Abstract:
The present invention is directed to attaching drugs and other functional groups to surfaces of nano-sized diamonds (NDs) to enhance the efficacy of drugs and other substances. The method involved enhancing the efficacy of a drug having an active site by acquiring a plurality of nanodiamond (ND) particles having a plurality of carbon chain surface molecules on its surface. Intermediate amine entities are covalently attached to the surface molecules of the ND particles. These are then replaces with said drug molecules such that the active sites of said drug molecules point away from the ND particle exposing them for enhanced activity and enhanced drug efficacy. The efficacy of antimicrobial drugs are enhanced, however, this may be used with many different types of drugs.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This patent application is A Continuation-In-Part of earlier-filed provisional patent application Ser. No. 61/034,173 filed Mar. 6, 2008, by S. Charles PICARDI and Ali RAZAVI. This application also claims priority from Ser. No. 61/118,281 entitled “Nanodiamond Enhanced Drugs” by Salvatore Charles PICARDI and Ali RAZAVI filed Nov. 26, 2008. This patent application also incorporates by reference Ser. No. 60/831,438 entitled “Biofunctional Articles For Personal Care Applications and Method of Making the Same” by Ali RAZAVI filed Jul. 18, 2006, and PCT patent application PCT/US2007/016,194 “Multifunctional Articles And Method For Making The Same” by Ali RAZAVI filed Jul. 17, 2007 as if both were set forth in their entirety herein. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    1. Field of the Invention 
         [0003]    The present invention relates to a substance and method of enhancing the efficacy of drugs and more specifically a substance and method of increasing the efficacy of antimicrobials (AMs). 
         [0004]    2. Discussion of Related Art 
         [0005]    There has always been a need to increase the efficacy of various drugs and preparations. One such class of drugs to be used as an example in this application are the antimicrobials (AMs). AMs are typically used to limit or stop the spread of unwanted microbes. AMs are effective when used in the proper level but lose their ability as the concentration drops below a critical concentration. This may be due to the fact that enough active sites on antimicrobial molecules must make contact with active sites on critical molecules inside of a microbe to cause the microbe to have an effect. 
         [0006]    AMs are typically used in an aqueous solution inside of a person or animal. Molecules flowing in a solution are randomly dispersed and oriented. Also, since AMs flow in solution to attach to active sites on the microbe, it is important to have a large amount of the AMs in solution, increasing the local concentration and the potential of attaching to an active site on a microbe molecule. 
         [0007]    Currently, there is a need for AMs that are more soluble in a fluid, and attach more readily to active sites on molecules of microbes to inactivate the microbes. 
       SUMMARY OF THE INVENTION 
       [0008]    One embodiment of the present invention is a method of enhancing efficacy of a drug having an active site, comprising the steps of:
       a) acquiring a plurality of nanodiamond (ND) particles having a plurality of carbon chain surface molecules on its surface, the ND particles having a diameter of less than 10 nanometers;   b) covalently attaching a plurality of intermediate amine entities to the surface molecules of the ND particles, and   c) replacing at least a portion of the attached intermediate amine entities attached to the surface molecules of the ND particles with said drug molecules such that the active sites of said drug molecules point away from the ND particle exposing them for enhanced activity and enhanced drug efficacy.
 
This method is very effective in enhancing the efficacy of antimicrobial agents; however other drugs may be employed.
       
