Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/38—Silver; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B22—CASTING; POWDER METALLURGY
  • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
  • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
  • B22F1/05—Metallic powder characterised by the size or surface area of the particles
  • B22F1/054—Nanosized particles
  • B22F1/0547—Nanofibres or nanotubes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B22—CASTING; POWDER METALLURGY
  • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
  • B22F2998/00—Supplementary information concerning processes or compositions relating to powder metallurgy

Definitions

• the present invention relates in general to the field of antivirals, and more particularly, to compositions, methods and treatment of viral particles with silver nanoparticles to reduce or eliminate viral infection and/or transmission.
• Nanowires as one dimensional nanostructured materials, have become the focus of intensive research owing to their great potential for use as building blocks in the fabrication of electronic, optoelectronic and sensor devices with nanoscale dimensions. The most common applications of nanowires are expected to be in electromagnetic and energy storage devices.
• Silver (Ag) has many important applications due to its high electrical and thermal conductivity and its unique optical properties that depend on size and shape. Therefore, the study of Ag nanowires has led to great interest.
• Glycerin is also used in many body care products.
• U.S. Patent No. 6,720,006 teaches a body care product is a product that is brought into contact with human and/or animal skin or mucosa to provide a cleaning, protective, therapeutic, cosmetic or soothing benefit. These products can also be found on surfaces contacting the skin such as diapers, incontinence articles, catamenial devices, training pants, panty liners, etc.; or skin care compositions such as emulsions, lotions, creams, ointments, salves, powders, suspensions, gels, soaps, etc.
• the present invention provides compositions and methods for making and using an anti-viral composition for use in treating and preventing viral infection.
• the present invention includes compositions, methods of making and methods of using silver nanoparticles.
• the method includes the synthesis of silver nanoparticles (particles of sizes between 1 and 100 nm) and nanowires (1-D structures with diameters between 1 and 100 nm with lengths up to several hundreds of nanometers) using glycerin as both the reducing agent and the solvent of the nanostructures.
• this technique may be extended but not limited to nanoparticles and nanowires of gold, platinum, palladium, copper, iron, and alloys composed of these metals. It can be also extended to metal oxides nanoparticles and nanowires such as titanium dioxide, zirconium dioxide, etc. It is important to mention that the method can be also expanded to the production of particles in the mesoscopic range, specifically from 100 to 500 nm.
• capping agents can be used, e.g. polyvinylpyrrolidone (PVP).
• a current problem is the resistance developed by bacteria to current antibiotics, hi addition, there are no 100% efficient treatments and vaccines to prevent or combat diseases due to viruses such as HTV, hepatitis C (HCV), human papillomavirus (HPV), etc. Due to its strong toxicity to a wide range of microorganisms, silver has been used against bacteria and fungi. There is a possibility of using nanotechnology to improve and develop silver nanoparticles to use as a biocide in substitution of current products like antibiotics. In fact, it is disclosed herein that the properties of silver nanoparticles in different forms are able to deactivate HIV with concentrations below the cytotoxic concentrations for MT2 cells.
• glycerin is the solvent for the nanoparticles and/or nanowires allows these structures to be used in almost any current commercial application of glycerin, such as preservation of fruit, prevention of freezing in hydraulic jacks, lubrication for molds, some printing inks, cake and candy making, and as an antiseptic.
• the present technology offers the possibility of combining the biocidal properties of silver nanoparticles with the versatile properties of glycerin in body care products.
• the present invention is not limited to body care products. Glycerin is miscible with water so other applications, such as paints, plastics and other composite materials can be implemented.
• the present invention includes the synthesis and characterization of silver nanowires synthesized by the polyol method.
• ethyleneglycol (EG) may be used as both reducing reagent and solvent.
• Poly(vinylpyrrolidone) (PVP) plays a role of structure-directing agent or capping agent.
• Nanowires were also synthesized by a modified polyol method using glycerin (G) instead of EG and poly(diallyldimethyl ammonium chloride) (PDDAM) replacing PVP.
• G glycerin
• PDAM poly(diallyldimethyl ammonium chloride)
• Figure Ia is an SEM image of the synthesized silver nanowires. The faceting in the nanowires is clearly observed. The inset shows a lower magnification SEM image of the same sample.
• Figure Ib is a schematic model of the nanowires.
• Figure Ic is an XRD pattern of the same sample.
• Figure Id is an EDS spectrum of one nanowire. The C signal comes from both the TEM grid and the PVP coating of the nanowires; O and N are also from the PVP coating, while Cu comes from the TEM grid.
• Figure 2a is an X-ray photoelectron spectra of pure PVP.
• Figure 2a is the PVP repeating unit, the three different carbon species are labeled as 1, 2, and 3.
• Figure 2b is a C Is spectrum.
• Figure 2c is an N Is spectrum.
• Figure 2d is an O Is spectrum.
• Figure 3a to 3d are X-ray photoelectron spectra of PVP-coated silver nanowires.
• Figure 3a is C Is spectrum.
• Figure 3b is an N Is spectrum.
• Figure 3c is a O Is spectrum.
• Figure 3d is Ag 3d 5/2 and Ag 3d 3/2 spectra.
• Figures 4a to 4f are TEM images of the same sample at different times after exposure to air at ambient conditions.
• Figure 4a is a sample just after synthesis.
