WO2016054311A1

WO2016054311A1 - Antimicrobial articles and methods

Info

Publication number: WO2016054311A1
Application number: PCT/US2015/053390
Authority: WO
Inventors: Taylor M. COLVIN
Original assignee: Colvin Taylor M
Priority date: 2014-10-03
Filing date: 2015-10-01
Publication date: 2016-04-07

Abstract

Disclosed are articles and methods that may be used to reduce the risk of a mammal contracting a microbe-borne disease. The articles comprise a fabric material that contains an antimicrobial amount of a metal, wherein the metal is present in the fabric material in an amount of from about 0.0002% to about 0.0008% by weight.

Description

TITLE OF THE INVENTION

ANTIMICROBIAL ARTICLES AND METHODS

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefit of U.S. provisional application number 62/059,178 filed October 3, 2014, the contents of which are incorporated herein by reference.

STATEMENT REGARDI NG FEDERALLY^' SPONSOR ED

RESEARCH OR DEVELOPMENT ,

Not applicable.

BACKGROUND OF THE I VENTiON

FIELD OF THE INVENTION

The present invention relates to antimicrobial articSes and methods for their use. DESCRIPTION OF RELATED ART

Infant mortality is the death of a child less than one year of age. Globally, ten million infants and children die each year before their fifth birthday; 99% of these deaths occur in developing nations. Infant mortality takes away society's potential physical, social, and human capital.

Many factors contribute to infant mortality such as the mother's level of education and prenatal care, environmental conditions, and political and medical infrastructure. Improving sanitation, access to clean drinking water, immunization against infectious diseases, and other public health measures could help reduce high rates of infant mortality.

Neonatal mortality is newborn death occurring within 28 days postpartum. Neonatal death is often attributed to inadequate access to basic medical care, during pregnancy and after delivery. This accounts for 40-60% of infant mortality in developing countries. Low birth weight accounts for approximately 75% of the infant mortality rate in developing countries. As compared with normal-birth- weight infants, those with low weight at birth are almost 40 times more likely to die in the neonatal period; for infants with very low weight at birth the relative risk of neonatal death is almost 200 times greater. Infant mortality due to low birth weight is usually a direct cause stemming from other medical complications such as preterm birth, poor maternal nutritional status, lack of prenatal care, maternal sickness during pregnancy, and an unhygienic home environment.

Seven out of ten childhood deaths are due to infectious diseases with about 25% of these deaths occurring during the critical neonatal period, including acute respiratory bacterial infections, diarrhea, and sepsis. Acute bacterial respiratory infection such as pneumonia, bronchitis, and bronchiolitis account for 30% of childhood deaths; 95% of pneumonia cases occur in the developing world. The UN Millennium Development Goals include reducing infant mortality by 2/3 within the decade.

From the reported statistics listed above, of about 10 million developing world childhood deaths annually, approximately 1.5 to 2 million babies born annually in developing world countries die from bacterial causes during the first 28 days of life. Babies are particularly vulnerable during the critical neonatal period during which time their immune systems are developing to provide innate protection. However, unlike developed world conditions, these babies are immediately under pressure from low hygiene conditions and lack of adequate medical care against otherwise preventable infections and diseases which are the reality of present circumstances and conditions into which they are born.

Although the developing world infant mortality problem is vast, Mozambique can serve as a model for an invention need as having one of the highest infant mortality rates in the world. Although prenatal care, socioeconomic and cultural factors are identified as comprising 75% of those causing infant mortality, the reported data also indicate that approximately 25% of these infant deaths are attributable to bacterial infections which could be otherwise preventable. Babies are particularly vulnerable to infections in their first 28 days of life.