 
       OBJECTS OF THE INVENTION 
       [0012]    It is an object of the present invention to provide an antimicrobial which is more potent than previous antimicrobials. 
         [0013]    It is another object of the present invention to provide an antimicrobial which is more soluble than prior art antimicrobials. 
         [0014]    It is another object of the present invention to provide a method of amplifying the effect of an antimicrobial in-situ. 
         [0015]    It is another object of the present invention to provide a method of holding antimicrobial molecules in an orientation to maximize interaction with microbes. 
         [0016]    It is another object of the present invention to provide a method for locally increasing the effective concentration of an antimicrobial while keeping the overall concentration constant. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0017]    The advantages of the instant disclosure will become more apparent when read with the specification and the drawings, wherein: 
           [0018]      FIG. 1  is a schematic illustration of how molecules react under normal prior art conditions. 
           [0019]      FIG. 2  is a schematic microscopic view of a portion of a nanodiamond showing the structure of chemical entities attached to the surface of the nanodiamond. 
           [0020]      FIG. 3  is an illustration of the entities of first part of chemical reactions for creating coated nanodiamonds according to the present invention. 
           [0021]      FIG. 4  is an illustration of the entities of the second part of chemical reactions for creating coated nanodiamonds according to the present invention. 
           [0022]      FIG. 5  is an illustration of test plates used for testing the effectiveness of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Theory 
       [0023]      FIG. 1  is a schematic illustration of how molecules react under normal prior art conditions. 
         [0024]    As stated in the “Background of the Invention”, chemical functional groups, antimicrobials AM  11  here for this description, typically in solution, randomly orient themselves and by random chance align in the proper orientation to have an active chemical site  13  of the AMs make contact with the proper active chemical site  15  of a molecule in a microbe  17 . 
         [0025]    If these active sites  13  are hidden inside a clump of molecules  11  (shown in the center of the figure) or otherwise inaccessible, the chances that the active sites  13  make contact another active site  15  of the microbe is reduced. It is better if the active sites are exposed. 
         [0026]    When enough of these reactions occur, the reaction may cause the microbe to cease functioning. In one case it may cause them to stop their pathogenic function. In another case, the AMs may kill the microbe. This is the basis for fighting pathogens with antimicrobial chemicals. 
         [0027]    These may be by numerous different mechanisms. One such mechanism is to impede a chain reaction which creates cell walls. This causes offspring to have weak cell walls making them more vulnerable to attack by the body&#39;s natural defenses such as macrophages. 
         [0028]    Other mechanisms attack the microbe&#39;s ability to reproduce, or attack the energy producing mitochondria. Some AMs may use a combination of these mechanisms. 
         [0029]    Since each of these are based upon the random motion of molecules in solution, the chances that an active site of a molecule having the proper orientation makes contact with an active site of the proper molecule of the microbe is a matter of chance. The greater the number of molecules and active sites in solution, the greater the chances of the desired chemical bindings between active sites. Therefore, by exposing and holding the active sites of the AMs outward in an exposed, fixed orientation and gradually varying the orientations across a surface, there will be an orderly array of exposed active sites. 
         [0030]    This may be due to the fact that enough active sites on antimicrobial molecules must make contact with active sites on critical molecules inside of a microbe to cause the microbe to become deactivated. 
         [0031]    Molecules flowing in a solution are randomly dispersed and oriented. Also, since AMs flow in solution to attach to active sites on the microbe, it is important to have a large amount of the AMs in solution, increasing the local concentration and the potential of attaching to an active site on a microbe molecule. 
         [0032]    Also, the orderly arrangement of active sites must be able to move to meet up with the molecules of the microbe to interact with the active sites of these molecules. Therefore, this orderly arrangement must be mobile. 
         [0033]    Foreign objects in the body are identified by the body&#39;s immune system and either destroyed or ejected from the body. The immune cells of the body may seek out and kill, or engulf and carry foreign objects out of the body. This would greatly reduce the efficacy of any drug introduced into the body which is recognized as a foreign substance. 
         [0034]    The body ignores particles which are 10 Nanometers (nm.) or smaller. This may be due to the fact that there are many naturally occurring objects in the body fluids which are 10 nm. or smaller. 