• Figures 4b and Figure 4c are images of the sample after 3 weeks.
• Figures 4d - Figure 4f are images after 4, 5, and 24 weeks, respectively.
• Figure 5a to 5d are SEM images of silver nanowires at different times after exposure to air at ambient conditions.
• Figure 5a and Figure 5b are images of the sample after 4 weeks.
• Figure 5c and Figure 5d are SEM images of the sample presented in Figure 4f.
• Figures 6a and 6b are TEM images of two different samples that were not exposed to periodical electron irradiation. Sample after ( Figure 6a) 6 weeks and ( Figure 6b) 24 weeks. Figure 7 are HAADF images at different magnifications of the nanowire shown in Figure 6b.
• Figures 8a to 8b are a compositional analysis of one of the tips of the nanowire presented in the previous figure.
• Figure 8b is an EDS line scan across the shell of crystallites.
• Figure 8c is an EDS line scan across the core region of the nanowire.
• Figure 8d Punctual EDS analysis of three different regions of the tip of the wire.
• Figures 9a and 9b are high-magnification TEM image of the body of one nanowire after 24 weeks of exposure to air at ambient conditions.
• Figure 9b is a high-resolution TEM image of one of the crystallites that compose the shell. The inset corresponds to the FFT of the image.
• Figure 10 includes electron microscopy images of different regions of the sample after 24 weeks of exposure to air.
• Figures 11a to 11s are SEM image of the sample of silver nanowires after sulfidation.
• Figure 1 Ib to Figure 1 Id are HAADF images of the sulfidized silver nanowires.
• Figures 12a to 12d are EDS mapping of the sulfidized nanowire presented in Figure 12a.
• Figure 12b is a silver map.
• Figure 12c is a sulfur map.
• Figure 12d is a carbon map. In the last panel, the lacey carbon grid is clearly observed.
• Figures 13a and 13b are EDS punctual analysis of (Figure 13b) two different regions in one of the tips of the sulfidized nanowires presented in ( Figure 13a).
• Figures 14a to 14e are X-ray photoelectron spectra of sulfidized silver nanowires.
• Figure 14a is a C Is spectrum.
• Figure 14b is an N Is spectrum.
• Figure 14c is an O Is spectrum.
• Figure 14d is an Ag 3d 5/2 and Ag 3d 3/2 spectra.
• Figure 14e is an S 2p 3/2 and S 2pi /2 spectra.
• antiviral and “antiviral composition” refer to an amount of anti-viral protein associated noble metal nanoparticles treated with a polyol or polymer that suppress the replication and the spread of viruses, prevent viral attachment, prevent viral replication within the host cell, and/or improving or alleviating the symptoms caused by viral infection.
• a polyol or polymer that suppress the replication and the spread of viruses, prevent viral attachment, prevent viral replication within the host cell, and/or improving or alleviating the symptoms caused by viral infection.
• One example of the present invention is a glycerol-treated silver nanoparticle, nanorod or nanotube.
• the criteria for effective therapy include lower viral load, lower mortality rate, and/or lower morbidity rate, etc.
• derivatives refers to any derivative of the polyol-treated noble metal nanoparticles or nanowires and combinations thereof.
• protein associated noble metal nanoparticles include nanoparticles that associate with one or more proteins via covalent or non- covalent bonding and may include combinations of proteins and even concatamers of protein- nanoparticle-protein, etc., into bi-, tri-, terta-, multimers, oligomers, polymers and the like in two or three-dimensions .
• delivering refers to contacting polyol-treated noble metal nanoparticles or nanowires to a location or target defined as effecting the placement of the nanoparticles attached to, next to, or sufficiently close to the location such that any heat generated by the nanoparticles is transferred to the location.
• Delivery may be targeted or non-targeted as the term “targeted” is used herein.
• Nanoparticle refers to defined as a noble-metal particle having dimensions of from 1 to 5000 nanometers, having any size, shape or morphology.
• the nanoparticles are noble metals, such as gold colloid or silver and may be, e.g., nanospheres, nanotubes, nanorods, nanocones and the like.
• nanoparticle refers to one or more nanoparticles.
• nanoshell means one or more nanoshells.
• shell means one or more shells.
• non-tissue is defined as any material that is not human or animal tissue.
• targeted refers to the use of protein-protein binding, protein-ligand biding, protein- receptor binding, and other chemical and/or biochemical binding interactions to direct the binding of a chemical species to a specific site.
• polyol refers to a compound, polymer or oligomer containing two or more hydroxyl groups. Furthermore, the polyol may have one or more hydroxyl groups supplied from a carboxylic acid.
• the polyols of the present invention may be aliphatic, aromatic, heteroaliphatic, saturated alicyclic, saturated heteroalicyclic, aromatic, heteroaromatic, or polymeric.
• the hydroxyl groups of the polyol may be located at the terminal groups or as groups that are pendant from the backbone chain.
• the molecular of the polyol can generally vary depending on the application and, e.g., if the polyol portion is a monomer, di-mer, tri-mer, oligomer, polymer, whether linear, branched and/or aromatic.
• General examples of polyols include glycerin, glycols, polyglycols and polyglycerols, polyethers and polyesters.
• the polyol refers to the attachment of such a moiety to the noble metal nanoparticles or nanowires described herein.
