WO2023101653A1

WO2023101653A1 - Detergent compositions for cleaning in the cosmetic and pharmaceutical industry

Info

Publication number: WO2023101653A1
Application number: PCT/US2021/061074
Authority: WO
Inventors: Gaetan Rauwel; Jean Noel BERTHO
Original assignee: Ecolab Usa Inc.
Priority date: 2021-11-30
Filing date: 2021-11-30
Publication date: 2023-06-08

Abstract

The present disclosure relates to disinfectant compositions comprising chlorhexidine digluconate, an anionic dye, polyvinylpyrrolidone, from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols and a solvent other than the C1-C4 alkyl alcohol(s). Further disclosed are methods of manufacture and use for the disinfectant compositions. The compositions are particularly intended for skin disinfection, and in particular, before surgery.

Description

TITLE: DETERGENT COMPOSITIONS FOR CLEANING IN THE COSMETIC AND PHARMACEUTICAL INDUSTRY

TECHNICAL FIELD

The present disclosure relates to a ready to use stable colored disinfectant compositions particularly intended for skin disinfection, and in particular, before surgery. The compositions comprise chlorhexidine digluconate, an anionic dye, polyvinylpyrrolidone and from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols. The disinfectant composition presents very good physical and chemical stability for at least about 3 months at ambient temperature.

BACKGROUND

Disinfection is the destruction or inhibition of microorganisms that are present on living tissue. Disinfectant allows to kill or prevent the growth of the microorganisms. The most commonly used agents include alcohol-based solutions, chlorhexidine gluconate, and iodophors such as povidone-iodine. Alcohol is an excellent germicidal against bacteria, viruses, and fungi; however, its benefit is limited by its flammability and lack of residual germicidal activity. Chlorhexidine and povidone-iodine are both very effective in reducing bacterial counts on contact and have excellent activity against skin structure bacteria, but chlorhexidine is superior in terms of long-lasting activity. Chlorhexidine, a cationic bisbiguanide that achieves its antiseptic activity by causing disruption of microbial cell membranes and precipitation of cell contents, is an ideal agent for skin cleaning and surgical scrubs. Its noteworthy properties include persistent activity on the skin when used regularly, rapid bactericidal activity, a broad antibacterial spectrum, little evidence of irritation or allergy, activity in the presence of body fluids, and minimal absorption.

Chlorhexidine is often applied preoperatively to disinfect materials and surfaces or skin of a patient prior to surgery. An important consideration for the user is the appearance of a chlorhexidine composition. For example, upon visual inspection, it is essential for the user to be able to determine that a) the disinfectant composition has been applied, and b) where the disinfectant composition has been applied whatever the skin type, i.e. white to black type. However, an aqueous chlorhexidine digluconate (CHG) solution is a non-colored or clear liquid, which makes it difficult for the user to make such a determination. Thus, it is desirable to use sufficiently coloured chlorhexidine composition.

However, numerous problems are encountered when the amount of the dye is increased in aqueous CHG compositions. Indeed, the dye can react with chlorhexidine to form a precipitate which can lead either to the inactivation of chlorhexidine, either to a non-uniform spread of the colored disinfectant composition upon its application or either to unstable composition which results in shortened shelflife.

Therefore, the development of colored disinfectant compositions comprising CHG and a dye, with a sufficient shelflife has proven to be difficult.

W02007/130982 or W02007/130981 aims at solving the above mentioned problems by providing an aqueous antiseptic solution comprising chlorhexidine or one of its salts, an anionic dye and a cationic excipient such as a cationic surfactant or a quaternary ammonium such as cetylpyridinium chloride (CPC), hexadecyl trimethyl ammonium bromide, benzethonium chloride and benzalkonium chloride. These documents teach that the use of a cationic excipient together with an anionic excipient is essential because the negative charge of the anionic dye is "hidden" from the chlorhexidine by a cationic excipient. Therefore, the chlorhexidine-dye salt will not immediately form.

However, using additional excipients in disinfectant composition, especially cationic excipients may cause dangerous adverse effects related with allergies, intolerance and/or irritation.

In view of the foregoing, there is a need to provide a stable and safe colored disinfectant composition comprising chlorhexidine digluconate.

It is to the credit of the applicant to have developed, based on numerous research studies, a novel disinfectant composition suitable for disinfecting the skin or surgical field prior to invasive medical procedures.

SUMMARY OF PREFERRED EMBODIMENTS

The disinfectant compositions disclosed herein comprise chlorhexidine digluconate exhibits a high stability and excellent compatibility with anionic dyes, by using polyvinylpyrrolidone and from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols instead of cationic excipients. Accordingly, the disinfectant compositions are not contra-indicated in patients having a hypersensitivity to cationic excipients, in particular cationic dyes.