         [0035]    Nanodiamonds (“ND”) are diamonds which are 6 nm or smaller. These are typically produced according to the process explained in U.S. Pat. Nos. 5,916,955 and 5,861,349 assigned to NanoBlox, Inc. issued June and January 1999 respectively. In this process, carbon is converted in an explosive process to create NDs in which the vast majority of the NDs produced are approximately 6 nm. 
         [0036]    These can be cleaned to take any graphite off of the surface to result in pure NDs of about 5 nm in diameter. 
         [0037]    NDs have been shown to stabilize suspensions and solutions and greatly increase solubility of substances in solutions. 
         [0038]    NDs have also been known to be functionalized to attach fluorine groups to its surface. This was intended to alter the surface composition of the NDs, but not for the purposes similar to that of the present invention. 
         [0039]    Since particles of 10 nm or less are allowed to freely pass in and out of microbes, it is believed that these may be perfect transport vehicles for many different AMs. Therefore AMs would be attached to the NDs to create an AM-ND complex. 
         [0040]      FIG. 2  is a schematic microscopic view of a portion of a nanodiamond showing the structure of chemical entities attached to the surface of the nanodiamond. 
         [0041]    The ND  20  exhibits a spherical shape. Here one is covered with a plurality of chemical entities, which are antimicrobial chemical entities, the AMs  11 . The AMs  11  are fixed in an orientation which extends them outwardly. 
         [0042]    This causes the active sites  13  of each of the AMs  11  to be exposed and point outwardly. Since the surface of ND  20  is curved, as one moves along the surface in any direction, the orientation of the AMs  11  and their active sites  13  changes slightly, allowing a continuum of orientations for the active sites  13 . Therefore, there is a greater chance of randomly oriented molecules to come in contact with an active site  13  of Am  11  having the proper orientation for reaction. 
         [0043]    Therefore, if one were to supply an orderly arrangement of such AM molecules covering the surface of the NDs with the active sites facing outwardly, it is believed that the efficacy of the AMs would be greatly increased. 
         [0044]    It was found, by extensive trial and error, that the efficacy of substances can be amplified by attachment to functionalized NDs. Modifying NDs has two major components. The first component is to cover the surface of the NDs with an intermediate compound. It was found that by replacing covalently attaching amine radicals to the exposed carbon chains of the NDs creates a platform which may then be used to attach other functional groups. 
         [0045]    The second step would be to attach functional molecules and/or groups to the exposed amine groups. 
         [0000]    Covalent Functionalization of Nanodiamond with Ethylenediamine. 
         [0046]      FIG. 3  is an illustration of the entities of first part of chemical reactions for creating coated nanodiamonds according to the present invention. 
         [0047]    This wet chemistry procedure has been developed to selectively create amino functionalities at the surface of nanodiamond (ND)  20 . Amino-terminated ND  20  has potential applications in medicine and as a component of novel versatile Nan composites. High temperature annealing in NH 3  atmosphere is non-selective resulting in a mixture of various surface functional groups including —NH 2 , C═O—O—H, C═N etc. Wet chemistry rooted in mild conditions allows selectively create only —NH 2  surface functionalities-a strict requirement for the sophisticated applications mentioned above. 
         [0048]    The sequence of reactions yielding the NH 2 -terminated product attached to ND and Ethylenediamine (EDA) is presented below: 
       Materials and Reagents. 
       [0049]    Nanodiamond powder UD90 produced by detonation synthesis (FRPC “Altai”, Russia) was supplied by NanoBlox, Inc., USA. The powder was purified by oxidation in air [1] and then boiled with 35% wt. aqueous HCl under reflux for 24 hours to remove traces of metals and metal oxides. After removing the excess of HCl, ND powder was rinsed with distilled water and adjusted to a neutral pH and dried in the oven at 110° C. overnight. 
         [0050]    In  FIG. 3 , this purified material is shown as entity A which is ND  20 . This is used in subsequent functionalization. Here is can be seen that each ND entity A has a plurality of outwardly pointing COOH carboxyl groups covering the entire surface of the ND. (Only one is shown here for clarity.) 
         [0051]    The reagents used were thionyl chloride purum ˜99.0% (Fluka), methanol anhydrous 99.8% (Sigma-Aldrich), tetrahydrofuran 99.85% ExtraDry (Acros Organics), ethylenediamine SigmaUltra (Sigma-Aldrich), N,N-dimethylformamide anhydrous, 99.8%. All reagents were used without additional purification. 
       Synthesis of ND Acylchloride Derivative B of FIG. 3: 
       [0052]    50 ml of SOCl 2  and 0.5 ml of anhydrous dimethylfomamide (DMF) (catalyst) were added to ˜1.5 g of carboxyl terminated ND particles (A) in round-bottom 100 ml flask. This was mixed with a Teflon-coated magnetic stirrer bar. 