Many of these infections could be prevented with simple practices if the barriers to successful adaptation of appropriate or new technology could be overcome. How might we reduce neonatal mortality in, for example, Mozambique due to bacterial infections by some means familiar and readily adapted within the existing lifestyle and culture of developing world mothers without training or special requirements or imposition of education or change in routine practices? By the de-facto recognition that mothers are the primary health care providers within these developing world conditions and not trained physicians as within the developed world, and recognizing the limitations of education, cultural realities, and actual on the ground circumstances, there is needed an effective, invisible and effortless intervention that can make a difference in standard of care for newborn infants that can help protect from bacterial infections. An appropriate invention must improve the standard of care within the actual confines of existing conditions without placing new burden or requirement of knowledge or significant change in practice for the caregiver in order to realize actual benefit.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an antimicrobial article that may be used to reduce the risk of a mammal contracting a microbe-borne disease, which comprises a fabric material that contains an antimicrobial amount of a metal, wherein the metal is present in the fabric material in an amount of from about 0.0002% to about 0.0008% by weight.

In another aspect, the invention relates to a method for reducing the risk of a mammal contracting a microbe-borne disease, which comprises contacting a said mammal with a fabric material that contains an antimicrobial amount of a metal, wherein the metal is present in the fabric material in an amount of from about 0.0002% to about 0.0008% by weight.

DETAILED DESCRIPTION OF THE INVENTION

The antimicrobial materials of the present invention may include a wide range of materials, such as blankets, swaddles, clothing articles, onesies, etc., with blankets or swaddles being particularly preferred. The present invention is particularly suitable for protecting human neonates (generally understood to be up to about four weeks old); therefore particularly preferred articles include baby blankets, receiving blankets, and the like.

Particularly preferred are receiving blankets typically having dimensions of about 30 inches by 30 inches (about 76 cm by about 76 cm), although the precise dimensions of any particular article is not critical. The materials may be made of any suitable natural or synthetic fabric, such as cotton, wool, etc., as well as blends of materials. In another embodiment, the material comprises a reusable shopping bag in which the risk of spread of food-borne pathogens (such as from meats or vegetables placed in the bag) is reduced.

The metal may include any metal with suitable antimicrobial properties, such as silver, copper, iron, tin, zinc, etc., as well as combinations thereof. In a preferred embodiment, the metal comprises silver nanoparticles or nanofibers.

The amount of metal incorporated into the antimicrobial article will depend on a number of factors that would be apparent to one of ordinary skill. Such would include the potency of the metal used, the size of the article, the immobilization method, the desired rate of antimicrobial activity {e.g., 97% killed within 10 minutes), etc. Preferably, the amount of metal used may be in the range of from about 0.0002% to about 0.0008%, more preferably from about 0.0003% to about 0.0007%, or from about 0.0004% to about 0.0006%, all percentages given by weight.

The particle size of the metal used will preferably be in the nanometer range.

Preferably, the particle size may be from about 5 nm to about 100 nm.

The bactericidal action of nanoparticulate metals (silver for example) is surface area dependent. The smaller the particle, the greater the surface area to volume ratio. For example, at a fixed mass concentration (mg/ml), fixed (Ag) mass %, and fixed atomic (Ag) molarity (mmol/L), decreasing the particle size from 100 nm down to 10 nm increases the particle concentration from 1.8 x lOⁿ to l .8 x l0¹⁴, a factor of 3 orders of magnitude, and increases the surface area to volume ratio per particle (and sum of the particles) by 10 times (.06 to 0.6) as shown in Table 1.

Table 1 : surface area to volume spherical particle diameter scaling

In general, metal nano particles (e.g., silver) with an average size of 10 nm or less greatly increase their bactericidal activity, consistent with as particle size decreases, reactivity increases due to the surface area to volume ratio increasing. As is shown in Table 1 (above), decreasing the diameter from 100 nm to 10 nm increases the surface area to volume ratio and the overall mass of silver can be adjusted downward by increasing the surface area while preserving bactericidal activity (at the expense of overall bactericidal longevity - a larger particle can leach silver ions for a longer period of time before it becomes spent). A lower overall mass of silver is achieved by increasing the surface area to maintain effective antimicrobial activity at lower risk to the baby for potential toxicity. The lower overall mass at lower particle diameter also increases particle density within the fabric (particles/cm²) for higher probability of particle (or ion) contact with a potential infectious agent.

