percentages are expressed in weight).
  • Formulation 7 sodium piperacillin 0.416 % polycarbophil 51.619 % vaseline oil 41.0 % methylparaben 0.028 % ethylparaben 0.014 % propylparaben 0.014 %
  • Formulation 9 sodium piperacillin 0.416 % xanthan gum 60.584 % vaseline oil 35.0 % methylparaben 0.028 % ethylparaben 0.014 % propylparaben 0.014 %
  • CPR1 , CPR9 and CPR10 Some formulations were excluded on the basis of preliminary screen- ing. Some of them (CPR1 , CPR9 and CPR10) did not swell and did not show signs of adherence to the walls of the glass vessel, while others (CPR4 and CPR5) dissolved in a few minutes with effervescence.
  • the evaluation of the mucoadhesive properties of the formulations under study was carried out by measuring the work necessary to separate two mucous surfaces between which the formulation under study was placed.
  • the mucous surfaces were composed of portions of rabbit vaginal mucous: the vagina was cut longitudinally and spread out taking care not to touch the mucous layer; then two sections of the vagina were mounted on two supports of the tensile apparatus.
  • the equipment used consisted of a microbalance, a mobile platform and a computerised system that could record the force necessary to separate the two surfaces (sample under study/mucous layer) by stretching.
  • the tablets were weighed, placed on a wire gauze of known weight and immersed at room temperature in 60 ml of simulated vaginal fluid having the following composition: NaCI (3.51 g), KOH (1.40 g), Ca(OH)2 (0.222 g), bovine serum albumin (0.018 g), lactic acid (2.00 g), acetic acid (1.00 g), glycerol (0.16 g), urea (0.4 g), glucose (5.0 g), enough water to make up 1 litre taking the pH to 4.2.
  • the samples were periodically (30 min) weighed after removing the excess surface water.
  • the hydrating capacity of the tablets was quantified by means of the swelling index according to the following ratio:
  • Figure 3 shows the dissolution profiles of the studied formulations as a percentage of the active ingredient dissolved in the medium with respect to the theoretical quantity contained in each tablet, equivalent to 100% of PPC released. The results are comparable regardless of the method used.
  • Formulations CPR6 and CPR12 both containing chitosan, sodium alginate and CMCNa, do not dissolve but swell a great deal: drug release is therefore much slower due to the long passage through the gelatinous mass that the PPC must cross. Moreover, the drug that is strongly soluble in water tends to stay within the hydrated tablet.
  • the piperacillin was assayed at concentrations from 0.06 mg/L to 256 mg/L.
  • MIC evaluation was determined by means of the broth dilution method in microslides, according to the NCCLS (1997), using Wilkins-Chalgren broth added with hemin and vitamin K1.
  • the microslide wells were inoculated with a bacterial suspension of 5x10 5 CFU/mL, and the slides were then placed in an anaerobic atmosphere and read after 48 hours.
  • ASA agar blood for anaerobic bacteria
  • the culture mediums used were: Mac Conkey agar (OXOID) for E. coli, Bile Escu- line agar (OXOID) for enterococcus spp. and agar blood CNA (OXOID) for S. agalactiae.
  • OXOID Mac Conkey agar
  • OXOID Bile Escu- line agar
  • OXOID agar blood CNA
  • the lactobacilli (the main ones responsible for vaginal flora equilibrium in fertile-age women) were also isolated by using MRS agar (OXOID). After inoculation, the slides were incubated at 37°C for 24h; the Streptococcus agalactiae and lactobacilli were incubated in the presence of CO 2 .
  • E. coli and Enterococcus spp. The inoculum was prepared by diluting 1-2 colonies of the examined bacteria strains in 5 ml of Muller Hinton broth (OXOID) in order to obtain a turbidity of 0.5 McFarland. The tubes containing the inoculum were incubated at 37 0 C for 24 h.
  • OXOID Muller Hinton broth
  • MIC was determined by means of the solid medium technique. Scalar dilutions of the antibiotic from 1/128 to 1/0.125 were prepared in sterile tubes.
  • the inoculum was obtained in Muller Hinton broth, but the MIC was instead determined by using the microdilution method in a liquid medium (Muller Hinton broth). For incubation, the mi- crowells were sealed with parafilm in order to obtain an oxygen-free atmosphere.
  • MIC/MBC ratio determination After determining the MIC of piperacillin, the subcultures were arranged on ISO sensitest agar slides, taking the inoculum by means of a calibrated handle/loop starting from those samples which did not show any visible growth to the naked eye. The slides were incubated at 37°C for 24h (for the lactobacilli, in the presence of CO 2 ). The MBC is defined as the lowest concentration determining the absence of visible growth.
  • Gardnerella vaginalis ATCC anaerobic optionally Gram-
  • piperacillin activity on the anaerobic pathogens involved in bacterial vaginosis is good and is of the bactericide type.
  • 100% of the assayed strains were sensitive to the antibiotic.
  • piperacillin can be the preferred antibiotic in infections of women's lower genital tract, such as bacterial vaginitis (vaginosis and aerobic vaginitis), where the therapeutic decision is difficult owing to the polymicrobic nature of these pathologies and the little availability of antibiotics having a broad range of activity against both Gram-positive and Gram- negative anaerobic/aerobic bacteria.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Reproductive Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP07713470A 2006-02-24 2007-02-23 Use of piperacillin in topical intravaginal preparations for the treatment of vaginal bacterial infections Withdrawn EP1991224A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000094A ITRM20060094A1 (it) 2006-02-24 2006-02-24 Uso della piperacillina in preparati topici intravaginali per il trattamento di infezioni vaginali batteriche ginecologiche ed ostetriche
PCT/IT2007/000131 WO2007096931A2 (en) 2006-02-24 2007-02-23 Use of piperacillin in topical intravaginal preparations for the treatment of vaginal bacterial infections