         [0053]    The flask was closed with a stopper and sonicated in an ultrasound bath until there were no visible chunks of nanodiamond. 
         [0054]    The flask was then connected to a reflux condenser closed with a desiccating tube (Drierit) and heated under refluxing at 70° C. for 24 hours. 
         [0055]    After cooling down to room temperature, excess of SOCl 2  was removed by vacuum distillation at a temperature of 50° C. to prevent its decomposition. 
         [0056]    The content of the flask was then rinsed with anhydrous tetrahydrofuran (THF) (2 rinses 50 ml THF each); ND powder was allowed to precipitate. Excess THF was removed by decantation. 
         [0057]    The flask was transferred into a desiccator with Drierit and left under vacuum at room temperature overnight to dry the ND acylchloride powder (B) of  FIG. 3 . 
       Synthesis of ND Amino Derivative C of FIG. 3: 
       [0058]    ˜1.5 g of B was mixed with 50 ml of anhydrous EDA in round-bottom 100 ml flask. This was stirred with a Teflon-coated magnetic stirrer bar 
         [0059]    The NDs now have EDA molecules covalently attached to them. The NDs have a spherical geometry. The EDAs are attached to the outermost surface making them the most exposed portion of the complex. 
         [0060]    The functional groups and/or specific molecules may now be attached to each EDA of each ND-EDA complex. 
       Step 2—Functionalization 
       [0061]    The second step would be to attach functional molecules and/or groups to the exposed amine groups. 
         [0000]    Covalent Functionalization of Aminated Nanodiamond with Antimicrobials. 
         [0062]      FIG. 4  is an illustration of the entities of the second part of chemical reactions for creating coated nanodiamonds according to the present invention. 
         [0063]    This wet chemistry procedure has been developed to selectively create antimicrobial functionalities at the surface of nanodiamond (ND). Amino-terminated ND has potential applications in medicine and as a component of novel versatile nanocomposites. High temperature annealing in NH 3  atmosphere is non-selective resulting in a mixture of various surface functional groups including —NH 2 , C═O—O—H, C═N etc. Wet chemistry rooted in mild conditions allows selectively create only —NH 2  surface functionalities-a strict requirement for the sophisticated applications mentioned above. 
         [0064]    The sequence of reactions yielding the AM-terminated product attached to the aminated NDs. 
       Materials and Reagents. 
       [0065]    Aminated nanodiamond powder was reacted with K peroxymono sulfate (Fisher) and traditional antimicrobial moieties by salt synthesis. 
         [0066]    The reagents used were thionyl chloride purum ˜99.0% (Fluka), methanol anhydrous 99.8% (Sigma-Aldrich), tetrahydrofuran 99.85% ExtraDry (Acros Organics), ethylenediamine SigmaUltra (Sigma-Aldrich), N,N-dimethylformamide anhydrous, 99.8%. All reagents were used without additional purification. 
       Synthesis of ND Biofunctional Derivative D of FIG. 4: 
       [0067]    In this part of the reaction, 5 grams of antimicrobial moieties and 0.5 ml of anhydrous dimethylfomamide (DMF) (catalyst) were added to ˜25 g of aminated ND particles (C) of  FIG. 3  in round-bottom 200 ml flask. These are the NDs 20 having attached amine groups. This was mixed with a Teflon-coated magnetic stirrer bar. 
         [0068]    The flask was closed with a stopper and sonicated in an ultrasound bath until there were no visible chunks of nanodiamond. 
         [0069]    The flask was then connected to a reflux condenser closed with a desiccating tube (Drierit) and heated under refluxing at 70° C. for 24 hours. 
         [0070]    After cooling down to room temperature, excess of liquid was removed by vacuum distillation at a temperature of 50° C. to prevent its decomposition. 
         [0071]    The content of the flask was then rinsed with anhydrous tetrahydrofuran (THF) (2 rinses 50 ml THF each); ND powder was allowed to precipitate. Excess THF was removed by decantation. 
         [0072]    The flask was transferred into a desiccator with Drierit and left under vacuum at room temperature overnight. 
         [0073]    Freeze drying overnight produced the final bio-functional powder entity D of  FIG. 4 . Here it can be seen that NH-peroxymonosulfate is the antimicrobial attached to the ND  20 . It has a reactive sites not shown here which are each numbered  13  in  FIG. 2 . 
         [0074]    This has been described using terminal amine groups as the preferred embodiment. However, or chemical entities may be used as well. For example, the surface molecules on the nanodiamonds could be terminated with COOH groups. These will be replaced with the drug which is to be enhanced. 
       Antimicrobials 
       [0075]    A number of different antimicrobial functional groups may be attached to the EDA groups. In this example, potassium monopersulfate was used with the antimicrobial. Formulation of potassium monopersulfate is described in U.S. Pat. No. 7,090,820 B2 Martin, issued Aug. 15, 2006. It is understood that the present invention includes numerous different functional groups to enhance reactivity and efficacy. 