Table 2 below correlates particle size with particle count, mass concentration, and area density of the particle within a standard size baby blanket (approximately 30 inches square or about 5800 cm²) for silver nanoparticles.

TABLE 2

The metal may be incorporated into the fabric material by methods that would be apparent to one of ordinary skill. Such would include post treatment of textile fabrics such as chelation, covalent immobilization, physical entrapment of colloids, nanoparticles, fibers, or microwires, plasma deposition of metals, etc. For nanometallic fibers incorporation may also include interweaving during textile fabrication and plasma or other immobilization pretreatment of individual fibers or fiber bundles prior to final fabric weaving.

An infectious (or infective) dose (ID) is defined as: "the amount of pathogen

(measured in number of microorganisms) required to cause an infection in the host".

(Leggett, H. C, et al. (2012). "Mechanisms of Pathogenesis, Infective Dose and Virulence." PLoS Pathog 8(2): el002512 ref: http://en.wikipedia.Org/wiki/Infectious_dose#cite_note-l). An infectious dose can range from a count of only 10 microbes delivered for a highly infectious organism such as pathogenic E.Coli strain 0157:H7, to much higher levels such as Cholera (< 10,000 count), or even higher in the millions for other infectious species

Most studies in determining infective dose levels were originally researched and measured as part of the US biological weapons program conducted as classified during the 1940s by the US Army and today largely remain held as classified in the interest of non- proliferation of biological weapons of mass destruction regarding the count numbers for various possible pathogens with the potential for weapons development. However, in all cases, there were determined to be specific threshold values (or ranges) for pathogenic organisms for each species which established the infective dose for disease and illness (along with susceptibility factors). The common factor within the definition of infective dose is that by lowering the ambient bacterial count within the host occupied space, the odds are shifted toward non infection, (ref: Pathogenesis, Virulence, and Infective Dose, Paul Schmid- Hempel* and Steven A Frank, PLoS Pathog. Oct 2007; 3(10): el47. Published online Oct 26, 2007. doi: 10.1371/journal.ppat.0030147 ref:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042013/). Table 3 below shows infectious dose levels for some known organisms in order to consider orders of magnitude.

TABLE 3

From inspection of Tables 2 and 3, at an upper concentration of about 0.00077% Ag nanoparticles per kg of blanket, and nanoparticle sizes ranging from about 10 nm to about 100 nm diameter, with an extremely conservative simplification metric of one nanoparticle killing one organism, the data show that each square centimeter of such a blanket contains a number of particles at least equal to an entire infectious dose for any of the organisms listed. One Ag ion has a mass of 1.79 x 10^~22 g. Each 10 nm Ag nanoparticle (Table 2) has a mass of about 5.5 x 10^~18 g. Therefore, with the stated mechanism of Ag ion as the actual antimicrobial agent from nanoparticulate silver, there are potentially 30,000+ available Ag ions from each 10 nm nanoparticle through complete dissolution of the particle over the useful life. This indicates the total potentially available Ag ion antimicrobial agent exceeds the highest count (listed) infectious dose by almost 4 orders of magnitude at a concentration of 0.00077% and a 10 nm Ag particle.

In one embodiment, it is believed that the invention works not by killing all potential pathogens within an area surrounding the baby, but instead to decrease to the greatest extent possible the numbers of potential ambient pathogens within the immediate environment surrounding the baby against the infectious dose number for that organism. The blanket does not need to kill 100% of ambient threat organisms. For example, assume there is a high local concentration of E. coli within the baby's immediate surroundings at the minimum infectious dose (10⁶ for E. coli). If the bactericidal activity of the blanket kills only half of the ambient organisms, the local count as a threat against the baby will drop from 10⁶ to 5 x 10⁵, which is below the infective dose level for that organism, and thereby decrease the probability of the baby contracting an infection.

