Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Aldehyde doai
Reexamination Certificate
1999-08-13
2003-02-25
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Aldehyde doai
C514S693000, C514S705000, C514S724000, C514S738000, C514S970000, C514S974000, C514S975000
Reexamination Certificate
active
06525101
ABSTRACT:
TECHNICAL FIELD
The present invention relates to disinfectant concentrate compositions.
BACKGROUND OF THE INVENTION
New, more efficient machinery recently developed for cleaning, disinfecting and sterilising heat sensitive fibre optical surgical instruments requires a new generation of concentrated glutaraldehyde based instrument disinfectants for optimal operation. A concentrated glutaraldehyde solution is required which is desirably capable of being repeatedly heated to accelerate disinfecting action. Additionally, it is desirable that the solution is diluteable by mechanical means to as low as 0.10 percent glutaraldehyde as part of normal machine operation. To be successful in the market place, the disinfectant is desirably noncorrosive, economical and practical to use in the machinery as well as highly efficient as a disinfectant and chemical sterilant.
Traditional alkaline activated glutaraldehyde disinfectants, now widely used for low temperature disinfecting and sterilising of fibre optical (endoscopic) surgical instruments, are unsuitable for use under heated dilute conditions due to the rapid internal polymerisation of monomeric glutaraldehyde.
In order to attempt to overcome the problems of the prior art, two glutaraldehyde concentrates are presently commercially available for use in new washer-disinfector machines. One concentrate is an undiluted acidic 23 to 25 percent glutaraldehyde concentrate used as manufactured. The second and preferred concentrate is a two component system comprising a first component containing a concentrated 23 to 24 percent glutaraldehyde solution and a phosphate buffer, and a second component containing a surfactant, an optional corrosion inhibitor such as sodium nitrite, and a free alkali to adjust the pH of the two parts when mixed. The two components are mixed to form the working buffered biocidal solution. Both concentrates suffer from the disadvantage that they have limited disinfecting power particularly to mycobacteria, eg Mycobacterium tuberculosis, and to some bacterial and fungal spores as well as some viruses found in whole blood.
The chemistry of glutaraldehyde has been widely described in the literature since its introduction to medical practice as a chemical substitute for heat and ethylene oxide sterilisation. First patented by Pepper, U.S. Pat. No. 3,016,328 in 1962, so called “Activated” glutaraldehyde has become a standard means of sterilising surgical instruments and other complex and heat sensitive surgical instruments. The term “activated”, as originally proposed by Pepper, means the pH of the chemical glutaraldehyde whether in its monomeric and/or hydrated forms is adjusted upwards from its stable acidic form to a pH of 7.5 to 9.5 by addition of an “alkalinating” agent in which pH range the biocidal properties of the glutaraldehyde are maximized, in particular its sporicidal activity.
In 1976 Boucher, U.S. Pat. No. 3,969,248 and U.S. Pat. No. 3,968,250 demonstrated that addition of certain non-ionic surfactants to a 2% aqueous glutaraldehyde solution at a pH of 6.3 to 6.5 provided similar “activation”, although later findings clearly demonstrated that the degree of “activation” achieved by non-ionic surfactants addition to such mildly acidic glutaraldehyde solutions is less than that achieved by “alkalination” to a pH 7.5 to 9.5. This is believed due to the beneficial affect of the bicarbonate in conjunction with the sodium ion in aiding penetration of glutaraldehyde into bacterial spores. (Scott E. M. & Gomian S. P., Antimicrobial Activity, Uses and Mechanism of Action of Glutaraldehyde, J. Appl. Bacteriol., 1980, 48, 161-190; Scott E. M. & Gorman S. P., Sterilizaton with Glutaraldehyde, in Disinfection, Sterilization and Preservation, 3rd Ed, 1983, Lea & Febiger, pp 65-88). These effects are enhanced at alkaline pH and are optimal at around pH 9.5, above which glutaraldehyde becomes too unstable (polymerises) for use as a practical disinfectant.