         [0076]    Another preferred antimicrobial intended to be used with the present invention is: peroxymonosulfate triple salt and antimicrobial/antifungal chemistries as described in U.S. Pat. Nos. 7,090,820 and 4,131,672 issued Aug. 15, 2006 and Jan. 26, 1978 respectively. 
         [0077]    Some other anti-microbial agents that can be used with the present invention include Cipro (Phizer), fluoroquinilone, Amoxycillin, 2-bromo-2-nitropropane-1,3-diol (for example, Canguard® 409 made by Angus Chemical Co., Buffalo Grove, Ill. 60089) and 3,5-dimethyltetrahydro-1,3,5-2H-thiazine-2-thione (for example, Nuosept® S made by Creanova, Inc., Piscataway, N.J. 08855 or Troysan®. 142 made by Troy Chemical Corp., West Hanover, N.J. 07936). 
         [0078]    Other solid anti-microbial agents include N-(trichloromethyl)-thiop-hthalimide (for example, Fungitrol® 11 distributed by Creanova, Inc.), butyl-p-hydroxy-benzoate (for example, Butyl Parabens®. made by International Sourcing Inc., Upper Saddle River, N.J. 07458), diiodomethyl-p-tolysulfone (for example, Amical®. WP made by Angus Chemical Co.), and tetrachloroisophthalonitrile (for example, Nuocide® 960 made by Creanova, Inc.). 
         [0079]    Drugs such as azithromycin, penicillin, clarithromycin, etc can be bound to the aminated and/or functionalized nanodiamond to increase efficacy as well. 
         [0080]    Metals such as silver, copper and zinc and their metal ions also have anti-microbial properties. Silver ions have widespread effect as an anti-microbial agent. For example, silver ions may be effective against bacteria such as  Escherichia coli  and  Salmonella typhimurium , and mold such as  Aspergillus.    
         [0081]    Sources of silver for functional groups for anti-microbial use include metallic silver, silver salts and organic compounds that contain ionic silver. Silver salts may include for example, silver carbonate, silver sulfate, silver nitrate, silver acetate, silver benzoate, silver chloride, silver fluoride, silver iodate, silver iodide, silver lactate, silver nitrate, silver oxide and silver phosphates. Organic compounds containing silver may include for example, silver acetylacetonate, silver neodecanoate and silver ethylenediaminetetraacetate in all its various salts. 
         [0082]    Silver containing zeolites (for example, AJ10D containing 2.5% silver as Ag(I), and AK10D containing 5.0% silver as Ag(I), both distributed by AgION™ Tech L.L.C., Wakefield, Mass. 01880) are of particular use. Zeolites are useful for functional groups because when carried in a polymer matrix they may provide silver ions at a rate and concentration that is effective at killing and inhibiting microorganisms without harming higher organisms. 
         [0083]    Silver containing zirconium phosphate (for example, AlphaSan® C 5000 containing 3.8% silver provided by Milliken Chemical, Spartanburg, S.C. 29304) is also particularly useful. In general zirconium phosphates act as ion exchangers. However, AlphaSan® C 5000 is a synthetic inorganic polymer that has equally spaced cavities containing silver, wherein the silver provides the anti-microbial effects. Silver zirconium phosphates are typically incorporated into powder coatings between 0.1 and 10 percent by weight and particularly 0.5 to 5 percent by weight of the total powder coating formulation. 
         [0084]    Using AMs listed above in combination with NDs, the present invention greatly increases efficacy in fighting microbes. Below are microbes which may be reduced or stopped with greater efficacy. 
         [0085]    Bacteria 
         [0086]    The present invention, using nanodiamonds to enhance the effectiveness of the above-referenced AMs against bacteria such as:  Bacillus cereus, Campylobacter jejuni, Chlamydia psittaci, Clostridium perfringens, Listeria monocytogenes, Shigella sonnei, Streptococcus pyogenes, Helicobacter pylori, Campylobacter pyloridia, Klebsiella pneumoniae, Escherichia coli, Salmonella typhimurium, Salmonella choleraesuis, Pseudomonas aeruginosa, Staphylococcus aureus , MRSA (Methicillin-Resistant  Staphlococcus aureus ),  Staphylococcus epidermis  and VRE (Vancomycin-Resistant Enterococci  faecalis ). 
         [0087]    Viruses 
         [0088]    It is also effective at increasing efficacy against viruses such as: 
         [0089]    Hepatitis A (HAV), Hepatitis B (HBV), Hepatitis C(HCV), HIV-1 (AIDS Virus), Influenza A, Norovirus (Norwalk-like viruses) and RSV (Respiratory syncytial virus). 
         [0090]    Fungi 
         [0091]    It is also effective at increasing efficacy against fungi such as: 
         [0092]      Candida albicans  and  Trichophytou mentagrophytes.    
       Method of Delivery 
       [0093]    There are various known methods of introducing the ND-AM complexes into the body of the patient. For example, the most obvious would be in a pill or liquid form which the subject ingests. This is only allowable for drugs which are not effected by the acids of the digestive tract. 
         [0094]    The ND-AM complexes may injected, administered by air gun, nose spray, be inhaled, or used as a suppository. 
         [0095]    The ND-AM complexes may be used as a disinfectant as an air spray, applied to the hands, or incorporated into materials around the patient, such as sheets and bedding. 
