Patent Application
20210400984
The present invention relates to an adhesive composition, to be used for fixing dentures, which includes copper nanoparticles (CuNPs) that provides antimicrobial properties against dental pathogens such as Candida albicans, Streptococcus mutans, Staphylococcus aureus and Aggregatibacter actinomycetemcomitans. The invention also relates with the method for obtaining said composition and the use of the composition against the oral pathogens Candida albicans, which causes subprosthetic stomatitis, Streptococcus mutans, responsible for caries formation, Staphylococcus aureus, which causes periprosthetic infections and Aggregatibacter actinomycetemcomitans, which causes gingivitis.
The use of dental prostheses continues to be the most widely used dental rehabilitation solution, particularly in the lower socioeconomic strata. Prosthetic cleaning is essential to maintaining good oral hygiene and to prevent Subprosthetic Stomatitis, a chronic inflammation of the oral mucosa that is in contact with the prosthesis. Despite the fact that its etiology remains undefined, its main cause is linked to fungal infections. Since the vast majority prosthesis users are elderly seniors, cleaning habits are often poor, in part due to the visual and psychomotor limitations of this patient group. The current treatment for this type of infection is via oral and topical anti-fungal agents; however, these agents can lead to undesirable side effects for patients, such as general discomfort and a particularly unpleasant taste.
Patients who use removable dental prostheses often resort to the use of adhesives that improve the retention and fit of their prosthesis, which gives it an improved chewing function, as well as greater psychological safety, comfort, and confidence. The substances that make up the adhesive, when mixed with saliva, generate retentive forces that fix the prosthesis to the oral mucosa. Despite the important benefits that dentures adhesives provide, their use also favors the accumulation and proliferation of microorganisms. Especially fungi (yeasts) of the genus Candida responsible for producing sub-prosthetic stomatitis and angular cheilitis, oral infections highly prevalent in dentures users. Stomatitis is characterized by causing redness, inflammation, irritation and pain on the palate and gums of patients. For this reason, it is necessary to develop more advanced prosthetic adhesives that can reduce the proliferation of yeasts such as Candida albicans in patients who use this type of product.
It is well known the antimicrobial properties of metals, that's why they are currently being studied for use in many applications with the help of nanotechnology, such as surface disinfection and topical application in gels and pastes. Copper, which has been widely used in medicine since the 19th century, was indicated in the treatment of skin infections, lupus, and was even used as an antimicrobial agent until the appearance of antibiotics in 1932 (Grass, G., C. Rensing, and M. Solioz, Metallic Copper as an Antimicrobial Surface. Applied and Environmental Microbiology, 2011. 77(5): p. 1541-1547). Copper has been used for decades for its antifungal properties (Cioffi, N., Torsi, L., Ditarantano, N., Tantalillo, G., Ghibelli, L., Sabbatini, L., Bleve-Zacheo, T., D'Alessio, M., Zambonin, P G., Traversa, E., Copper nanoparticle/polymer composites with antifungal and bacteriostatic properties. Chem. Mater, 2005, 17, 5255-5262; and Palza, H., Quijada, R., Delgado, K, Antimicrobial polymer composites with copper micro- and nanoparticles: Effect of particle size and polymer matrix. Journal of Bioactive and compatible polymers. 2015, 1-15).
Copper is an active agent in toothpaste formulations with microbial plaque control properties. Thus, document U.S. Pat. No. 4,332,791 describes a toothpaste containing silica and copper salt (0.001-5%) as active components, whereas in document EP 0471396 A1, the active ingredient consists of a copper salt (0.01-5%), sodium bicarbonate and an alkylamine that acts as a stabilizer of the metal ion. Salts such as copper salicylate (0.05-0.3%) have also been used in the formulation of mouthwashes for the control of oral ulcers and irritations, as described in document US 2011/0229534 A1.
In particular, for adhesive compositions, document EP 1003791 A4 relates to the use of copper for the control of subcutaneous stomatitis and describes a formulation of an antimicrobial adhesive cream for dental prostheses, in which the active ingredient of the adhesive consists of 8-hydroxyquinoline (0.0001-0.5%) and a copper salt II (0.001-0.3%), which shown greater activity against C. albicans in in-vitro tests.
Besides, document U.S. Pat. No. 7,008,976B2 relates to a denture adhesive composition comprising mixed salts of an alkyl vinyl ether-maleic acid or anhydride copolymer and/or terpolymer with isobutylene, wherein the mixed salt contains a cationic salt function comprising at least about 1% strontium cations, from about 1% to about 40% of zinc cations, from 0% to about 2.5% of a cation selected from the group consisting of iron, boron, aluminum, vanadium, chromium, manganese, nickel, copper, yttrium, titanium, and mixtures thereof; from about 36% to about 60% free acid component; and from 0% to about 65% of a cation selected from the group consisting of magnesium, calcium, and mixtures thereof. The invention also includes a method of increasing the adhesion of dentures to the oral cavity by applying the above compositions to dentures, directly to the oral cavity, palate or ridge of the oral cavity, or applying it to both, and thereafter securing the dentures to the ridge or palate of the oral cavity.