• polymeric polyols include polyoxyethylene, polyoxypropylene and ethylene oxide-terminated polypropylene glycols and triols; polytetramethylene glycols; polydialkylsiloxane diols; hydroxy-terminated polyesters and hydroxy-terminated polylactones (e.g., polycaprolactone polyols); hydroxy-terminated polyalkadienes (e.g., hydroxyl-terminated polybutadienes); and the like. In addition mixtures of polymeric polyols can be used if desired.
• polyols include 1,2-ethanediol; 1,2- and 1,3-propanediol; 1,3- and 1,4-butanediol; neopentylglycol; 1,5-pentanediol; 3-methyl- 1,5-pentanediol; 1,2-, 1,5-, and 1,6-hexanediol; bis(hydroxymethyi)cyclohexane; 1,8-octanediol; 1,10-decanediol; di(ethylene glycol); tri(ethylene glycol); tetra(ethylene glycol); di(propylene glycol); di(isopropylene glycol); tri(propylene glycol); polyoxyethylene diols; polyoxypropylene diols; polycaprolactone diols; resorcinol; hydroquinone;
• viral infection refers to viral invasion of a target cell. When the virus enters the healthy cell, it takes advantage of the host reproduction mechanism to reproduce itself, ultimately killing the cell. As the virus reproduces, newly produced viral progeny infect other cells, often adjacent cells. Some viral genes can also integrate into host chromosome DNA to cause a latent infection via a provirus. The provirus reproduces itself with the replication of the host chromosome, and can bring the infected people into morbidity at any moment if activated by various factors inside and outside the body.
• synergic action refers to a joint protein associated polyol-treated noble metal nanoparticles or nanowires drug administration that is more effective than the additive action of merely using any of two or more therapeutics to cure or to prevent viral infection.
• the synergic effect can increase the efficacy of the antiviral drugs and the protein associated noble metal nanoparticles to avoid or alleviate viral tolerance against any single medicine.
• therapeutics refers the protein associated noble metal nanoparticles or nanowires whether alone or compounded in a delivery system, whether liquid, solid, gel-like, dried, frozen, resuspended and the like.
• the protein associated noble metal nanoparticles drug or active agent is conductive to the treatment of viral infection or virus-caused diseases, as taught herein.
• the protein associated noble metal nanoparticle or nanowire antiviral agents of the present invention may be used alone or in combinations with agents that include, but are not limited to antiviral agents, such as the cytokines rIFN ⁇ , rIFN ⁇ , and rIFN ⁇ ; reverse transcriptase inhibitors, such as AZT, 3TC, ddl, ddC, Nevirapine, Atevirdine, Delavirdine, PMEA, PMPA, Loviride, and other dideoxyribonucleosides or fr ⁇ orodideoxyribonucleoside; viral protease inhibitors, such as Saquinavir, Ritonavir, Indinavir, Nelfmavir, and VX-478; hydroxyurea; viral mRNA capping inhibitors, such as viral ribovirin; amphotericin B; ester bond binding molecule castanospermine with anti-HTV activity; glycoprotein processing inhibitor; glycosidase inhibitors SC-48334 and MDL-
• the anti-viral protein-nanoparticles described herein may be used as part of a method and kit for improved antiviral therapy for the treatment of broad viral (including HIV) infection.
• the present invention provides a method of joint drug administration aimed at boosting the therapeutic effect, including the use of combination therapy, its derivatives, a second active agent or nutraceutical or dietary supplement, generally provided alone or in combination within a pharmacologically acceptable carrier.
• An advantage of combination therapy is that it may preclude viral adaptation or mutation that increases its tolerance against each therapeutic alone.
• Another advantage of combination therapy is that drugs may be provided at lower doses to reduce drug toxicity and enhance the therapeutic index. It is known that size confinement produces dramatic changes on the physical properties of matter.
• the present invention may be used alone or in a medium or carrier, where the silver nanoparticles are homogeneously dispersed, and is very friendly to the human body and can be rapidly incorporated to a variety of body care products to exploit the biocidal properties of silver nanoparticles against a wide range of toxic microorganisms (bacteria, viruses and fungi).
• glycerin as both the solvent and the reducing agent in the production of silver nanoparticles.
• glycerin and equivalent compounds as the solvent and reducing agent allows noble metal nanoparticles and nanowires, e.g., silver nanoparticles, to be dispersed well in a solvent that is extensively used in many applications, so the biocidal properties of silver nanoparticles can be exploited in many of those products.
• a well-established method found in the literature for the synthesis of metal and metal oxide nanoparticles and nanowires is known as the polyol method.
• ethylene glycol is used as both the reducing agent and the solvent.
• the main difference in the proposed technology is the replacement of ethylene glycol by glycerin (propylene glycol) which is a friendlier and less toxic compound.
• the physical properties of both compounds are different, so the general behavior of the final product will be different.
• PVP polyvinylpyrrolidone
• PDAM polydiallyldimethyl ammonium chloride
• TEM analysis demonstrated that for all cases (EG or G and PVP or PDDAM) the obtained nanowires have the same structure, being single crystalline and having several defects like twin boundaries, dislocations and stacking faults.