         [0096]    They may also be incorporated into medical disposables, such as surgical drapes, bandages and disposable coverings. 
         [0097]    The ND-AM complex may be used to coat the woven or non-woven fabrics. These may be for disposable or non-disposable fabrics. The ND-AM complexes may also be incorporated into the actual fibers used to create the woven or non-woven fabrics; and, includes but is not limited to applications in producing sutures, wound dressings, and medical cable coatings. 
       Test Results 
       [0098]    NDs coated with AMs showed exceptional results in fighting microbes. The coated NDs showed significantly enhanced efficacy when compared to the AMs used alone. 
         [0099]    In  FIG. 5  an illustration of the test results are shown. Three petri disks are shown filled with agar gel.  Staphlococcus Aureus  was previously grown evenly across the surface of the gels. 
         [0100]    Sixteen approximately ¼″ diameter discs were fabricated from of DuPont Sontara 8801 non-woven fabric. 
         [0101]    Four disks  511  were placed on the surface of the agar in dish  510 . 
         [0102]    Four disks  531  were coated with nanodiamond powder (A of  FIG. 3 ) and were placed on the surface of the agar in dish  530 . 
         [0103]    Four disks  551  were coated with potassium monopersulfate, the antimicrobial described above and were placed on the surface of the agar in dish  550 . 
         [0104]    Four disks  571  were coated with potassium monopersulfate used as the antimicrobial attached to, and covering the entire surface of the NDs being entity D of  FIG. 5  described above and were placed on the surface of the agar in dish  570 . 
         [0105]    The plates were all please in the same environment overnight, then examined. 
         [0106]    Plate  510 ,  530  had continuous growth of the bacteria and were not changed. 
         [0107]    Plate  550  developed a clear area  553  around each disk  551  which was due to the destruction of the bacteria previous growing in this region. This area extended approximately 1/16″ away from each of the disks  551 . 
         [0108]    Plate  570  developed a clear area  573  around each disk  571  which was due to the destruction of the bacteria previous growing in this region. This area extended approximately ⅛″ away from each of the disks  551 . 
         [0109]    This indicates that the disks  511  and the disks with ND  531  did not have any effect on the microbes. 
         [0110]    The antimicrobial on disks  553  killed bacteria a small distance away and the antimicrobial attached to ND on disks  575  killed bacteria a significantly larger distance away. 
         [0111]    The surface are of a spherical surface increases surface area based upon the square of the radius. Therefore if a given number of molecules has to cover a larger surface area, the concentration drops proportionally. Therefore, the ND-AM complex kills at a significantly lower concentration. This shows increased antimicrobial efficacy. 
         [0112]    Medical Foam 
         [0113]    The nanodiamond enhanced particles shown as ND-AM entity D on  FIG. 4 , may be mixed with a thermoplastic, then pumped with air to create either closed cell, or open cell medical foam. As a liquid, the foam resembles suds. Many different known plastics may be used. For our example below, the foam was created from polyurethane. It was then hardened into a spongy-like foam material with antimicrobial properties. This foam will be useful as a medical wound dressing. 
         [0114]    Animal Testing 
         [0115]    Medical foam was created as indicated above then sent to a medical laboratory for testing. An animal study was performed on 20 mice by an independent lab testing authority. 
         [0116]    This activated polyurethane foam was created with approximately almost 4% active material (ND-AM entity D on  FIG. 4 ). The thickness of the used foam is 1.5 mm. This is referred to in the figures as the “Test Article”. 
         [0117]    Wound areas having a diameter of about 4 mm. on each of the mice were infected by cultured Methycillin Resistant  Staphlococcus Aureus  (MRSA) infected with a 0.1 ml volume dose of inoculum which occurred only on Day 0. 
         [0118]    There was also polyurethane foam without the ND-AM of the same size and thickness placed on the mice as a control for comparisons. This is referred to in the figures as the “Control”. 
         [0119]    The foam was changed daily on each of the wounds, and the results tabulated. 
         [0120]    The data is listed below. Table A shows Mean Erythema Scores of both the tested group and the control group for consecutive 14 days. This is shown graphically in  FIG. 6 . 
         [0121]    Table B shows the Mean Edema Scores for the same groups for 14 consecutive days. This is shown graphically in  FIG. 7 . 
         [0122]    Table C shows the Mean Wound Diameters for the same groups for 14 consecutive days. This is shown graphically in  FIG. 8 . 
         [0123]    Table D shows the Average Time to Exfoliation for both groups. 
         [0124]    Table E shows the Body Weights of the test groups over the test period. 
       Other Test Results 
       [0125]      
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE A 
               
