Abstract:
A method for reducing allergenicity of natural latex rubber. The natural latex rubber, prior to its vulcanization, is admixed with silica compounds dissolved an alkali solution to denature the antigenic protein thus reducing the total protein level. Alternatively, liquid sodium silicate is added directly to natural rubber latex to reduce antigenic protein value. Ideally, when fumed silica is used as the silica compound, it is characterized as having a density of approximately 2.2 g/cm 2  and surface area of 255 m 2 /g.

Description:
TECHNICAL FIELD  
       [0001]     The present invention relates to a method of reducing the allergenicity of natural latex rubber prior to its vulcanization. In doing so, the potential for allergic reactions due to the protein content of the natural latex rubber has been greatly reduced while maintaining its desirable physical properties when used in such products as latex gloves and similar medical and consumer goods.  
       BACKGROUND OF THE INVENTION  
       [0002]     Beginning in the late 1980&#39;s allergic reactions associated with the use of latex gloves began to receive widespread recognition. These reactions varied greatly in degree but seemed to exhibit similar characteristics to acquired sensitivity reactions seen with other allergens. Although latex gloves have enjoyed a long history of usage dating back to the 1800&#39;s, the perceived need for protection from AIDS and HIV exposure during the 80&#39;s caused a tremendous increase in the use of gloves. This, in turn, resulted in a much-heightened exposure to the naturally occurring antigenic proteins contained in raw latex.  
         [0003]     The last decade and a half has seen a great change in latex use as a result of publicity concerning these allergies. Today in the U.S. there is almost universal awareness of the risks associated with repeated latex exposure, particularly in the healthcare fields where exposure is more profound. Awareness of the risks, however, extends into the industrial glove market, and even to the general public, who have received risk warnings from various government and health-watch groups. As a result there exists much interest in the market, fueling a strong trend to reduce exposure to latex-associated allergens.  
         [0004]     Manufacturers have responded in several ways: 1) reduction or elimination of donning powder, 2) utilization of chlorinated glove washing and additional processing steps to reduce antigenic protein load, 3) use of coatings to reduce actual contact with latex, and 4) introduction of alternative materials that mimic, natural latex performance characteristics. Each of these industry reactions represents compromises either from ease of use, performance, or cost standpoint. In short, nothing beats the tactile, comfort, and barrier protection that is provided by natural latex products.  
         [0005]     In the last ten years there has been an increasing awareness of the possible immunologic and other reaction risks associated with the use of latex gloves. This awareness is the result of the proliferation in glove usage among healthcare workers in order to avoid potential exposure to HIV/AIDS transmission sources.  
         [0006]     An increase in the reported incidence of latex allergic sensitivity and other skin reactions has been concomitant with increased glove usage. This has spurred an effort by industry leaders and manufacturers to reduce exposure to latex. Glove makers have initiated latex substitution in the manufacturer of gloves, elimination of donning powder (antigenic proteins leach in to the cornstarch powder and become airborne-a source of respiratory exposure and subsequent sensitization), and the introduction of methods to reduce overall protein content of gloves.  
         [0007]     Latex rubber in its natural form consists of polymer, long chain molecules consisting of repeating units of isoprene:  
                         
 
 R and R1 are unidentified terminal units; n-value is in the range of 600-3000 
 
         [0008]     When it is harvested from the rubber tree, Hevea brasiliensis, the liquid, sticky substance also contains proteins like heavamine, hevein, and rubber elongation factor (REF). Although the basic isoprene polymer is non-antigenic, the associated proteins are highly antigenic. It is important to note this difference in order to minimize the antigenic impact of natural latex without destroying its underlying structure.  
         [0009]     In its natural state, natural latex does not possess characteristics that are commercially useful. In order to achieve utilitarian value, including strength, elasticity, and memory, the chains of isoprene must be cross-linked to one another. Depending on the type of rubber end product desired, this is achieved with either application of heat and sulfur, or in the case of latex rubber used in the manufacture of gloves, various chemical accelerators that donate or bind sulfur, thus speeding the cross-linking process. The major accelerators are thiurams, mercaptobenzothaizoles (MBTs), and carbamates.  
         [0010]     In addition to accelerators, latex glove manufacturers utilize another class of additives, called sensitizers, which most frequently consist of substituted phenols. These substances are used to impede oxidation, and resultant degradation, of natural latex.  
         [0011]     Foreign materials, natural latex proteins, accelerators, and sensitizers can all provoke human reactions, but the allergenic reactions due to the proteins are considered to be by far the most problematic in the healthcare field. The following briefly describes three major types of foreign material reactions most commonly associated with latex use:  
         [0012]     Irritant dermatitis is skin irritation that does not involve the body&#39;s immune response, that is, it is not an allergic response. Frequent hand washing and inadequate drying, aggressive scrubbing technique or detergents, mechanical abrasive effect of powder, climatic irritation, and emotional stress can all cause this condition. Even though this is not an allergic reaction, irritant hand dermatitis can cause breaks in the skin which can facilitate entry of the sensitizing latex protein or chemicals found in the commercial product, and in turn lead to latex allergy.  