• EDS analysis on different samples showed that they are composed only of Ag and have a very thin amorphous layer of capping agent (PVP or PDDAM). Further analysis to fully understand the growth mechanism and the role that the defects play on it is in progress. However, it is expected that these type of nanowires will have mechanical properties that strongly deviate from the bulk material.
• the glycerin method disclosed herein eliminates the problem of finding an agent which will facilitate the contact of the silver nanoparticles with the body.
• the reason is because glycerin is a lot friendlier with the human body than ethylene glycol. That is why glycerin, in contrast to ethylene glycol, plays an important role in a vast range of body care products.
• Use of well-known and characterized compounds that are biocompatible and non- allergenic is especially important because of the possibility to generate products to prevent the infection against, e.g., HTV.
• the present invention may be further characterized as follows.
• inorganic nanostructures have attracted growing interest due to their potential applications in catalysis 1 , biological sensors 2 , and nanoelectronics 3 among others.
• these materials have at least one of their dimensions between 1 nm and 100 nm, interesting properties arise due to phenomena such as quantum confinement and high surface-to- volume ratio 4 .
• the physicochemical properties are highly influenced by shape and size 1 ' 5 .
• shape and size 1 ' 5 the optical absorption spectra of metal nanoparticles are dominated by surface plasmon resonances (SPR) 6 , being the case of gold and silver unique. Both have the proper density of free electrons for their nanoparticles to possess SPR peaks in the visible region of the electromagnetic spectrum 7 , which in addition to their large effective scattering cross section, makes them ideal candidates for molecular labeling 8 .
• SPR surface plasmon resonances
• TEM transmission electron microscopy
• the total potential surface energy for the possible nanoparticle morphologies consists of several minima, and that the barriers between them are low enough ( ⁇ AT), so that thermal fluctuations provide sufficient energy to produce changes between the different morphologies.
• ⁇ AT low enough
• the five fold symmetry twinned structures such as the icosahedron and the decahedron tend to be slightly more stable, while cuboctahedral nanoparticles become more stable at larger sizes 12 .
• the size of the nanocrystals increases the structural fluctuations cease, thus fixing the nanoparticle morphology either as single-crystalline or multi-twinned 11 .
• the polyol method is one of the most employed routes for the synthesis of metal nanostructures.
• a metal precursor is dissolved in a liquid polyol, e.g. ethylene glycol, in the presence of capping agent molecules such as poly-vinyl pyrrolidone (PVP).
• PVP poly-vinyl pyrrolidone
• the final product is composed of monodispersed cubes, tetrahedrons and octahedrons, while if multi-twinned particles (MTPs) with decahedral shape were primarily formed; the final product is mainly composed of nanorods and nanowires with a remarkable multi-twinned structure with pentagonal cross sections.
• MTPs multi-twinned particles
• Gao, et al. found that when the molar ratio between PVP and AgNO 3 is six to one, only a monolayer of PVP is adsorbed into the surface of the wires 23 . Therefore, it may be expect that when the nanowires are exposed to air, the polymer membrane will be permeable enough to atmospheric gases and water vapor. Thus, the stability of the nanowires exposed to air against atmospheric corrosion needs to be explored. Furthermore, the higher reactivity of metal nanomaterials compared to their bulk state is also commonly known, so phenomena such as corrosion might be enhanced.
• Atmospheric corrosion in metals is a frequent phenomenon. Unlike other metals, atmospheric corrosion of silver, also known as tarnishing, occurs towards sulf ⁇ dation and not the formation of silver oxide 24 .
• the atmospheric sulf ⁇ dation of silver has been extensively investigated 24"28 . It has been demonstrated that silver sulfidizes upon exposure to several gaseous sulfur-containing compounds, being hydrogen sulfide (H 2 S) and carbonyl sulfide (OCS) the most important silver corrodents 25 .
• H 2 S hydrogen sulfide
• OCS carbonyl sulfide
• the present inventors tested the stability of PVP-coated silver nanowires synthesized by the polyol method when they are extracted from solution and exposed to air at ambient conditions.
• the stability of such silver nanostructures is demonstrated when a thin layer of silver sulfide nanocrystals is formed on the surface of the nanowires.
• a new method for the production of core-shell silver-silver sulfide nanoparticles and nanowires is presented.
• Metal nanostructures such as nanoparticles and nanowires have been proposed as building blocks for several applications in nanofabrication and nanoelectronics.
• metals Even when atmospheric corrosion is common in metals, there is a lack of information about the stability of those nanostractures against such phenomenon. Therefore, atmospheric corrosion of silver nanowires and nanoparticles synthesized by the polyol method using poly-vinyl pyrrolidone (PVP) as capping agent by different techniques, including transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS) was determined. After synthesis and purification, the silver nanostructures were deposited on different substrates and exposed to laboratory air at ambient conditions.
• PVP poly-vinyl pyrrolidone
• AgNOs silver nitrate
• PVP poly-vinyl pyrrolidone
• Crystal structure identification by X-ray diffraction was carried out in a Phillips automated vertical scanning powder diffractometer. The spectrum was obtained from 10 to 70 2 ⁇ degrees.
• X-ray photoelectron spectroscopy XPS was conducted in a PHI 5700 system equipped with dual Mg X-ray source and monochromated Al X-ray source with depth profile and angle resolved capabilities. The spectra were fitted using Gaussian curves. Samples for SEM, XRD and XPS were prepared by covering a substrate (Si for SEM and XPS, and amorphous glass for XRD) with the original suspension and letting the water to evaporate. In the case of the sulfidized products, the samples were analyzed directly from the substrates (TEM Cu grids, glass slides and Si- wafers) used in the reaction.