Accordingly, a first object of the disclosure relates to a disinfectant composition comprising chlorhexidine digluconate (CHG), an anionic dye, polyvinylpyrrolidone (PVP), from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols, and a solvent other than the C1-C4 alkyl alcohol(s).

Another object of the disclosure relates to the disinfectant composition for its use as disinfectant prior to invasive medical procedures. The present disclosure also relates to a process for preparing the disinfectant composition , comprising: a. dissolving an anionic dye in a solvent other than one or more C1-C4 alkyl alcohol to provide an anionic dye solution, b. adding poly vinyl pyrrolidone, c. adding 25%w/w to 80%w/w of one or more C1-C4 alkyl alcohols , d. adding chlorhexidine digluconate, and e. harvesting the disinfectant composition thus formed.

Steps a, b, c, and d may be carried out in any order before step e, i.e. steps a, b, c, and d may be carried out simultaneously or in non-sequential order prior to step e, or steps a, b, c, d, and e may be carried out in sequential order.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The disclosure relates to a disinfectant composition comprising chlorhexidine digluconate (CHG), an anionic dye, polyvinylpyrrolidone (PVP), from 25%w/w to 80%w/w of one or more C1-C4 alkyl alcohol, and a solvent other than the C1-C4 alkyl alcohol(s). Definitions

It should be understood that all terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting in any manner or scope. For example, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” can include plural referents unless the content clearly indicates otherwise. Further, all units, prefixes, and symbols may be denoted in its SI accepted form.

Numeric ranges recited within the specification are inclusive of the numbers defining the range and include each integer within the defined range. Throughout this disclosure, various numeric descriptors are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges, fractions, and individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6, and decimals and fractions, for example, 1.2, 2.75, 3.8, 1 !4, and 4%. This applies regardless of the breadth of the range.

As used herein, the term "disinfectant composition" refers to any liquid composition which comprises chlorhexidine digluconate. Preferably, it refers to any liquid or aqueous composition wherein all the components are completely dissolved, and the obtained solution is ready for use. More preferably, the disinfectant composition does not require any further preparation such as reconstitution prior to its use. The disinfectant composition of the disclosure is suitable as an antibacterial and/or disinfectant solution for skin disinfection; handwashing; oral care; irrigation of surgical wounds, the urinary bladder or vagina; topical treatment of bum wounds; for treatment of peritonitis in peritoneal dialysis; and/or for all the purposes related to its antiseptic and/or disinfectant properties to prevent infections such a nosocomial infections, surgical-site infections, catheter-related infections, surgical wound infections, oral infections.

As used herein, the term “C1-C4 alkyl alcohol” is intended mean a linear or branched alkyl alcohol compound having 1 to 4 carbon atoms, including thus methanol, ethanol, n- propranol, isopropanol, n-butanol, iso-butanol and tert-butanol.

As used herein, the term "anionic dye" refers to any colored substance, for example, those containing auxochromes, and thus capable of coloring substances to which they are applied or incorporated. Such colorants are used, for example, for staining and coloring, as a test reagent, and as a therapeutic agent. Anionic dyes are characterized in that they have a negative charge and attach to cationic surfaces. Anionic dyes include many compounds from various classes of dyes having differences in structure (e.g., azoic, anthraquinone, triphenylmethane and nitro dyes) but possess ionic substituents as a common, water-solubilizing feature.

As used herein, the term "cationic excipient" refers to the cationic excipient as disclosed in WO 2007/130982. Cationic dyes are also considered as cationic excipients in the context of the present disclosure.

As used herein, the term "surgical field" refers to a sterile, isolated area of the operative field, where surgery is performed, including but not limited to the patient and surfaces surrounding the patient (e.g. operating table and surgical equipment).

As used herein, “precipitation” refers to the formation of any solids in the disinfectant composition of the disclosure such as particles that consists of extraneous, mobile, undissolved particles, other than gas bubbles, unintentionally present in the solution. Precipitation can be measured, for example, by any suitable tests that provide an assessment of the quality of the solution. For example, precipitation of the disinfectant composition of the disclosure can be measured by visual examination. One skilled in the art will recognize that other test methods are also suitable.