         [0013]     Delayed cutaneous hypersensitivity (type IV allergy) is contact (hand) dermatitis generally due to the chemicals used in latex production. It is mediated via T-cells causing a skin reaction that is typically seen 6-48 hours after contact. The reaction is local and limited to the skin that has contact with the glove. While not life threatening, those with type IV allergy are at increased risk to develop type I allergy. As in irritant dermatitis, the broken skin barrier can provide an entry site into the body for foreign materials. This can produce sensitization to latex proteins leading to a more serious type of reaction.  
         [0014]     The third and potentially most serious type of reaction associated with latex use is a true IgE/histamine-mediated allergy to protein (also called immediate, or type I hypersensitivity). This type of reaction can involve local or systemic symptoms. Local symptoms include contact urticaria (hives), which appears in the area where contact occurred, i.e., the hands, but can spread beyond that area and become generalized. More generalized reactions include allergic rhinoconjunctivitis and asthma. The presence of allergic manifestations to natural latex indicates an increased risk for anaphylaxis, a rare but serious reaction experienced by some individuals who have developed an allergy to certain proteins (e.g., insect stings, natural rubber, penicillin). This type I reaction can occur within seconds to minutes of exposure to the allergen. When such a reaction occurs, it can progress rapidly from swelling of the lips and airways, to shortness of breath, and may progress to shock and death, sometimes within minutes. While any of these signs and symptoms may be the first indication of allergy, in many workers with continued exposure to the allergen, there is progression from skin to respiratory symptoms over a period of months to years. Some studies indicate that individuals with latex allergy are more likely than latex non-allergic persons to be atopic (have an increased immune response to some common allergens, with symptoms such as asthma or eczema). Once natural latex allergy occurs, allergic individuals continue to experience symptoms, which have included life-threatening reactions.  
         [0015]     There are several classes of people known to be at increased risk for latex allergy. Medical patients who have had multiple hospitalizations and have been exposed numerous times to latex medical products, healthcare workers, and atopic individuals comprise this high-risk group. Current estimates are that 8-17% of healthcare workers become sensitized. Despite the recent emphasis on universal precautions, the marked increase in glove usage due to commutable disease prevention is largely blamed for the increase in latex allergies among these groups. Atopic individuals (those with other allergies or asthma) are at significantly greater risk to develop latex allergy than the general population. It is estimated that as many as 25-30% of atopic healthcare workers may become sensitized.  
         [0016]     The problems presented by allergic reactions to latex are exacerbated by the proliferation and widespread use of latex-based products. Latex presents great risk to persons in the health care industry where latex products are used extensively in the form of gloves, casts, dressings, tapes, catheters, tubes, drains, airway management devices, med delivery, tourniquets, monitoring devices, and others. One persistent threat lies in the cornstarch powder used to lubricate and ease donning of rubber gloves. The proteins absorb onto the powder and become aerosolized during use and when the gloves are donned and removed.  
         [0017]     Products containing latex are also found throughout the home in the form of balloons, art supplies, toys, swimming equipment, contraceptive devices, cosmetics, bottle nipples, pacifiers, clothing, chewing gum, rubber bands, and others. Groups at risk include particularly children with spina bifida, those who have been shown to have a very high risk of latex sensitivity, patients with congenital urologic abnormalities, healthcare providers and rubber industry workers.  
         [0018]     Since the severe allergic reactions to latex are due to their naturally occurring proteins, the prior art offers little in the way of solutions. For example, “hypoallergenic” latex products are free from the vulcanization accelerator compounds that can cause dermatitis, but do not prevent immediate hypersensitivity reactions. Likewise, ammonia treatment of the natural rubber latex proteins can cause breakdown and precipitation of some latex proteins, but the allergenicity appears to be preserved and other antigenic latex proteins are unextractable. In short, the literature recommends that the only treatment available for latex allergy is avoidance.  
         [0019]     The Food and Drug Administration (FDA), as well as other state and federal agencies, has received requests to ban the use of glove powder. It has been suggested that experimental and clinical studies demonstrate that glove powder on medical gloves can enhance foreign body reactions, increase infections and act as a carrier of natural latex allergens. The National Institute of Occupational Safety and Health (NIOSH) recently issued a safety alert recommending the use of powder-free, reduced protein content latex gloves to reduce exposure to natural latex proteins (allergens).  