• the ratio between the relative intensities of the ⁇ 111 ⁇ and ⁇ 100 ⁇ planes is higher than the expected for bulk silver ( ⁇ 4.6 vs. ⁇ 2.2), indicating the relative abundance of ⁇ 111 ⁇ planes.
• the role of the capping agent is not limited to the growth mechanism. Once the products are formed, it provides stability by protecting the surface of the nanocrystals. Additionally, the capping agent can modify the interactions of the metal nanostructure with external systems. In fact, the physicochemical properties of nanostructures are strongly dependent upon their interactions with capping agent molecules 3 . Therefore, it is important to understand the interaction between the capping agent and the surface of the nanowires.
• the fitted C 1 s peaks can be explained in terms of the electronegativity of the substituents of the different carbon atoms that compose the PVP repeating unit.
• the electronegativity of the substituent is higher the more it withdraws electron density from the carbon atom, causing an increase in the binding energy of the C Is electrons.
• the binding energies for the Ag 3d 5/2 and the Ag 3d 3/2 electrons are smaller than the binding energies of metal silver (368.2 eV for Ag 3d 5/2 , and 374.2 eV for Ag 3d 3/2 ) but higher than the binding energies of silver (I) oxide (367.5 eV for Ag 3d 3/2 , and 373.5 eV for Ag 3d 3/2 ) 32 .
• This is also a clear indication of the strong interaction between the oxygen atom of the carboxyl (C O) groups in the PVP chain and the silver surface of the nanowires.
• Figure 4 includes electron microscopy images of the same TEM sample of silver nanowires analyzed at different times.
• Figure 4a shows the condition of the silver nanowires just after synthesis. As can be observed in the image, the surface of the nanowire is smooth and the presence of a twin boundary in the middle of the nanowire is clear. This twin boundary results from the five-fold symmetry of these type of nanowires.
• Figure 4b presents an image of the same sample after three weeks of exposure to ambient air. The surface of the nanowire is rougher than the observed in panel a, and nanoparticles start to appear on the surface and the surroundings of the wires. A higher magnification of the nanoparticles on the surface of the nanowires is shown in Figure 4c. The crystalline nature of such nanoparticles is evident from the image.
• Figure 6 shows TEM images of samples that were not exposed to periodical electron irradiation.
• the TEM samples were prepared using product from the same solution batch of the silver nanowires presented in previous figures.
• Figure 6a and 6b present images of two different samples observed after six and twenty four weeks, respectively. Both images show that the degradation results are congruent with the ones presented in the previous discussion, and that a thin layer of crystallites is formed on the surface of the nanowires.
• the observed structural changes are not generated by the periodical irradiation of the electron beam.
• the fact that no significant irradiation damage was observed can be explained by the fact that for a material to experience knock-on displacements a specific energy threshold needs to be surpassed.
• the electron beam just enhances atom vibrations in the sample and the provided energy is dissipated as phonons.
• the threshold energy is 20-3OeV and, unless long exposures and or high current densities are achieved, knock-on damage does not occur for accelerating voltages less than 300 kV 33 .
• the ionization effects decrease significantly as the acceleration voltage of the electron beam increases up to 100 kV and remain low at higher voltages 33 .
• Figure 7 presents high angle annular dark field (HAADF) images of the nanowire that appeared in Figure 6b.
• HAADF high angle annular dark field
• this shell of crystallites is also noticeable in two nanoparticles that remained attached to the original nanowire (Panels a and c).
• the thickness of the shell is also of ⁇ 15 nm.
• Three regions without the brighter core are also distinguishable.
• the observed contrast suggest that these are hollow structures only composed by a shell of nanocrystals. It is important to note that all these observations suggest that the PVP coating is still there, promoting that all the nanocrystals that composed the shell remain together adopting the shape of the original silver nanostructure.
• the measured ratio of the outer part in the shell was of 2.25 while in the low-density region of the shell was of 2.09.
• the atomic ratio between silver and sulfur was of 29.90, confirming that the core is formed by pure silver surrounded by a shell of silver sulfide nanoparticles.
• the principal product from the atmospheric corrosion of silver is silver sulfide, and that the corrosion layers do not include carbonates, sulfates or nitrates 28 .
• the silver corrosion process is primarily influenced by the type and the amount of reduced-sulfur gases such as H 2 S, OCS, SO 2 and CS 2 present in the atmosphere, as well as the amount of water on the silver surface 24'28 . It has been reported that among the reduced sulfur-containing gases, H 2 S and OCS are the principal corrodents of silver, since the sulf ⁇ dation rates of those gases are about one order of magnitude higher than the rates of SO 2 and CS 2 25 . Even though the typical concentrations of these reduced-sulfur gases in the atmosphere are low, they are sufficient to initiate the corrosion process 28 .
• OCS is the principal corrodent of silver hi atmospheric conditions 25 . As shown in reaction (4), in the presence of water, this gas rapidly decomposes to form hydrogen sulfide. The corrosion produced by OCS is important since it is the most abundant sulfur species in the atmosphere.