As used herein, the terms “stable” or “stability” refer to the disinfectant composition of the disclosure not showing precipitation or any modification of the aspect visible to the naked eye such as phase separation, cloudy aspect, or color change. Desirably, the disinfectant composition of the disclosure is stable over a prolonged period of time, preferably at least for 8 weeks at 40°C. It is generally recognized in the art that storage data generated at 40°C can be used to make reliable forecasts on the stability of a biocidal product at ambient temperature (see e.g. ECHA guideline). Indeed, storage data generated at 40°C for 8 weeks gives an indication of the stability of the product for 24 months at ambient temperature, i.e. at about 20°C. Suitable test protocols are described in the Example section. The state of the art is to follow the “Guidance on the BPR: Volume I Parts A+B+C version 2.0 May 2018 page 68”. Accelerated storage data generated can be used to give an indication that the biocidal product will be stable for two years at ambient temperature. Preferably, the disinfectant composition of the disclosure is stable over a period of time of at least 3 months, more preferably at least 4 months and even more preferably at least 5 months at 40°C. Further, it is desirable that the disinfectant composition of the disclosure remains free of visible particles upon storage and during use.

As used herein, “about,” refers to variation in the numerical quantity that can occur, for example, through typical measuring techniques and equipment, with respect to any quantifiable variable, including, but not limited to, concentration, mass, volume, time, distance, pH, and temperature. Further, given solid and liquid handling procedures used in the real world, there is certain inadvertent error and variation that is likely through differences in the manufacture, source, or purity of the ingredients used to make the compositions or carry out the methods and the like. The term “about” also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term “about,” the claims include equivalents to the quantities.

In light of the foregoing, a preferred aspect of the disclosure provides that the term “about” means in particular within ±3%, preferably ±2%, more preferably ±1%, most preferably ±0.5% of the given value.

Unless otherwise provided, all percentages are given as %w/w, that is % by weight based on the total weight of the composition.

Preferably a disinfectant composition comprising chlorhexidine digluconate (CHG), an anionic dye, polyvinylpyrrolidone (PVP), from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols, and a solvent other than the C1-C4 alkyl alcohol(s).

In a preferred embodiment, the disinfectant composition comprises chlorhexidine digluconate. Chlorhexidine digluconate, also referred hereafter as CHG, is a disinfectant and antiseptic which is active against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts. Chlorhexidine digluconate is commonly used for skin disinfection before surgery to disinfect the skin of the patient and the hands of healthcare professionals, as well as to disinfect surgical instruments.

Chlorhexidine digluconate is also used for cleaning wounds, preventing dental plaque, treating yeast infections of the mouth, and to keep urinary catheters from blocking. Chlorhexidine digluconate can be in the form of a liquid or powder. Preferably, chlorhexidine digluconate is in the form of a liquid, such as an aqueous solution of chlorhexidine digluconate which is colorless.

The chlorhexidine digluconate may be present in the disinfectant composition in an amount from about 5%w/w to about 20%w/w, preferably from about 8%w/w to about 17%w/w, more preferably from about 10%w/w to about 15%%w/w, even more preferably from about 12 %w/w to about 13%w/w.

The disinfectant composition comprises an anionic dye. Although prior art documents have reported that adding an anionic dye to chlorhexidine digluconate causes numerous problems of precipitation affecting the stability of the composition, it is believed that the present inventors are the first to report a disinfectant composition comprising an anionic dye, and chlorhexidine digluconate without the need of further additional cationic excipients which does not precipitate and is chemically stable during shelflife.

Suitable anionic dyes that may be employed within the disinfectant composition of the present disclosure include, but are not limited to, FD&C (Food, Drug and Cosmetic) dyes (i.e. dyes approved for these uses by the FDA), such as, for example, FD&C Blue No. 1 (Brilliant Blue FCF), FD&C Blue No. 2 (Indigo Carmine), FD&C Green No.3 (Fast Green FCF), FD&C Red No.3 (Erythrosine), FD&C Red No. 40 (Allura Red), Food Red 3 (Carmoisine), FD&C Red No. 33 (Azo grenadine), FD&C Yellow No.5 (Tartrazine), and FD&C Yellow No. 6 (Sunset Yellow FCF). Preferably the anionic dye is FD&C Red No. 40 (Allura Red), alone or in combination with FD&C Blue No. 1 (Brilliant Blue FCF), FD&C Blue No. 2 (Indigo Carmine), FD&C Green No.3 (Fast Green FCF), FD&C Red No.3 (Erythrosine), Food Red 3 (Carmoisine), FD&C Red No. 33 (Azo grenadine), FD&C Yellow No.5 (Tartrazine), and FD&C Yellow No. 6 (Sunset Yellow FCF.

In a preferred embodiment, the anionic dye is an azo dye selected from the group consisting of FD&C Red No. 40 (Allura Red), FD&C Red No. 33 (Azo grenadine), FD&C Red No.3 (Erythrosine), Food Red 3 (Carmoisine), FD&C Yellow No. 5 (Tartrazine), FD&C Yellow No. 6 (Sunset Yellow FCF), and mixtures thereof. More preferably the anionic dye is FD&C Red No. 40 (Allura Red), alone or in combination with FD&C Red No. 33 (Azo grenadine), FD&C Red No.3 (Erythrosine), Food Red 3 (Carmoisine), FD&C Yellow No. 5 (Tartrazine), and/or FD&C Yellow No. 6 (Sunset Yellow FCF).