On the other hand, better antimicrobial properties have been observed in copper nanoparticle form when compared to micro size (Theivasanthi, T., Studies of Copper Nanoparticles Effects on Micro-organisms. Annals of Biological Research, 2011. 2(3): p. 368-373). It has also been an effective killer of numerous strains of hospital-acquired infections, although there is a need for controlled release of ions into the local environment to achieve optimal antimicrobial activity (Ren, G., et al., Characterisation of copper oxide nanoparticles for antimicrobial applications. International Journal of Antimicrobial Agents, 2009. 33(6): p. 587-590). The antimicrobial properties of CuNPs have so far been assessed against the bacteria Escherichia coli, Staphylococcus aureus, Klebsiella pneunomiae, Lysteria monocytogenes and Pseudomonas aeruginosa, as well as against Saccharomyces cerevisiae yeast. However, the prior art shows no evidence regarding its effect on oral bacteria.
Research on the bactericidal mechanism of copper as a nanoparticle shows that the effect is largely due to its small size and large contact surface, in relation to its volume, which allows for easy interaction with microbial membranes. (Chatterjee A K, Ruchira C, Tarakdas B. Mechanism of antibacterial activity of copper nanoparticles. Nanotechnology. 2014; 25(13):135101).
The antimicrobial capacity of these particles has led to exploring the possibility of incorporating copper nanoparticles into adhesive compositions that are used in those people in need of dentures.
Our present aim is to contribute with the oral hygiene by providing an adhesive composition to be used with dentures, which shows antimicrobial properties. This adhesive contains, as main ingredient, copper nanoparticles (CuNPs). As far as we know, there are no denture adhesives containing copper nanoparticles (CuNPs) as active component.
In one embodiment the present invention relates to an antimicrobial denture adhesive composition, wherein the composition comprises:
In one preferred embodiment of the present invention, the antimicrobial denture adhesive composition comprises:
In another preferred embodiment of the invention the copper nanoparticles (CuNPs) of the antimicrobial denture adhesive composition have dimensions of 5 to 200 nm and they have a morphology selected from the group consisting spherical, tubular, cubic fibrous, wire, laminar morphology and any other morphology having at least one of its dimensions in nanometric scale.
In another yet preferred embodiment of the present invention said copper nanoparticles (CuNPs) contain copper having an oxidation number of 0, 1, 2 or one intermediate oxidation state, so the nanoparticles could be made of Cu, Cu2O or CuO. In another yet preferred embodiment of the present invention said copper nanoparticles (CuNPs) has a structure of copper supported on ceramic nanoparticles selected from the group consisting in silica, clay, zeolite, titanium and zirconium oxides.
In a second embodiment of the present invention, it relates with said antimicrobial denture adhesive composition which is obtained by a method comprising the following main steps:
In a third embodiment of the present invention, it relates with the use of the antimicrobial denture adhesive composition based on copper nanoparticles (CuNPs) which is useful against the oral pathogens C. albicans, which causes subprosthetic stomatitis; Streptococcus mutans, responsible for caries formation; and Staphylococcus aureus, which causes periprosthetic infections.
The present invention focuses on the development of a new composition for a denture adhesive with antimicrobial properties to be used in fixing dentures in people in need of it.
Surprisingly, the composition for a denture adhesive comprising copper nanoparticles (CuNPs) not only shown excellent antimicrobial properties, but also improved adhesive properties in comparison with another denture adhesives existing currently in the marked, which do not contain said CuNPs.
The denture adhesive composition of the invention comprises also an hydrophobic carrier or vehicle selected from petrolatum or petrolatum combined with mineral oil, natural wax, synthetic wax, polyvinyl acetate, natural oils, synthetic oils, fats, silicone, silicone derivatives, dimethicone, silicone resins, hydrocarbons, hydrocarbon derivatives, essential oils, caprilic/capric triglycerides, polybutene, oleic acid, stearic acid, and combinations thereof; and a polymer material derivated from cellulose selected from hydroxypropyl methylcellulose, carboxymethyl-cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylmethylcellulose, methyl-cellulose, methylcarboxymethyl cellulose, hydroxyethylcarboxymethyl cellulose, hydroxyethylmethylcarboxy methylcellulose, sulfoethylcarboxymethyl cellulose, hydroxyethylhydroxypropyl cellulose, hydroxyethylethyl cellulose, hydroxyethylsulfoethyl cellulose or combinations thereof.
In a preferred embodiment, the polymer material derivate from cellulose is carboxymethyl-cellulose.
The invention further comprises a polymer material selected from poly(methylvinyl ether-co-maleic acid) (PVM/MA) and its derivatives, such as acids, salts or anhydride.
In addition to the above-mentioned components, the present composition may optionally contain other components to improve or enhance the adhesive nature of the base components, including those commonly known and used by the denture adhesive industry. Examples include but are not limited to dicalcium phosphate and nanoclay.
