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Formulations of aminoglycoside and fosfomycin combinations and methods and systems for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis

a technology which is applied in the field of formulations of aminoglycoside and fosfomycin combinations and methods and systems for treating ventilator-associated pneumonia and ventilator-associated tracheal pneumonia (vat) bronchitis, can solve the problems of poor activity against gram negative bacteria in biofilms, limited activity of mrsa inhibitors, and inability to inhalation therapy. to achieve the effect o

Inactive Publication Date: 2015-02-26
SAVARA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes an ideal aerosol delivery system for ventilators that can deliver small particle aerosols without adding airflow that could trigger ventilator alarms or control systems. The system uses a nebulizer that creates small particles through a membrane and is placed inline with the ventilator. The nebulizer is connected to the ventilator and the antibiotic is stored inside until delivery. The system can deliver the antibiotic quickly without causing additional airflow, and the particles are small enough to be inhaled without causing issues like rain out in the breathing tube. The system utilizes humidification to reduce the osmolar load and can be used with different types of ventilators. The system reduces the risk of bacterial contamination and patient-to-patient transmission of resistant bacteria. The treatment can be done quickly and the system can be easily sterilized for reuse. The electronic control unit for the nebulizer is small and can be easily plugged into a ventilator circuit. The invention provides a safe and effective way to deliver therapeutic antibiotics to patients who require ventilators.

Problems solved by technology

The limitations of amikacin are that its activity against MRSA is limited, and activity against Gram negative bacteria in biofilms is poor.
Also, amikacin formulated for intravenous use is the sulphate of the amikacin base and is not ideal for inhalation therapy because sulphate is not a permeant anion.

Method used

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  • Formulations of aminoglycoside and fosfomycin combinations and methods and systems for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis
  • Formulations of aminoglycoside and fosfomycin combinations and methods and systems for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis
  • Formulations of aminoglycoside and fosfomycin combinations and methods and systems for treatment of ventilator associated pneumonia (VAP) and ventilator associated tracheal (VAT) bronchitis

Examples

Experimental program
Comparison scheme
Effect test

example # 1

Example #1

Preparation of Fosfomycin / Amikacin Solution for Aerosolization

[0046]A solution having a ratio of amikacin to fosfomycin of equal to or greater than 2.5-2.6:1 is prepared as follows: Fosfomycin disodium (12.90 g, 10.00 g free acid) was dissolved in 250 mL of water and the pH was adjusted to 7.41 by the dropwise addition of 4.5 N HCl (estimated 1 mL). 25 gm Amikacin base was added to the resulting solution. The pH of the solution was adjusted to 7.60 by the addition of 4.5 N HCl (total amount of 4.5 N HCl was 1.7 mL). The solution was diluted to 500 mL with water and filtered through a 0.2 μm Nalge Nunc 167-0020 membrane filter for sterility. The chloride content can be calculated by using 1.7 mL of 4.5N HCl in 50 L total for a total 306 mg chloride. As 1 mEq Cl=35.5 mg in 1 L then in 50 mL 1 mEq Cl=1.775 mg. Therefore, 306 mg / 1.775 mg=172.4 mEq / L. The osmolality of this formulation was measured at 592 mOsm / kg, which is above the normal physiologic value of 310 mOsm.

example # 2

Example #2

Reduction of the Osmolality of the Solution by Humidification

[0047]A solution having a fosfomycin / amikacin ratio of 2.5-2.6-1 amikacin to fosfomycin was prepared as above. Using an inline electronic vibrating late nebulizer (PARI, Starnberg GR), the formulation was nebulized in dry (4%) and humid (100%) humidity. The mean particle size, as measured by Malvern X laser particle sizer, was 2.9 μm under dry conditions, increasing to 3.2 μm under 100% humidity.

[0048]Since the volume of sphere is function of the third power of the radius, the following equation yields the dilution factor:

1.45×1.45×1.451.6×1.6×1.6=0.75

[0049]Thus, the formulation on average is diluted by a factor of 0.75, indicating the delivered formulation has an osmolality of 592×0.75=444 mOsm / Kg.

example # 3

Example #3

Randomized, Double-Blind, Placebo-controlled, Dose-escalation Phase 1b Study of Aerosolized Amikacin and Fosfomycin Delivered Via the PARI Investigational eFlow® Inline Nebulizer System in Mechanically Ventilated Patients

[0050]A dry powder fosfomycin, liquid amikacin solution can be prepared by use of 200 mg neat dry powder disodium fosfomycin filled in a glass vial or two-part dry liquid syringe. In either a separate syringe, blow fill seal container, or a two-part syringe, 500 mg of amikacin base dissolved in 10 mL of sterile water, with the pH adjusted to a range of 4.5 to 7.5 with HCl. The two components are then mixed together giving a solution with 20 mg / mL fosfomycin, 50 mg / ML amikacin. The osmolality of the solution would be approximately 600 mOsm / Kg, but could vary up to 10% depending on the amount of HCl used to adjust the pH of the amikacin solution. Also by employing the chlorine counter anion with the amikacin base, the sulfate salt of amikacin is not used.

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Abstract

The present invention is antibiotic compositions, ventilator-based systems and methods relating to ventilator-associated pneumonia (VAP) and ventilator-associated tracheal (VAT) bronchitis. Antibiotic combinations of fosfomycin and an aminoglycoside, preferably amikacin, are administered via an inline nebulizer within the airway of the ventilator. Humidified conditions create an improved aerosol mist to treat VAP and VAT.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. application Ser. No. 13 / 844,244 filed Mar. 15, 2013, now U.S. Pat. No. 8,826,904, which is a continuation-in-part of U.S. application Ser. No. 13 / 548,115 filed Jul. 12, 2012, now U.S. Pat. No. 8,603,439, which claims the benefit of U.S. Provisional Application No. 61 / 572,225 filed Jul. 12, 2011. U.S. Ser. No. 13 / 844,244 is a continuation-in-part of PCT / US12 / 46559 filed Jul. 12, 2012 which claims the benefit of U.S. Provisional Application No. 61 / 572,225 filed Jul. 12, 2011, which applications are incorporated herein by reference.BACKGROUND[0002]Considerable medical literature and clinical experience establish that ventilator associated pneumonia (VAP) is a feared and often fatal complication of mechanical ventilation. In the United States, over 250,000 patients per year are stricken with VAP or approximately 800 cases per million population. In Melbourne, the incidence in 2006 was reporte...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7036A61K31/665
CPCA61K31/665A61K31/7036A61M16/14A61K9/0078A61M11/005A61M16/16A61P11/00A61K2300/00A61M11/04A61M16/0057A61M16/0875
Inventor MONTGOMERY, ALAN BRUCE
Owner SAVARA
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