Publications (1)

Publication Number Publication Date
EP1991224A2 true EP1991224A2 (en) 2008-11-19

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EP07713470A Withdrawn EP1991224A2 (en) 2006-02-24 2007-02-23 Use of piperacillin in topical intravaginal preparations for the treatment of vaginal bacterial infections

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EP (1) EP1991224A2 (it)
IT (1) ITRM20060094A1 (it)
WO (1) WO2007096931A2 (it)

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US12543982B2 (en) 2021-01-22 2026-02-10 Cilag Gmbh International Method of adjusting a surgical parameter based on biomarker measurements
US12569203B2 (en) 2021-01-22 2026-03-10 Cilag Gmbh International Bariatric surgery post-surgical monitoring
US12440285B2 (en) 2021-01-22 2025-10-14 Cilag Gmbh International Prediction of hemostasis issues based on biomarker monitoring
US12527515B2 (en) 2021-01-22 2026-01-20 Cilag Gmbh International Colorectal surgery post-surgical monitoring
US12100496B2 (en) 2021-01-22 2024-09-24 Cilag Gmbh International Patient biomarker monitoring with outcomes to monitor overall healthcare delivery
US12011163B2 (en) 2021-01-22 2024-06-18 Cilag Gmbh International Prediction of tissue irregularities based on biomarker monitoring
US20220240869A1 (en) * 2021-01-22 2022-08-04 Ethicon Llc Hysterectomy surgery post-surgical monitoring
US11694533B2 (en) 2021-01-22 2023-07-04 Cilag Gmbh International Predictive based system adjustments based on biomarker trending
US11682487B2 (en) 2021-01-22 2023-06-20 Cilag Gmbh International Active recognition and pairing sensing systems
US12239407B2 (en) 2021-01-22 2025-03-04 Cilag Gmbh International Adaptable surgical instrument control

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US4581028A (en) * 1984-04-30 1986-04-08 The Trustees Of Columbia University In The City Of New York Infection-resistant materials and method of making same through use of sulfonamides
US4731360A (en) * 1985-08-16 1988-03-15 Merck & Co., Inc. Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments
IT1280428B1 (it) * 1995-07-14 1998-01-20 R R A S R L Composizione farmaceutica per uso topico

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Publication number Publication date
WO2007096931A2 (en) 2007-08-30
WO2007096931A3 (en) 2007-11-08
ITRM20060094A1 (it) 2007-08-25

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