         [0020]     Experimental and clinical data demonstrate that natural rubber latex (NRL) proteins are allergenic. Further, natural latex proteins bind to cornstarch while aerosolized powder on NRL gloves is allergenic and can cause respiratory allergic reactions. Published studies support the conclusion that airborne glove powder represents a threat to individuals allergic to natural rubber latex and may represent an important agent for sensitizing non-allergic individuals. There are also published data (although limited) and clinical experience that cornstarch powder on NRL gloves may also be a contributing factor in the development of irritation and type IV allergy.  
         [0021]     In addition to dusting powder, other lubricants may also be used in the manufacturing process. Latex and some polymers are tacky and gloves made of these materials stick to the mold or former. A mold-release lubricant such as calcium carbonate or a mixture of calcium carbonate and cornstarch is used to enable the removal of gloves from molds. The other side of the glove may be coated with a donning lubricant, such as cornstarch or silicone oils, to make donning gloves easier and to prevent gloves from sticking during the manufacturing process.  
         [0022]     Over the past three years, the FDA has received requests to ban the use of all glove powders. These requests have been based on repeated clinical and experimental studies reporting that cornstarch on surgical gloves can damage tissue&#39;s resistance to infection, enhance the development of infection, serve as a potential source of occupational asthma, and provide a source of natural latex protein exposure to natural latex allergic individuals. The issues regarding the use of glove powder, except for the transport of natural latex protein allergens, apply to the use of glove powder on both natural rubber latex and synthetic gloves. Several states, acting on their own initiative have banned the sale and use of glove powders.  
         [0023]     Current applicant as well as others have suggested protocols for reducing the allergenicity of latex rubber by removing allergenic proteins from natural rubber compositions. For example, applicant&#39;s previously issued U.S. Pat. No. 6,906,126 directed to a method for reducing allergenicity of natural latex rubber by admixing the natural latex rubber, prior to its vulcanization, with mineral oil which is extracted together with proteins. The disclosure contained within published application no. 2002/0156159 teaches the use of fumed silica, a known thickener, to increase the viscosity of vulcanized natural rubber latex. The &#39;159 application, now abandoned, further notes that the fumed silica addition reduces allergenicity by reducing the amount of allergenic protein present in latex articles dipped from compositions which include fumed silica. Theoretically, the applicant of the cited application proposes that the silica particles attached to the surface of the rubber particles thereby displacing allergenic proteins.  
         [0024]     It is an object of the present invention to employ silica-based compounds such as described in published U.S. Application No. 2002/0156159 in a way which significantly increases their efficacy.  
         [0025]     As a further object of the present invention to teach a protocol for reducing the allergenicity of natural latex rubber prior to vulcanization to enable the creation of commercial products relatively free of allergenicity with no apparent loss of physical properties.  
       SUMMARY OF THE INVENTION  
       [0026]     The present invention is directed to a method of reducing allergenicity of natural latex rubber. The method comprises subjecting the natural latex rubber, prior to vulcanization, to silicon contained compounds dissolved in a fixed alkali solution to reduce protein levels in it or by adding liquid sodium silicate directly to natural rubber latex. These silicon compounds include; -silica SiO 2  (fumed silica, silica, quartz), silica acid H 4 SiO 4  (or Si(OH) 4 ), silane SiH 4  and silicon halides such as SiCl 4  and SiF 4 , silicates both individual and mixtures such as Na 2 SiO 3 , K 2 SiO 3 , CaSiO 3 , MgSiO 3 , CaMg(SiO 3 ) 2 , K(AlSi 3 O 8 ,), Na 2 (Al 2 Si 3 O 10 )●2H 2 O, and organo-silicones, for example 1,1,1,3,3,3-hexamethyldisilazane. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0027]     These compounds of use herein can be solid (silica, silica acid, silicates), gaseous (silane and silicon halides) or liquid (organic-silicon). Many of them are natural compounds and some are synthesized (organosilicones, silica acid, some zeolites). All these compounds as well as silicon itself, are more or less soluble in strong alkalis, due to hydrolysis and chemical interaction of silica ions, such as SiO 3   2− , SiO 4   4− , Si 2 O 7   6− , Si 3 O 9   6−  etc. The structures of possible complex silica-based ions that are formed due to this interaction and hydrolysis are indicated below  
         [0028]     It is preferred that at least approximately 0.05% of SiO 2  in a silicon compound (by weight) is admixed with the natural latex rubber and, ideally, approximately 0.001-0.1% of SiO 2  in a silicon compound by weight is employed. The silicon compound is dissolved with either potassium hydroxide(KOH) or sodium hydroxide(NaOH), then is admixed with the natural latex rubber up to 72 hours, and ideally approximately 24 hours, with agitation or in the case of liquid sodium silicate, can be added to the natural latex rubber directly. The antigenic protein is denatured thus enabling the natural latex rubber to be further processed.  