The present invention recognizes these relationships within the context of the overall mission and maximum safety toward the intended purpose of a specifically designed product for newborn baby protection within a limited targeted efficacy period so as to load a significantly lower concentration of silver nanoparticles into the material and maintain bactericidal efficacy, and thus lower the risks of total antimicrobial agent exposure concentration to the baby maximizing overall safety margin during the limited period of exposure.

As a result of the relatively low concentrations of metal used herein, the present invention has the advantage of low toxicity. For example, one study suggests that slight liver toxicity results in rats from ingestion of 300 mg of silver nanoparticles (Kim, Y. S.; Kim, J. S.; Cho, H. S.; Rha, D. S.; Kim, J. M.; Park, J. D.; Choi, B. S.; Lim, R.; Chang, H. K.; Chung, Y. H.; Kwon, I. H.; Jeong, J.; Han, B. S.; Yu, I. J., "Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in sprague-dawley rats." Inhalation Toxicol. 2008, 20 (6), 575-583; DOI 10.1080/08958370701874663).

Adjusted for a child weighing approximately 3 kg at birth, this slight toxicity exposure value would be approximately 369 mg/day total silver threshold value. In a preferred embodiment, the present invention loads a 0.45 kg blanket with about 35 mg of silver. Therefore, under these approximations, the entire loading of silver from the presently-preferred blanket is less than one-tenth of the estimated slight toxicity threshold. Consequently, that receiving blanket is incapable of delivering or even approaching within a factor of 10-X the full estimated toxicity threshold value to a baby, under even unreasonably extreme conditions of leaching 100% of the silver load all in one day or even throughout the useful life of the article. The present invention also is very cost effective. Particularly in applications of helping to combat infant mortality in the developing world, affordability is a high priority, which is achieved by the relatively low cost of the small amounts of metal used in the present invention. While certain embodiments of the present invention are particularly advantageous for use in developing countries, it will be understood that the invention is not so limited and indeed would have utility anywhere.

EXAMPLE 1

In this example, the advantages of a baby blanket preferred embodiment of the present invention are discussed. Mothers throughout the world generally recognize the fundamental need within the standard of care to keep a newborn infant warm. All mothers employ a baby blanket of some sort for keeping an infant warm and most employ the universal practice of swaddling infants during their neonatal period. A baby blanket is familiar to all and accessible to all throughout both the developed and developing world. A baby blanket is consistent with developing world initiatives on education of expectant mothers from handouts provided by the World Health Organization.

This preferred embodiment of the invention adapts the familiar form of a low cost baby blanket with recent discoveries and published methods of conferring antimicrobial properties using nanotechnology treatments and immobilization of nano-fiber and colloidal metals. The blanket may be used by developing world mothers not only for keeping newborn babies warm, but also for the additional benefit of adding a substantial protection factor against bacterial diseases and illness for these babies during the critical neonatal period during the first 28 days of life.

The nanotechnology of antimicrobial action conferred on textiles is well known. Applications include military uniforms and underwear, socks, hospital garb and linens, and sportswear. Importantly, the mode of action is through direct treated textile contact antimicrobial action of the nano-particles disabling key enzymes which in turn kill the microorganism. Testing shows that nanotechnology antimicrobial action on contact can kill 97% of microbes within 10 minutes of direct contact. This confers the intended advantage to reduce smells for clothing, either sports or military, or reduce potential patient to patient transfer of potential clinical infections for hospital garb or linens, (see http://phys.org/news/2014-05-antibacterial-fabric-revolutionise-infection.html). Heretofore, however, the art has taught that much higher concentrations than used in the present invention are necessary, and not applied or suggested the use of such technology for the purpose of, for example, protecting neonates at risk for infections.

In this embodiment, the present invention combines the timeless, universally used, and familiar baby blanket with a recent nanotech innovation to create an effective and novel dual use vector to deliver key beneficial and protective technology into the developing world in fighting a massive human problem of infant mortality of which approximately 25% is attributed to bacterial causes that do not occur under the standard hygienic practices in developed world circumstances, norms and standards of care. The invention can be employed seamlessly and without special requirement directly by untrained mothers under their actual circumstances of life and culturally imposed standards of practice and care within their means right now and where the invention contains and provides within itself all the technical protection advancement as invisible dual use technology to the mother as necessary to confer the advantage directly to the infant.