In an embodiment, the anionic dye of the antiseptic solution is selected from the group consisting of FD&C Blue No.l, FD&C Blue No.2, FD&C Green No.3, FD&C Red 40, FD&C Red No. 33 (Azo grenadine), FD&C Yellow No.5, and FD&C Yellow No.6, and mixtures thereof. Preferably, the anionic dye is FD&C Red No. 40 (Allura Red), alone or in combination with FD&C Blue No.1, FD&C Blue No.2, FD&C Green No.3, FD&C Red No. 33 (Azo grenadine), FD&C Yellow No.5, and/or FD&C Yellow No.6.

In a particular embodiment, the anionic dye is FD&C Red No. 40 (Allura Red). The anionic dye is preferably used in an amount sufficient to stain or color a body surface. In particular, the anionic dye may be present in the composition in an amount from about 0.01%w/w to about 0.1 %w/w, preferably from about 0.03%w/w to about 0.07%w/w, more preferably from about 0.04%w/w to about 0.06%w/w, even more preferably in an amount of about 0.05%w/w.

Applicant has surprisingly discovered that a disinfectant composition comprising an anionic dye and chlorhexidine digluconate can be stabilized by adding polyvinylpyrrolidone (PVP) and a specific amount of one or more C1-C4 alkyl alcohols. Without wishing to be bound to a particular theory, it is believed that the disinfectant compositions comprising chlorhexidine digluconate and an anionic dye, are stable through the specific combination with a polyvinylpyrrolidone and from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols. This specific combination prevents precipitation and assures stability and shelflife of the disinfectant composition. For example, disinfectant compositions are stable for at least about 3 months, of at least 6 months, preferably at least 12 months, more preferably at least 18 months, and even more preferably at least 24 months at ambient temperature, i.e. at about 20°C. Moreover, the disinfectant composition of the present disclosure is stable in relative extreme hot or cold temperature conditions for at least 8 weeks, i.e. as high as about 40°C to about 50°C and as low as about 4°C. Suitable test protocols are described in the Example section.

In consequence, the specific combination of polyvinylpyrrolidone and from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols ensures stability of the disinfectant composition through its synergistic effect and allows obtaining a disinfectant composition free of any cationic excipients which are known to cause dangerous adverse effects related with allergies, intolerance and/or irritation.

The expression “free of cationic excipients” means that the disinfectant compositions comprise less than about 0.01% w/w, preferably less than about 0.001% w/w of a cationic excipient. In a preferred embodiment the disinfectant compositions comprise 0% w/w of any cationic excipient or only in amounts under the detection limit.

The polyvinylpyrrolidone may be present in the composition in an amount of at least about 0.02%w/w, e.g. from about 0.02%w/w to about 5%w/w, preferably from about 0.025%w/w to about 3%w/w, more preferably from about 0.03%w/w to about l%w/w, even more preferably from about 0.04 w/w to about 0.5% w/w, even more preferably from about 0.05% w/w to about 0.1% w/w.

In a particular embodiment, the one or more C1-C4 alkyl alcohols are selected from C2-C3 alkyl alcohols, preferably from C3 alkyl alcohols. More preferably the C1-C4 alkyl alcohol is isopropanol. In another embodiment, the one or more C1-C4 alkyl alcohols are ethanol and isopropanol.

The one or more C1-C4 alkyl alcohols may be present in the composition at an amount from about 40% w/w to about 70% w/w, preferably from about 50% w/w to about 68% w/w, more preferably from about 60% w/w to about 65% w/w, even more preferably about 62% w/w. The disinfectant compositions comprise a solvent in addition to the about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols. The solvent selected to be compatible with the other components of the composition and to be non-toxic when applied to human or animal skin. Suitable solvents include, but are not limited to water, alcohols other than one or more C1-C4 alkyl alcohols, such as acetone, esters, chlorinated hydrocarbons and chlorofluorohydrocarbons. Preferably, the solvent of the disinfectant composition is water, preferably deionized water. The solvent, preferably water, may be added in an amount from about 10% w/w to about 40% w/w, preferably from about 15% w/w to about 35% w/w, more preferably from about 20% w/w to about 30% w/w, even more preferably about 25% w/w. In this embodiment, the disinfectant composition of the disclosure is in the form of an aqueous solution.

The disinfectant compositions may be employed for a myriad of purposes. More specifically, the disinfectant composition as described above may be used to disinfect a body surface or an object.