         [0029]     The reaction and structure for this denaturing is illustrated below:  
                         
 
         [0030]     As a preferred embodiment, the natural latex rubber is subjected to a specific silicon compound mixed in a fixed alkali solution with agitation to produce an intimate admixture. Further, a specific amount of liquid sodium silicate (solution of Na 2 SiO 3  in H 2 O) can be added directly to natural latex rubber to reduce the antigenic protein value. Ideally, at least approximately 0.05% of SiO 2  in a silicon compound by weight is admixed with the natural latex rubber and, preferably, 0.001-0.1% of SiO 2  in a silicon compound by weight is employed.  
         [0031]     Once the suitable admixture is created, it is found that at least some agitation is required to enable appropriate denaturing of the antigenic protein content from the natural latex rubber whereupon, the treated latex containing denatured protein is vulcanization into a latex article. Agitation can be carried out for up to 72 hours, with 24 hours being ideal.  
         [0032]     Although there are various suitable candidates for use herein, it has been found that fumed silica having a density of approximately 2.2 g/cm 2  and a surface area of approximately 255 m 2 /g is ideal. Specifically, the use of liquid silicate Na 2 Si 3 O 7  and organic silicon, particularly, hehamethildisilazane was tested to determine the affect on protein removal. After the protein has been denatured pursuant to the present invention, vulcanizing the latex is possible without disrupting the physical or chemicals properties of the natural latex rubber.  
         [0000]     Experimental Data  
         [0033]     A series of films were created, a first being a control sample of natural latex rubber not involving the teachings of the present invention. This material was applied to a glass plate.  
         [0034]     A series of six additional films were created, in each instance, using the same natural latex rubber which was employed to make the above-reference film. 0.01% fumed silica by weight having a density of 2.2 g/cm 2  and surface area of 255 m 2 /g was dissolved in a KOH solution then agitated with the natural latex rubber for 24 hours. Next, this sample was processed into a film on a glass plate and labeled “CSP-11”. A second film was created labeled “CSP-10”. Sample CSP-10 differed from sample CSP-11 in that 0.02% fumed silica by weight was dissolved in KOH and mixed with natural latex rubber for 24 hours. This sample was processed into a film on a glass plate. A third film was created labeled “CSP-9”. Sample CSP-9 differed from the other samples in that 0.03% fumed silica by weight was dissolved in KOH and mixed with natural latex rubber for 24 hours. This sample was processed into a film on a glass plate. A fourth film was created labeled “CSP-8”. Sample CSP-8 differed from sample CSP-9 in that 0.05% fumed silica by weight was dissolved in KOH and mixed with natural latex rubber for 24 hours. This sample was processed into a film on a glass plate. A fifth film was created labeled “CSLP-1”. Sample CSLP-1 contained 0.05% by weight liquid sodium silicate (Na 2 Si 3 O 7 ) and was mixed directly into natural latex rubber for 24 hours. This sample was processed into a film on a glass plate. A sixth film was created labeled “CSOP-1”. Sample CSOP-1 contained 0.05% by weight organic silicon (1,1,1,3,3,3-Hexamethyldisilazane) that was mixed with natural latex for 24 hours. This sample was processed into a film on a glass plate.  
         [0035]     Films CSP-11, CSP-10, CSP-9, CSP-8, CSLP-1 and CSOP-1 were analyzed by conducting LEAP assays. The following results were measured noting that, in addition to the films, the control sample of latex film was also scrutinized.  
         [0036]     ELISA Inhibition Assay (ASTM D6499-03). The data is expressed as antigenic latex protein in micrograms/gram of sample. The untreated liquid latex contained 1,341.8 μg/g while the control film from untreated liquid latex contained 33 μg/g of antigenic protein. The CSP-11 latex film sample contained 1.2 μg/g of antigenic protein. The CSP-10 latex film sample contained 0.8 μg/g of antigenic protein. The CSP-9 latex film sample contained 0.4 μg/g of antigenic protein. The CSP-8 latex film sample contained 0.6 μg/g of antigenic protein. The CSLP-1 latex film sample contained 1.4 μg/g of antigenic protein. The CSOP-1 latex film sample contained 3.9 μg/g of antigenic protein.  
         [0037]     It is quite apparent from the test data which was developed and reported above that dramatic reduction in protein levels is achieved by the relatively simple processes of denaturing protein found in natural latex rubber by either dissolving silicon compounds in a fixed alkali solution or by introducing liquid sodium silicate into latex as previously described. Unlike the teachings of published and abandoned application serial no. 2002/0156159, this process is employed prior to vulcanization of the natural latex rubber. In doing so, products can be produced while reducing risks imposed upon users of natural latex rubber products, including healthcare professionals, as a result of type I hypersensitivity. Most importantly, this is accomplished without diminishing the physical properties of natural latex rubber which makes commercial products made from this material so desirable.