The present embodiment has two primary infection pathway blocking modes of operation:

Potentially disease causing bacteria invade an infant's space with the potential to infect through any of one or both pathways. These include either direct contact as transference of organisms, such as from handler contact, contaminated surfaces, materials and settling aerosols, and indirect contact (ingestion by mouth, other of contaminated surface), or inhalation (lungs) of airborne bacteria or bacteria containing airborne particulates.

Direct and Indirect Contact Antimicrobial Baby Blanket Barrier Activity

In the case of direct contact, a baby is vulnerable to bacteria that are conveyed accidentally by handlers, materials, surfaces or contact with surroundings directly as a result of physical touching or contact. A baby's immune system is developing during the critical neonatal period trough normal physiological development and important breast feeding from mothers and is particularly susceptible during this time. Developing world immediate hygienic surroundings for the infant are typically substandard and place much higher probability on the infant for accidental contamination by direct handlers including the mother, father, siblings, pets, or others either through touching, or placing the baby on a contaminated or unclean surface such as a floor, crib, counter, or any other.

A standard and typical baby blanket or swaddling material can receive these accidental surface imparted contaminants from handlers and the bacteria can remain viable on the surface of the standard blanket, or within the material, even during inadequate washings, and be conveyed to the baby by wounds, sepsis (or umbilical healing), baby's hands in mouth or eyes, or other means. An antimicrobial blanket that can render, for example, 97% of all bacteria nonviable upon contact within 10 minutes shifts the odds away from infection strongly in the baby's favor. An example of bacterial infections in the developing world that can infect the baby by this route include diarrhea-causing infections, which are the second leading cause of death behind pneumonia, mostly stemming from accidental handling conveying fecal coliforms from substandard hygienic practices due to ambient conditions. Antimicrobial treatments have also been published for hospital garb to remain stable through as many as 20 wash cycles, thereby adding the additional protection against inadequate washing of the blanket and maintaining protection through the critical neonatal period. See, "New antibacterial fabric could revolutionise infection control," May 06, 2014

http://phys.org/news/2014-05-antibacterial-fabric-revolutionise-infection.html

and "New antibacterial fabric kills infectious bacteria within 10 minutes," By Nick Lavars, May 5, 2014 http://www.gizmag.com/antibacterial-fabric-infectious-bacteria-10- minutes/31922/.

Airborne Bacteria Antimicrobial Blanket Infectious Dose Sinking Activity

For an infection to take hold from a potentially pathogenic bacteria to cause illness or death within a susceptible host, such as a baby or others, that bacteria must be presented to the host at approximately the level of the infectious dose for that specific species of bacteria (see discussion above relating to Table 3). Actual contraction of the illness or disease also depends on other factors, including overall health, and most importantly pertaining to the immunological susceptibility of the host which can include various factors including age, being most vulnerable in newborns. But in all cases, there will be a threshold dose (bacterial count range) above which the bacterial threat must meet to cause disease for that species. Within an imaginary space surrounding the baby, the antibacterial material configured as a baby blanket occupying a relatively large surface area within the immediate baby space, can serve as a biological viability sink for bacterial count within the immediate vicinity of the baby to kill any airborne bacteria that may settle on and contact the blanket. For example, were airborne bacteria introduced to the baby's immediate space by a cough, sneeze, kicked up dirt or dust, aerosol, or any other means, the bacteria can be inhaled by the baby, or the bacteria can settle onto a surface and remain viable until kicked up again into the air, or the baby or handlers may contact the settled or airborne bacteria and secondarily transfer to the baby by direct contact.

Nano-particulate metal antimicrobial activity such as with silver colloids and microfibers has not been associated with bacterial resistance as has antibiotics, and is believed by current research and data to be a safe non-systemic alternative means to combat microbial resistance. So enhancing naturally progressive antibiotic resistance in creating "superbugs" is not believed to be a threat, and is in fact aided, by large scale deployment of antibacterial materials based on nano-particulate metals.