Accordingly, the present disclosure also relates to the disinfectant composition as described above for its use as disinfectant of a body surface, especially prior to medical procedures such as prior to surgical interventions, prior to injections, punctures and prior to inspections of hollow organs when the skin or the mucous membrane has to be disinfected. In other terms, the disinfectant compositions can be employed in a method of disinfection comprising applying a disinfectant composition as described above to a body surface of a patient, especially prior to medical procedures such as prior to surgical interventions, prior to injections, punctures and prior to inspections of hollow organs when the skin or the mucous membrane has to be disinfected. A patient within the meaning is a human or an animal. In still other terms, the disclosure relates to the use of the disinfectant composition as described above for the manufacture of a disinfectant of a body surface, especially prior to medical procedures such as prior to surgical interventions, prior to injections, punctures and prior to inspections of hollow organs when the skin or the mucous membrane has to be disinfected. The use for disinfecting a body surface prevents infection prior to medical procedures.

In addition, the disclosure also relates to the disinfectant composition as described above for its use for wound treatment and for the therapy of local superficial skin infections (e.g. bacterial or fungal infections). In other terms, the disinfectant compositions can be employed in a method of treating a wound or treating local superficial infections (e.g. bacterial or fungal infections), the method comprising the disinfectant composition as described above to a wound or a superficial infection of a patient. The patient may be a human or an animal. In still other words, the disclosure relates to the use of the disinfectant composition as described above for the manufacture of a composition for treating a wound or treating local superficial infections (e.g. bacterial or fungal infections).

As used herein, the term "body surface" refers to a skin, a tooth, a finger or toe nail, or a mucous membrane, e.g. the mucous membrane lining the mouth. Preferably, the disinfectant compositions do not traverse these body surfaces and enter the circulation. Such a body surface is contacted with the compositions for a period of time enough to disinfect the area where the composition has been spread.

The disclosure also relates to the use of the disinfectant composition as described above for disinfecting an object.

As used herein, the term “object” refers to objects which can be disinfected using the disinfectant composition of the present disclosure which includes, but are not limited to surgical instruments; catheters such as vascular catheter, urinary catheter, peritoneal catheter, epidural catheter and central nervous system catheter; tubes such as nephrostomy tube and endotracheal tube; stents; orthopedic devices; medical implants etc. Other examples include inorganic surfaces such as floors, table-tops, counter-tops, hospital equipment, wheelchairs, gauze and cotton. Such objects are contacted with the compositions of the present disclosure for a period of time sufficient to disinfect the contacted area. Suitable contact conditions may be one minute to fifteen minutes at room temperature. In an embodiment, the present disclosure also relates to the disinfectant composition for its use in dermal applications such as surgical scrubs, preoperative skin preparations and disinfectant hand washes.

The present disclosure further provides a process for preparing the disinfectant composition described herein. The Applicant has surprisingly found that particular good results in terms of stability are obtained when the disinfectant solution of the present disclosure is prepared by combining or adding the components in a particular manner (e.g., specific order), precipitation is avoided when compared to other processes.

A preferred process according to the disclosure, comprises the following steps: a. dissolving an anionic dye in a solvent other than one or more C1-C4 alkyl alcohols to provide an anionic dye solution, b. adding poly vinyl pyrrolidone, c. adding about 25%w/w to about 80%w/w of one or moreCl-C4 alkyl alcohols, d. adding the chlorhexidine digluconate, and e. harvesting the disinfectant composition thus formed.

Steps a, b, c, and d may be carried out simultaneously or in non-sequential order prior to step e, or steps a, b, c, d, and e may be carried out in sequential order. However, the best results are obtained when the steps are carried out in sequential order, i.e. a, b, c, d, e.

The solvent used in step a is selected to be compatible with the other components of the composition and to be non-toxic when applied to human or animal skin. Suitable solvents include, but are not limited to water, alcohols other than one or moreCl-C4 alkyl alcohols, such as acetone, esters, chlorinated hydrocarbons and chlorofluorohydrocarbons. Preferably, the solvent of the disinfectant composition is water, preferably deionized water. The solvent, preferably water, may be added in an amount from about 10% w/w to about 40% w/w, preferably from about 15% w/w to about 35% w/w, more preferably from about 20% w/w to about 30% w/w, even more preferably about 25% w/w.

Accordingly, the preferred process of the disclosure does not cationic excipients in such a way that the disinfectant composition thus formed is free of cationic excipients.