• nanowires that remained in the original solution for weeks were also evaluated by electron microscopy (images not shown here). After twenty four weeks, no corrosion was observed. Compositional analysis demonstrated that they are only composed by silver capped by PVP, and no sulfur was detected. This confirms that the corrosion occurs only when they are exposed to corroding sulfur sources, such as H 2 S and OCS.
• the binding energy of the O ls peak also confirms that no silver (I) oxide was formed, since the expected binding energy for the O ls peak in silver (I) oxide should be of 528.6 eV 32 , which is significantly lower than the value obtained for the sulfidized nanowires.
• the silver nanostructures produced by the polyol method of the present invention using a six to one molar ratio between PVP and silver nitrate, are susceptible to atmospheric corrosion. In most cases, a thin shell of silver sulfide nanocrystals is formed on their surface. Multi-twinned nanowires are more vulnerable to corrosion compared to the single-crystalline nanoparticles due to their higher proportions of defects. Importantly, the fact that the presented silver nanostructures are being corroded at ambient conditions might limit their use in nanoelectronics and nanofabrication.
• noble-metal nanostructures exhibit a phenomenon known as surface-enhanced Raman scattering (SERS) by which the scattering cross sections of adsorbed molecules are dramatically enhanced; thus, vibrational spectra for absorbates can be obtained 45 ' 46 .
• SERS surface-enhanced Raman scattering
• silver, gold and copper have appropriate values of the real and imaginary parts of the dielectric constants 47 .
• SERS is usually conducted on roughened substrates of these metals.
• NSL nanosphere lithography
• MFON metal film-over-nanosphere
• Ag-Ag 2 S core-shell nanostructures can be produced, as described herein.
• This type of conductor-semiconductor nanostructures might be of interest for sensing purposes, since it has been shown that silver sulfide thin films with excess of silver can be used as photodetectors in the infrared region 50 . Since the silver nanostructure acts as a template, the shape and size of the sulfidized nanostructures could be controlled.
• ethylene glycol especially in body care products, is much more limited than the use of glycerin.
• Glycerin can be dissolved into water or alcohol, but not oils.
• many things will dissolve into glycerin easier than they do into water or alcohol. So the nanoparticles and related products are easily incorporated in a large variety of applications.
• nanowires can be produced opens a whole new set of opportunities because of the intrinsic properties that 1-D structures in the nanometric range have. Therefore, other applications may arise from these systems.
• Vaginal Biocides An agent (e.g., a chemical or antibiotic) that destroys microorganisms in the vagina. Research is being carried out to evaluate the use of rectal and vaginal biocides to inhibit the transmission of sexually transmitted diseases, including HIV. Like today's spermicides, a biocide could be produced in many forms, including; gels, creams, suppositories, films, or in the form of a sponge or a vaginal ring that slowly releases the active ingredient over time, that would give women the power to protect themselves from sexually transmitted diseases (STDs) and AIDS. Around the world women's health and lives are at risk every day because there are too few options in STD protection. Disinfectant: A chemical which kills viruses and other microorganisms on a nonliving surface.
• Biocide a chemical substance, such as pesticides, which can be herbicides, insecticides, capable of killing different forms of organisms such as viruses used in fields such as agriculture, forestry, and mosquito control. Biocides can also be added to other materials (typically liquids) to protect them from biological infestation and growth. Filters: to inactivate viral pathogens such as rotavirus in water or any liquid such as human milk from infected women of HIV-I .
• Topical antiviral eye drops or skin creams or gels.
• Systemic antiviral providing the nanoparticles systemically by delivering the nanoparticles intravenously, intramuscularly, subcutaneously, intradermally, transdermally, and the like.
• the most important characteristic of the present invention is the use of silver nanoparticles as antivirals.
• biocides containing silver nanoparticles would work in one of three ways: killing STD and AIDS viruses and bacteria, creating a barrier to block infection, or preventing the virus from replicating after infection has occurred.
• biocides containing silver nanoparticles would be available either with or without spermicide in order to give women the option of becoming pregnant, while still protecting themselves from STDs.
• the present invention relates to a method of inhibiting the transmission of Acquired Immunodeficiency Syndrome (AIDS) using silver nanoparticles.
• AIDS Acquired Immunodeficiency Syndrome
• the present invention provides an inexpensive, easily available and convenient method of inhibiting the transmission of the AIDS virus in humans as a result of sexual intercourse.
• the method relies upon the action of silver nanoparticles which results in a rapid killing action within minutes. These compounds are effective to reduce the infectivity of the AIDS virus and also kill the causative organisms of many other STD's after short exposure.
• the method of the invention is therefore useful to reduce the immediate risk of AIDS transmission. It also reduces future risk of AIDS transmission by eliminating STD causing organisms which increase the risk of ADDS.
• the apparatus and method of the present invention is based on the finding that silver nanoparticles, are effective antiviral agents against retroviruses including the AIDS virus.
• Silver materials had previously been recognized as antibacterial agents useful in treating burns in man and animal. CL. Fox, Jr., U.S. Patent No. 3,761,590, relevant portions incorporated herein be reference.
• Silver in the form of AgSD has also been shown to be effective against certain viruses such as herpes simplex and herpes zoster and against the causative organisms of many STD's including Candida albicans, Treponema pallidum and gonorrhea.