             
             
               
                   
               
               
                 Mean Erythema Scores 
               
             
          
           
               
                   
                 Erythema Scores 
               
               
                   
                 (mean ± sem) 
               
             
          
           
               
                   
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Group 
                 Treatment 
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                   
               
               
                 1 
                 Vehicle 
                 0 
                 0 
                 1.0 ± 
                 1.5 ± 
                 2.4 ± 
                 2.1 ± 
                 1.4 ± 
                 1.3 ± 
                 1.3 ± 
                 1.2 ± 
                 1.1 ± 
                 1.0 ± 
                 0.7 ± 
                 0.5 ± 
                 0.3 ± 
               
               
                   
                   
                   
                   
                 0.2 
                 0.2 
                 0.2 
                 0.1 
                 0.2 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 2 
                 Activated 
                 0 
                 0 
                 0.5 ± 
                 1.4 ± 
                 1.4 ± 
                 0.8 ± 
                 0.8 ± 
                 0.8 ± 
                 0.8 ± 
                 0.7 ± 
                 0.7 ± 
                 0.6 ± 
                 0.5 ± 
                 0.5 ± 
                 0.3 ± 
               
               
                   
                 PU foam 
                   
                   
                 0.2 
                 0.2 
                 0.2** 
                 0.2*** 
                 0.2* 
                 0.2** 
                 0.1** 
                 0.1** 
                 0.1** 
                 0.1** 
                 0.1 
                 0.1 
                 0.1* 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE B 
               
             
             
               
                   
               
               
                 Mean Edema Scores 
               
             
          
           
               
                   
                 Edema Scores 
               
               
                   
                 (mean ± sem) 
               
             
          
           
               
                   
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Group 
                 Treatment 
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                   
               
               
                 1 
                 Vehicle 
                 0 
                 0 
                 1.0 ± 
                 1.5 ± 
                 2.4 ± 
                 2.6 ± 
                 2.8 ± 
                 2.6 ± 
                 2.6 ± 
                 2.4 ± 
                 2.0 ± 
                 1.7 ± 
                 1.4 ± 
                 1.1 ± 
                 0.7 ± 
               
               
                   
                   
                   
                   
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.1 
                 0.2 
                 0.2 
                 0.3 
                 0.2 
                 0.2 
                 0.3 
                 0.1 
               
               
                 2 
                 Activated 
                 0 
                 0 
                 0.5 ± 
                 1.4 ± 
                 1.4 ± 
                 1.5 ± 
                 1.7 ± 
                 1.9 ± 
                 2.1 ± 
                 1.8 ± 
                 1.4 ± 
                 1.3 ± 
                 1.2 ± 
                 1.1 ± 
                 1.0 ± 
               
               
                   
                 PU foam 
                   
                   
                 0.2* 
                 0.2 
                 0.2** 
                 0.2*** 
                 0.2** 
                 0.2* 
                 0.2 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE C 
               
             
             
               
                   
               
               
                 Mean Wound Diameters 
               
             
          
           
               
                   
                 Wound Diameters 
               
               
                   
                 (mean ± sem) 
               
             
          
           
               
                   
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Group 
                 Treatment 
                 0 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
               
               
                   
               
               