A relatively large surface within the space immediately surrounding the baby, at approximately baby blanket area of one square yard (about 0.8 square meters) of fabric, could contain trillions of nano-particulate colloids immobilized within the fabric. By the mechanisms described in the literature to date, microorganisms contacting a silver particle are killed by contact destruction of key enzymes within the bacteria. Taking into account simple surface contact, aerosol and airborne bacterial settling, one blanket of one square yard (about 0.8 square meters) has the potential to kill millions of microorganisms within 10 minutes of contact. This mechanism would act as a "biological sink" to reduce the airborne

concentration and numerical count of all bacteria, including the pathogens, within the immediate environment of the baby, against the threshold requirement of infectious dose, even if the blanket were just lying next to the baby without swaddling, or partially draped over a crib, or even a cardboard box crib surrogate. The mode example hypothetical mechanism is as follows.

If a cough or sneeze introduced a hypothetical infectious dose of airborne bacteria into the baby's space, and one or more of these airborne bacteria settled onto the area of the blanket, these bacteria would be killed within 10 minutes and thereby reduce (sink) the count toward below the infectious dose level greatly shifting the odds in favor of preventing infection of the baby. Since the blanket would have the surface area capability for killing millions of individual bacteria of all species toward sinking against the infective dose, the blanket can provide protection over the approximate 30 day critical neonatal period.

Common airborne bacterial infections include pneumonia, the number one assessed killer, and TB, which now infects nearly 2/3 of the world population, mostly in the developing world.

An average common baby blanket depending on material and size weighs

approximately 0.45 kilograms. A 0.45 kg cotton baby blanket would require approximately 3.5 milligrams of silver immobilized within. As of October 1, 2014, the market price of silver was $0.55428/gram which is approximately .19 cents (US) each for the cost of silver required for one blanket.

One skilled in the art will appreciate that the articles and methods described herein can be practiced with embodiments other than those disclosed. The disclosed embodiments are presented for purposes of illustration and not limitation.

Claims

WHAT IS CLAIMED IS:

1. An antimicrobial article that may be used to reduce the risk of a mammal contracting a microbe-borne disease, which comprises a fabric material that contains an antimicrobial amount of a metal, wherein the metal is present in the fabric material in an amount of from about 0.0002% to about 0.0008% by weight.

2. The article of claim 1, wherein the article comprises a blanket or a clothing article.

3. The article of claim 2, wherein the article comprises a blanket.

4. The article of claim 3, wherein the mammal is a human neonate, and the blanket has dimensions of about 30 inches by about 30 inches (about 76 cm by about 76 cm).

5. The article of claim 1, wherein the metal comprises silver, copper, zinc, or tin, or combinations thereof.

6. The article of claim 1, wherein the metal comprises silver nanoparticles or nanofibers.

7. The article of claim 6, wherein the metal has a particle size of from about 5 nm to about 100 nm.

8. The article of claim 1, wherein the article comprises a shopping bag.

9. A method for reducing the risk of a mammal contracting a microbe-borne disease, which comprises contacting a said mammal with a fabric material that contains an antimicrobial amount of a metal, wherein the metal is present in the fabric material in an amount of from about 0.0002% to about 0.0008% by weight.

10. The method of claim 9, wherein the article comprises a blanket or a clothing article.

11. The method of claim 10, wherein the article comprises a blanket.

12. The method of claim 11, wherein the blanket has dimensions of about 30 inches by about 30 inches (about 76 cm by about 76 cm) and the mammal is a human neonate.

13. The method of claim 12, wherein the blanket is used during the first 28 days of life.

14. The method of claim 9, wherein the metal comprises silver, copper, or tin, or combinations thereof.

15. The method of claim 9, wherein the metal comprises silver nanoparticles or nanofibers.

16. The method of claim 15, wherein the metal has a particle size of from about 5 nm to about 100 nm.

17. The method of claim 9, wherein the article comprises a shopping bag.