• the invention contemplates a method of inhibiting the transmission of AIDS in humans upon sexual intercourse, by the use of an effective antiviral amount of silver nanoparticles topically applied to a sexual canal of a human prior to or during sexual intercourse.
• This application can be carried out by introducing a cream or foam into the sexual canal, or by coating the inhibitory composition onto a condom or other device that is inserted into the sexual canal.
• the silver nanoparticles may also be administered, e.g., parenterally, intraperitoneally, intraspinally, intravenously, intramuscularly, intravaginally, subcutaneously, or intracerebrally.
• Dispersions may be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
• compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
• the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, poly-ol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
• the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
• isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
• Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
• Sterile injectable solutions may be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the therapeutic compound into a sterile carrier that contains a basic dispersion medium and the required other ingredients from those enumerated above.
• the methods of preparation may include vacuum drying, spray drying, spray freezing and freeze-drying that yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile- filtered solution thereof.
• the silver nanoparticles may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
• the therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
• the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied as will be known to the skilled artisan.
• the amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a subject.
• Aqueous compositions of the present invention comprise an effective amount of the nanoparticle, nanofibril or nanoshell or chemical composition of the present invention dissolved and/or dispersed in a pharmaceutically acceptable carrier and/or aqueous medium.
• the biological material should be extensively dialyzed to remove undesired small molecular weight molecules and/or lyophilized for more ready formulation into a desired vehicle, where appropriate.
• the active compounds may generally be formulated for parenteral administration, e.g., fo ⁇ nulated for injection via the intravenous, intramuscular, sub-cutaneous, intralesional, and/or even intraperitoneal routes.
• compositions that contain an effective amount of the nanoshell composition as an active component and/or ingredient will be known to those of skill in the art in light of the present disclosure.
• such compositions may be prepared as injectables, either as liquid solutions and/or suspensions; solid forms suitable for using to prepare solutions and/or suspensions upon the addition of a liquid prior to injection may also be prepared; and/or the preparations may also be emulsified.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions and/or dispersions; formulations including sesame oil, peanut oil and/or aqueous propylene glycol; and/or sterile powders for the extemporaneous preparation of sterile injectable solutions and/or dispersions.
• the form must be sterile and/or must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and/or storage and/or must be preserved against the contaminating action of microorganisms, such as bacteria and/or fungi.
• Solutions of the active compounds as free base and/or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and/or mixtures thereof and/or in oils. Under ordinary conditions of storage and/or use, these preparations contain a preservative to prevent the growth of microorganisms.
• Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium ' and/or the required other ingredients from those enumerated above.
• sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum- drying and/or freeze-drying techniques that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof
• the preparation of more, and/or highly, concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.
• solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and/or in such amount as is therapeutically effective.
• the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and/or the like may also be employed.
• the solution should be suitably buffered if necessary and/or the liquid diluent first rendered isotonic with sufficient saline and/or glucose.
• aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and/or intraperitoneal administration.
• sterile aqueous media that may be employed will be known to those of skill in the art in light of the present disclosure.
• one dosage could be dissolved in 1 ml of isotonic NaCl solution and/or either added to 1000 ml of hypodermoclysis fluid and/or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and/or 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
• other pharmaceutically acceptable forms include, e.g., tablets and/or other solids for oral administration; liposomal formulations; time release capsules; and/or any other form currently used, including cremes.
• Nasal solutions are usually aqueous solutions designed to be administered to the nasal passages in drops and/or sprays. Nasal solutions are prepared so that they are similar in many respects to nasal secretions, so that normal ciliary action is maintained. Thus, the aqueous nasal solutions usually are isotonic and/or slightly buffered to maintain a pH of 5.5 to 6.5.
• antimicrobial preservatives similar to those used in ophthalmic preparations, and/or appropriate drug stabilizers, if required, may be included in the formulation. Additional formulations that are suitable for other modes of administration include vaginal suppositories and/or suppositories.
• a rectal suppository may also be used.
• Suppositories are solid dosage forms of various weights and/or shapes, usually medicated, for insertion into the rectum, vagina and/or the urethra. After insertion, suppositories soften, melt and/or dissolve in the cavity fluids.
• traditional binders and/or carriers may include, for example, polyalkylene glycols and/or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably l%-2%.
• Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and/or the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations and/or powders.
• oral pharmaceutical compositions will comprise an inert diluent and/or assimilable edible carrier, and/or they may be enclosed in hard and/or soft shell gelatin capsule, and/or they may be compressed into tablets, and/or they may be incorporated directly with the food of the diet.
• the active compounds may be incorporated with excipients and/or used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and/or the like.
• Such compositions and/or preparations should contain at least 0.1% of active compound.
• the percentage of the compositions and/or preparations may, of course, be varied and/or may conveniently be between about 2 to about 75% of the weight of the unit, and/or preferably between 25-60%.
• the amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• the tablets, troches, pills, capsules and/or the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, and/or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and/or the like; a lubricant, such as magnesium stearate; and/or a sweetening agent, such as sucrose, lactose and/or saccharin may be added and/or a flavoring agent, such as peppermint, oil of wintergreen, and/or cherry flavoring.