Other patents issued in recent years have disclosed the beneficial effect of different surfactants on the biocidal action of dilute glutaraldehyde solutions at alkaline pH, including the divalent metals, calcium and magnesium. However, most surfactants at alkaline pH have received little acceptance in the market place as they have not demonstrated improved biocidal activity of the solutions in practice.
The steady increasing use of glutaraldehyde has been accompanied serious possibility of the development of allergy by users to the strong irritant vapour of glutaraldehyde. In light of this, two patents have disclosed means of decreasing the odour of dilute (1.0 to 3.5%) glutaraldehyde solutions at room temperature by the addition of polyglycols which can be shown to hydrogen bond to the dialdehyde. U.S. Pat. No. 4,436,754 (Taylor) demonstrated that at a pH of 7.5 to 9.5 (achieved by separate alkalination prior to use), glycols containing from 1 to 22 ethylene oxide groups were effective in suppressing the odour of chemical sterilants by reducing the vaporisation of glutaraldehyde. This product was, of necessity, supplied in two parts, one part containing a stabilised acidic glutaraldehyde-glycol complex and the second part containing a lesser quantity of buffer alkaline salts, surfactants and corrosion inhibitors. AU 562,017 (Whitely et al) and NZ 204,717 disclosed a stable near neutral chemical sterilant containing triethylene glycol and 1 to 2.5% glutaraldehyde. This was successfully marketed as Wavicide AID with greatly reduced odour compared with “alkalinated” glutaraldehyde preparations and a demonstrated reduced incidence of odour complaints and allergy reactions from regular uses of “alkalinated” glutaraldehyde based instrument sterilants. However, like all known alkalinated 2% glutaraldehyde preparations, this formulation was subsequently demonstrated to be less effective than claimed for killing mycobacterium, in particular Mycobacterium tuberculosis, which as a group of pathogens is assuming major significance as a complimentary infection in immune-depressed AIDS/HIV patients.
Subsequently, AU 589,267, (Whiteley) taught that a specific interaction occurs between a hydrogen bonded complex formed between 1.0 to 1.5 mole of triethylene glycol and 1 mole of monomeric glutaraldehyde when mixed with certain non-ionic surfactants. Small quantities of the non-ionic surfactants were reacted with the glutaraldehyde-glycol complex with a corresponding loss of surface activity as measured by change in the air/water surface tension of aqueous solutions. The resulting three part complex significantly enhanced the overall effectiveness of glutaraldehyde as a biocide in the pH range 6.0 to 7.5, especially against mycobacterium. Increase in biocidal action was achieved while still effectively reducing the vaporisation of glutaraldehyde. Killing time against mycobacteria was reduced at room temperature from 20 to 45 minutes for 2% “alkalinated” glutaraldehyde preparations to 5 to 10 minutes for the new three part complex in a 2% glutaraldehyde preparation. The complex was subsequently marketed under trade name AIDAL PLUS.
Patent literature also reveals many other attempts to improve the mycobiocidal effectiveness of 1 to 3.5% aqueous glutaraldehyde solutions. For example, U.S. Pat. No. 4,923,899 (Wachman) describes a composition comprising glutaraldehyde, a quaternary biocide, low molecular weight glycols and alcohols, monovalent metal nitrate, sulphite and chlorites and a chelating agent.
U.S. Pat. No. 5,252,606 (Martin) teaches the fortification of glutaraldehyde preparations by addition of a quaternary biocide, as well as a para tertiary amyl phenol, citric acid and isopropanol. The formulation disclosed contains 46% w/w of water in addition to other ingredients. Based on experience with similar experimental formulae such mixtures are subject to limited shelf life due to progressive loss of monomeric glutaraldehyde on storage, presumably as the formulation does not appear inhibited against internal polymerisation of glutaraldehyde. Research has clearly demonstrated that mycobio
Choi Frank
Dees Jose′ G.
Levisohn, Lerner, Berger & Langsam LLP
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