Dissolution of step a. may be conducted by starting stirring the solvent other than one or moreCl-C4 alkyl alcohols and then adding the anionic dye, thereby providing an anionic dye solution. The anionic dye may be added in an amount from about 0.01%w/w to about 0.1 %w/w, preferably from about 0.03%w/w to about 0.07%w/w, more preferably from about 0.04%w/w to about 0.06%w/w, even more preferably about 0.05%w/w. The polyvinylpyrrolidone may be added in an amount from about 0.02%w/w to about 5%w/w, preferably from about 0.025%w/w to about 3%w/w, more preferably from about 0.03%w/w to about l%w/w, even more preferably from about 0.04 w/w to about 0.5% w/w, even more preferably from about 0.05% w/w to about 0.1% w/w. Stirring is advantageously continued during the addition of the polyvinylpyrrolidone. The mixture obtained by adding the polyvinylpyrrolidone is advantageously stirred during about 15 to about 60 minutes, such as during about 20 to about 40 minutes, e.g. about 30 minutes. The one or moreCl-C4 alkyl alcohols is added in an amount from about 25%w/w to about 80%w/w, such as from about 40% w/w to about 70% w/w, preferably from about 50% w/w to about 68% w/w, more preferably from about 60% w/w to about 65% w/w, even more preferably about 62% w/w. Stirring is advantageously continued during the addition of the one or moreCl- C4 alkyl alcohols.

In a preferred embodiment, the one or more C1-C4 alkyl alcohols are selected from C2-C3 alkyl alcohols, preferably from C3 alkyl alcohols. More preferably the C1-C4 alkyl alcohol is isopropanol. In another embodiment, the one or more C1-C4 alkyl alcohols are ethanol and isopropanol. The chlorhexidine digluconate may be added in an amount from about 5%w/w to about 20%w/w, preferably from about 8%w/w to about 17%w/w, more preferably from about 10%w/w to about 15%%w/w, even more preferably from about 12 %w/w to about 13%w/w. Stirring is advantageously continued during the addition of the chlorhexidine digluconate. The mixture obtained by adding the chlorhexidine digluconate is advantageously stirred during about 15 to about 60 minutes, such as during about 20 to about 40 minutes, e.g. about 30 minutes. In a preferred embodiment, the process further comprises a step of adding water, preferably deionized water. The water may be added after step a, and/or after or concomitantly with any of steps b, c, or d, and/or after step e.

EXAMPLES

Example, non-limiting, embodiments of the disinfect compositions are further demonstrated in the following Examples. It should be understood that these Examples, while indicating certain embodiments of the disinfecting compositions, their methods of manufacture and use, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the essential characteristics of these inventions, and without departing from the spirit and scope thereof, can make various changes and modifications of the embodiments of the inventions to adapt them to various usages and conditions. Thus, various modifications of the embodiments of the inventions, in addition to those shown and described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Several disinfectant compositions comprising chlorhexidine digluconate and an anionic dye were evaluated for their ability to be stable without having recourse to cationic salts which are not safe.

The amounts of ingredients in Tables 1-5 are expressed in percentages weight/weight (w/w) unless stated otherwise.

Example 1: Anionic dye and CHG-based compositions comprising PVP and isopropanol

In order to determine the amount of isopropanol needed to obtain the synergistic effect between PVP and isopropanol, seven disinfectant compositions containing 0.05%w/w PVP and different amounts of isopropanol were prepared and tested according to Table 1 below. Table 1 gives the seven disinfectant compositions evaluating the minimum amount of isopropanol to have in order to obtain the synergistic effect.

The order of incorporation of each component is indicated in the second column. The anionic dye is first dissolved in deionized water, then the remaining constituents are added in the following order: PVP, isopropanol, CHG. Once prepared, the physical stability (absence or presence of precipitation) of each disinfectant composition was tested minimum 8 weeks at 4°C, 20°C, 40°C and minimum 4 weeks at 50°C.

Stability test protocol

The stability tests were carried out according to the following test protocol with the seven disinfectant compositions of table 1.

After manufacturing, samples are placed in incubators at ambient temperature, e.g about 20°C and for accelerated stability studies at 4°C, 40° and 50°C. Visual observation is monitored over the time in order to detect any change of the aspect. All compositions follow this protocol except those that already showed a precipitate or unclear appearance after manufacture.

Table 1

The above trials demonstrate that precipitation is only avoided in compositions comprising from 25%w/w to 80%w/w isopropanol. These compositions show indeed a synergistic effect of PVP and isopropanol. Compositions C2 to C5 present a stability above 8 weeks at 40°C, therefore these compositions are stable for 24 months at ambient temperature according to the ECHA guideline.