                 1 
                 Vehicle 
                 5.7 ± 
                 5.6 ± 
                 5.3 ± 
                 5.1 ± 
                 4.8 ± 
                 4.6 ± 
                 4.3 ± 
                 4.3 ± 
                 3.9 ± 
                 3.2 ± 
                 2.9 ± 
                 2.7 ± 
                 2.3 ± 
                 2.2 ± 
                 1.8 ± 
               
               
                   
                   
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.1 
                 0.1 
               
               
                 2 
                 Activated 
                 5.9 ± 
                 5.9 ± 
                 5.0 ± 
                 4.9 ± 
                 4.7 ± 
                 4.6 ± 
                 4.1 ± 
                 3.8 ± 
                 3.5 ± 
                 3.0 ± 
                 2.6 ± 
                 2.3 ± 
                 2.0 ± 
                 1.8 ± 
                 1.5 ± 
               
               
                   
                 PU foam 
                 0.4 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.2 
                 0.1 
                 0.1 
                 0.1 
                 0.1* 
                 0.1 
                 0.1* 
                 0.1* 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE D 
               
             
             
               
                   
               
               
                 Average Time to Exfoliation 
               
             
          
           
               
                   
                   
                 Exfoliation 
               
               
                   
                   
                 Time 
               
               
                   
                   
                 (days) 
               
               
                   
                   
                 Mean ± 
               
               
                 Group 
                 Treatment 
                 SEM 
               
               
                   
               
               
                 1 
                 Vehicle 
                  9.9 ± 0.8 
               
               
                 2 
                 Activated PU Foam 
                 10.8 ± 0.6 
               
               
                   
               
               
                 *Statistically significant difference compared to the Group 1 vehicle control (p &lt; 0.05) 
               
               
                 **Statistically significant difference compared to the Group 1 vehicle control (p &lt; 0.05) 
               
               
                 ***Statistically significant difference compared to the Group 1 vehicle control (p &lt; 0.05) 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
             
           
               
                 TABLE E 
               
             
             
               
                   
               
               
                 Body Weights 
               
             
          
           
               
                   
                 Body Weight (g) 
               
               
                   
                 (mean ± sem) 
               
             
          
           
               
                 Group 
                 Treatment 
                 Day 0 
                 Day 7 
                 Day 14 
               
               
                   
               
               
                 1 
                 Vehicle 
                 24.6 ± 0.4 
                 25.2 ± 0.6 
                 25.8 ± 0.6 
               
               
                 2 
                 Activated PU Foam 
                 23.2 ± 0.4 
                 23.9 ± 0.6 
                 24.4 ± 0.7 
               
               
                   
               
             
          
         
       
     
         [0126]    Wound infection is a major complication in diabetic patients. According to the American Diabetes Association, 25% of people with diabetes will suffer from a wound problem during their lifetime, and it has been estimated that lower limb amputations in diabetic patients account for &gt;60% of all amputations performed. 
         [0127]      Staphylococcus aureus  ( S. aureus ) is the most common single isolate (76%) in diabetic wounds and foot ulcers and leads to alterations in wound healing. Wound infection can also result in bacteremia or sepsis and is associated with high morbidity and mortality. In the United States  S. aureus  is the most common cause of skin and soft-tissue infections, as well as of invasive infections acquired within hospitals. Treatment of severe  S. aureus  infections is challenging, and the associated mortality rate remains high.  S. aureus  is a gram-positive bacterium that colonizes the skin and is present in the anterior nares in about 25-30% of healthy people. Over the last 40 years Methicillin-resistant  S. aureus  (MRSA) infections have become endemic in hospitals in the U.S. and worldwide. In 2002, the first clinical isolate of Vancomycin-resistant  S. aureus  (VRSA) was identified in a patient with diabetic foot ulcer. The progressive reduction of therapeutic efficacies of the available antibiotics underlines the need for the development of new therapeutic strategies for the treatment of infected wounds. 
         [0128]    Therefore, the medical foam incorporating the enhanced antimicrobial would be very useful in countering the problems which diabetics encounter, especially since it was tested as effective against MRSA. 
         [0129]    Even though this description was performed for a specific antimicrobial, it is believed that this applies to increasing the efficacy of other drugs and preparations. If these entities are used instead of the AM entities and attached to the surface of NDs, their efficacy will also increase. 
         [0130]    Since other modifications and changes varied to fit particular operating requirements and environments will be apparent to those skilled in the art, the invention is not considered limited to the example chosen for the purposes of disclosure, and covers all changes and modifications which do not constitute departures from the true spirit and scope of this invention.