• a binder as gum tragacanth, acacia, cornstarch, and/or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as corn starch, potato starch, alginic acid and/or the like
• a lubricant such as magnesium stearate
• a sweetening agent such as
• the substrate of the compositions of the present invention may be a powder or a multiparticulate, such as a granule, a pellet, a bead, a spherule, a beadlet, a microcapsule, a millisphere, a nan ⁇ capsule, a nanosphere, a microsphere, a platelet, a minitablet, a tablet or a capsule.
• a powder constitutes a finely divided (milled, micronized, nanosized, precipitated) form of an active ingredient or additive molecular aggregates or a compound aggregate of multiple components or a physical mixture of aggregates of an active ingredient and/or additives.
• Such substrates may be formed of various materials known in the art, such as, for example: sugars, such as lactose, sucrose or dextrose; polysaccharides, such as maltodextrin or dextrates; starches; cellulosics, such as microcrystalline cellulose or microcrystalline cellulose/sodium carboxymethyl cellulose; inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; and polyols, such as mannitol, xylitol, sorbitol or cyclodextrin.
• sugars such as lactose, sucrose or dextrose
• polysaccharides such as maltodextrin or dextrates
• starches starches
• cellulosics such as microcrystalline cellulose or microcrystalline cellulose/sodium carboxymethyl cellulose
• inorganics such as dicalcium phosphate, hydroxyapitite
• a substrate need not be a solid material, although often it will be a solid.
• the encapsulation coat on the substrate may act as a solid "shell" surrounding and encapsulating a liquid, semi-liquid, powder or other substrate material.
• substrates are also within the scope of the present invention, as it is ultimately the carrier, of which the substrate is a part, which must be a solid.
• the silver nanoparticle pharmaceutical compositions of the present invention may include optionally one or more additives, sometimes referred to as additives.
• the excipients may be contained in an encapsulation coat in compositions, which include an encapsulation coat, or can be part of the solid carrier, such as coated to an encapsulation coat, or contained within the components forming the solid carrier.
• the excipients may be contained in the pharmaceutical composition but not part of the solid carrier itself. Suitable excipients are those used commonly to facilitate the processes involving the preparation of the solid carrier, the encapsulation coating, or the pharmaceutical dosage fo ⁇ n.
• These processes include agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art.
• the excipients may also be pre-coated or encapsulated, as are well known in the art.
• the silver nanoparticles of the present invention may be used as a topical cream against HTV and other retroviruses.
• the cream described may also be used in condoms.
• Sterile intravenous (iv) solution such as saline may be effective in reducing virus load and slowing down the onset of immunodeficiency. Surgeons who also use saline washes in cleansing a particular area in the operating field may find it useful.
• the silver nanoparticles may be used alone or in conjunction with a liposome. These forms could be reconstituted in the form of mouthwash with the silver nanoparticles alone or in conjunction with antifungal reagents.
• An inhalant form alone or in conjunction with pentamidine.
• the oral use of the liposomal form would have to be given in a time release capsule to avoid lipase degradation.
• Buffered ophthalmic solution for patents suffering from HIV associated retinitis.
• the buffering is necessary due to pH changes the silver nanoparticles may cause.
• Highly concentrated solution for intramuscular injection would facilitate treatment of needle stick injuries of health care workers.
• use of DMSO as solvent would give extremely fast penetration delivering high concentrations of silver nanoparticles to a small area.
• Chemo-preventative Vaginal douche and creme - the douche may be of use in a pre-sexual exposure in a standard acetic acid solution.
• the creme may be mixed with 9-nonoxynol spermicide to use in conjunction with birth control.
• Gloves lined with silver nanoparticles may help surgeons and other health care workers dealing heavily with blood and bodily fluids.
• Noble metal nanoparticle or nanowire-polyols or polymer complexes may be added slowly to an aqueous solution of polyvinylpyrrolidone and mixed well.
• No. 25-30 mesh sugar spheres are coated with the noble metal nanoparticle or nanowire-polyols or polymer complex-drug solution in a fluid bed granulator.
• the drug containing pellets were dried, and a seal coat of Opadry Clear and the inner mixed release coating applied to the active particles by spraying a solution of ethylcellulose and diethyl phthalate in 98/2 acetone/water.
• the outer coating of a blend of ethylcellulose and HPMCP plasticized with diethyl phthalate was sprayed onto the active particles having the inner coating to produce modified release profile beads. These beads are filled into hard gelatin capsules using capsule filling equipment to produce noble metal nanoparticle or nanowire-polyols or polymer complex mini-tabs, 2.5, 5.0, 7.5, 8.0, 12.0, 16.0 and 20.0 mg.
• the noble metal nanoparticle or nanowire-polyols or polymer complexes may be freeze-sprayed, lyophilized, vacuum dried, heat dried, heat-vacuum dried, etc. to form a powder following isolation and purification.
• the following is an example of the noble metal nanoparticle or nanowire-polyols or polymer complexes as part of a capsule.
• these formulations may be prepared in mixed immediate, intermediate and long-term or extended release.
• Capsule 1 A formulation for release in a gelcap:
• a formulation for release of the active in a suppository A formulation for release of the active in a suppository:
• the present invention may be provided as follows: Noble metal nanoparticle or nanowire-polyols or polymer complexes Excipient Flavorant
• Biocompatible Isotonic liquid e.g., saline
• Buffer Biocompatible Isotonic liquid (e.g., saline) Buffer
• compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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