Example 2: Confirmation of synergistic effect between PVP and isopropanol by substituting PVP by a surfactant

In order to confirm the synergistic effect between PVP and isopropanol, two disinfectant compositions comprising the same component as the composition of Table 1 in which PVP is replaced by either 0,05% w/w of a non-ionic surfactant, butylglucoside SIMULSOL SL4, or 0,05%w/w of a mild amphoteric surfactant, Cocamidopropylbetain TEGOBETAIN F50, were prepared and tested according to the Table 2 below.

The order of incorporation of each component is indicated in the second column. Once prepared, the stability of each of the two disinfectant compositions was tested at 4°C, 20°C, 40°C & 50°C according to the protocol of example 1.

Table 2

The stability tests demonstrated that when PVP is replaced by a surfactant, the stability is impaired as some particles appeared after 20 days at temperatures of 4°C, 20°C, 40°C, and 50°C. This shows that the combined presence of from 25 %w/w to 80 %w/w of isopropanol on one hand and PVP on the other hand is necessary to obtain a stable disinfectant composition comprising an anionic dye and CHG. Compositions C8 and C9 are not stable at 20 days, therefore these compositions are not stable for 24 months at ambient temperature according to the ECHA guideline.

Example 3: Color stability of disinfectant compositions of the disclosure Eight disinfectant compositions according to the disclosure were prepared and tested according to the Table 3 below.

Table 3 gives the eight disinfectant compositions with different amounts of PVP: 0.01%w/w, 0.025%w/w, 0.05% w/w, 0.1% w/w, 0.5% w/w, 1% w/w, 3% w/w, 5% w/w.

The order of incorporation of each component is indicated in the second column. The anionic dye is first dissolved in deionized water, then the remaining constituents are added in the following order: PVP, isopropanol, CHG. Once prepared, the stability of each disinfectant composition was tested at 4°C, 20°C, 40°C and 50°C according to the protocol of example 1. Table 3

All eight disinfectant composition according to the disclosure are physically stable during at least 7 months, i.e. no precipitation is observed. However, composition Cll shows some loss of color intensity after 39 days and after 7 months, particles have been observed. Compositions

CIO and C12 to C17 are stable above 8 weeks at 40°C, therefore these compositions are stable for 24 months at ambient temperature according to the ECHA guideline.

Comparative Example 1: Anionic dye and PVP-based compositions without isopropanol

In order to determine if the solvent isopropanol contributes to the stability of the disinfectant composition, six disinfectant composition without isopropanol and with different amount of PVP 0.05%w/w, 0.1%w/w, 0.5% w/w, 2% w/w, 5% w/w were prepared according to Table 4 below. The order of incorporation of each component is indicated in the second column. The anionic dye is first dissolved in deionized water, then the PVP is added and finally CHG. Once prepared, the stability of each disinfectant compositions was tested at 4°C, 20°C, 40°C & 50°C according to the protocol of example 1. Table 4

The stability tests clearly demonstrated that without the presence of isopropanol in the disinfectant composition regardless of the amount of PVP, all compositions precipitated right after preparation. Compositions C18 to C23 are note stable above 8 weeks at 40°C, therefore these compositions are not stable for 24 months at ambient temperature according to the ECHA guideline. As shown in Example 3 compositions based on chlorhexidine digluconate and an anionic dye comprising both PVP and from 25%w/w to 80%w/w are however stable for at least 20 days. Therefore, PVP and isopropanol play a synergistic role in maintaining the stability of compositions comprising chlorhexidine digluconate and an anionic dye, initially incompatible. Comparative Example 2: Stability of disinfectant compositions according to W02007/130982 with and without cationic surfactant

In order to confirm that the disinfectant compositions of the present disclosure are better than those of the prior art, the recipe of example 4 of the W02007/130982 patent application was used to prepare six compositions according to the Table 5 below. The composition C24 of Table 5 is the compositions as described in example 4 of the W02007/130982 patent application.

Compositions C25 and C26 of Table 5 were the same as the composition C24 but wherein the dye was replaced by another anionic dye. Compositions C27, C28 and C29 of Table 5 correspond to compositions C24, C25 and

C26 of Table 5 respectively but without cetylpyridinium chloride (also called “CPC”), i.e. a cationic surfactant.

The order of incorporation of each component is indicated in the second column. Once prepared, the stability of each of the six disinfectant compositions was tested at 4°C, 20°C, 40°C & 50°C according to the protocol of example 1.

Table 5

The stability tests demonstrated that the composition C24 of the example 4 of W02007/130982 precipitates at 40°C after 24 days. Composition C24 is not stable above 8 weeks at 40°C, therefore this composition is not stable for 24 months at ambient temperature according to the ECHA guideline. Replacing the dye FD&C Yellow 6 by either FD&C Red 33 (C25) or FD&C Red 40 (C26), does not change the result.

Without the cationic surfactant, cetylpyridinium chloride, all compositions (C27, C28 and C29) precipitated at tO, i.e. right after preparation. Compositions C27, C28 and C29 are not stable above 8 weeks at 40°C, therefore these compositions are stable for 24 months at ambient temperature according to the ECHA guideline.

Therefore, even with the composition C29 which corresponds to the closest composition of the present disclosure but in different proportions, the disinfectant composition is not stable. Altogether, the tests confirmed that the composition of example 4 of W02007/130982 required 0.3%w/w of CPC to be stable.

In conclusion, the disinfectant composition of the present disclosure goes against a technical prejudice by dispensing with the use of a cationic surfactant, responsible for skin allergy, through the creation of a particularly inventive synergy between PVP and isopropanol. The features disclosed in the foregoing description, figures, or the following claims, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the inventions in diverse forms thereof.

The inventions being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the inventions and all such modifications are intended to be included within the scope of the following claims. The above specification provides a description of the manufacture and use of the disclosed compositions and methods. Since many embodiments can be made without departing from the spirit and scope of the invention, the invention resides in the claims.

Claims

1. A disinfectant composition comprising chi orhexi dine digluconate, an anionic dye, polyvinylpyrrolidone, from about 25%w/w to about 80%w/w of one or more C1-C4 alkyl alcohols and a solvent other than the C1-C4 alkyl alcohol(s).

2. The disinfectant composition according to claim 1, wherein the anionic dye is an azo dye selected from the group consisting of FD&C Red No. 40 (Allura Red), FD&C Red No.

33 (Azo grenadine), FD&C Red No.3 (Erythrosine), Food Red 3 (Carmoisine), FD&C Yellow No. 5 (Tartrazine), FD&C Yellow No. 6 (Sunset Yellow FCF), and mixtures thereof.

3. The disinfectant composition according to claim 1 or 2, wherein the anionic dye is FD&C Red No. 40 (Allura Red).

4. The disinfectant composition according to claims 1 to 3, wherein it is free of cationic excipient.

5. The disinfectant composition according to claims 1 to 4, wherein the anionic dye is present in an amount sufficient to stain or color a body surface, preferably from about 0.01%w/w to about 0. l%w/w, preferably from about 0.03%w/w to about 0.07%w/w, more preferably from about 0.04%w/w to about 0.06%w/w, even more preferably about 0.05%w/w.

6. The disinfectant composition according to claims 1 to 5, wherein the chlorhexidine digluconate is present in an amount from about 5%w/w to about 20%w/w, preferably from about 8%w/w to about 17%w/w, more preferably from about 10%w/w to about 15%%w/w, even more preferably from about 12 %w/w to about 13%w/w.

7. The disinfectant composition according to claims 1 to 6, wherein the polyvinylpyrrolidone is present in an amount from about 0.02%w/w to about 5%w/w, preferably from about 0.025%w/w to about 3%w/w, more preferably from about 0.03%w/w to about l%w/w, even more preferably from about 0.04% w/w to about 0.5% w/w, even more preferably from about 0.05% w/w to about 0.1% w/w.

8. The disinfectant composition according to claims 1 to 7, wherein the one or more C1-C4 alkyl alcohols are present in an amount from about 40% w/w to about 70% w/w, preferably from about 50% w/w to about 68% w/w, more preferably from about 60% w/w to about 65% w/w, even more preferably about about 62% w/w. The disinfectant composition according to claims 1 to 8, wherein the solvent other than one or more C1-C4 alkyl alcohols are present in an amount from about 10% w/w to about 40% w/w , preferably from about 15% w/w to about 35% w/w , more preferably from about 20% w/w to about 30% w/w, even more preferably about 25% w/w. The disinfectant composition according to claims 1 to 9, wherein the solvent other than the C1-C4 alkyl alcohol(s) is water, preferably deionized water. The disinfectant composition according to claims 1 to 10, wherein it has a stability of at least 8 weeks at about 40°C. The disinfectant composition according to claims 1 to 11, for use as disinfectant prior to medical procedures. A process for preparing the disinfectant composition according to claims 1 to 11, comprising the steps of: a. dissolving the anionic dye in a solvent other than one or more C1-C4 alkyl alcohols to provide an anionic dye solution, b. adding poly vinyl pyrrolidone, c. adding 25%w/w to 80%w/w of one or more C1-C4 alkyl alcohols, d. adding the chlorhexidine digluconate, and e. harvesting the disinfectant composition thus formed. The process according to claim 13, further comprising a step of adding water, preferably deionized water. The process according to either claim 13 or claim 14, wherein steps a, b, c, and d are carried out simultaneously or in non-sequential order prior to step e, or wherein steps a, b, c, d, and e are carried out in sequential order.