The dental adhesive composition of the invention may comprise additional components, such as plasticizers, rheology modifiers, preservatives, humectants, emulsifiers, antioxidants, super-disintegrants or absorbents, flavoring agents, colorants, cross-linking agents, non-metallic antimicrobial agents, control release agents, antifoaming agents, sweetening agents and viscosity modifiers.
Copper nanoparticles (CuNPs) can be obtained using well known technologies (Madhulika Bhagat et. al., Review—Multifunctional Copper Nanoparticles: Synthesis and Applications, ECS Journal of Solid State Science and Technology, 2021, 10, 063011).
Alternatively, enveloped CuNPS in ceramic material particles can be prepared. For that, zeolite particles (nanoporous crystalline aluminosilicate) and silica nanoparticles were used as support materials, using natural zeolite of national origin (MOR) and commercial 100 nm silica nanoparticles. CuNPs are formed on site in the material, whereby a certain MOR mass was contacted with a 0.1 M copper acetate solution for 24 h at room temperature. Once the ion exchange period was completed, the zeolite was separated and washed by repeated centrifugation/dispersion cycles. The resulting material was then dispersed in a starch/ascorbic acid reducing solution and microwaved for a few seconds.
This system for the formation of CuNPs in biopolymers was developed by our laboratory team under the concept of “Green Chemistry”, with the aim of synthesizing more benign metallic nanoparticles that are compatible with biomedical applications. The CuNPs/MOR particles were separated, washed and dried for further use in the preparation of the antimicrobial denture adhesive composition.
25 g of mineral oil (w/w) and 28.4 g of petrolatum (w/w) are mixed at 60° C. under a stirring speed of 300 ppm for 10 minutes. Next, 0.071 g of copper nanoparticles (w/w) are added and the mixture is stirred at the same temperature for 10 minutes. Next, 31.6 g of PVM/MA (w/w) and 14.9 g of carboxymethylcellulose are added (w/w), and the resulting mixture is stirred for 40 minutes at 60° C. The product obtained is allowed to cool to room temperature.
In order to compare the chemical structure of the antimicrobial denture composition with CuNPs with known denture adhesives in the market, adhesives were analyzed by using total attenuated reflectance with Fourier transform infrared spectroscopy (ATR-FTIR) in an Agilent Cary 630 ATR-FTIR spectrometer.
Additionally, the adhesive elemental composition was analyzed by X-ray dispersive energy spectroscopy (EDX) coupled to scanning electron microscopy (SEM) in a JEOL model JSMIT300LV microscope.
Antimicrobial properties of the denture adhesives were assessed against Candida albicans, pathogen responsible of denture stomatitis disease, by using the agar disk-diffusion method. Filter paper discs of 6 mm in diameter were impregned with the denture adhesives for 20 minutes. After that, 100 μL of 0.5 Mcfarland (1-5×106 CFU/ml) of ATCC 90029 strain of Candida albicans were seeded on plates of Sabouraud dextrose agar medium. Then, adhesive—impregnated disks were placed onto the surface of the inoculated agar plate. Each disk was pressed down to ensure complete contact with the agar surface, and they were distributed evenly so that they were no closer than 24 mm from center to center. The plates were incubated at 37° C. under aerobic conditions for 48 hours after which the disks were applied. Plates were examined after 48 h of incubation (
Adhesive properties were measured by using mechanical tensile tests in a DEBEN microtest machine (Suffolk, UK) using a 2 N load cell. Denture adhesives were applied on the surface of two dental acrylic specimens having a flat area of 60 mm2 and perpendicular to the long axis. The two acrylics were bonded and immersed in artificial saliva for 5 minutes to ensure adhesion between opposing acrylic specimens. After that, the specimens were debonded in tensile mode at a rate of 1 mm per minute by using the microtest machine. The maximum force before failure was then calculated (adhesive resistance).
The presence of CuNPs in the adhesive also gives it improved adhesive properties (
The tensile mechanical properties of the adhesive formulated with CuNPs are shown compared to other commercially available prosthetic adhesives. The adhesive strength of denture adhesive with CuNPs was statistically higher than that of two of the more well-known commercial adhesives currently in the market. These results demonstrate that CuNPs also produce a mechanical reinforcement of the adhesive which provokes greater fixation and stability of dental prostheses in users.
The antimicrobial denture adhesive composition containing CuNPs has been validated in its antimicrobial and adhesive properties. It has been obtained an optimized formulation that maximizes its antimicrobial and mechanical properties.
The scaling steps of the said adhesive composition making process were completed in a cosmetic/pharmaceutical/dental industrial plant. Likewise, a pilot of the packaging process of the new adhesive was carried out.
A product satisfaction and validation study is currently being carried out in a population of 30 patients compared to the conventional Corega® adhesive.
| Number | Date | Country | Kind |
|---|---|---|---|
| 3781-2015 | Dec 2015 | CL | national |
This application is a divisional-in-part application of the U.S. Ser. No. 16/067,053 application, filed on Jun. 28, 2018, which is a national stage application of International Application PCT/CL2016/050079, filed on Dec. 29, 2016, which claims priority to Chilean Application 3781-2015, filed Dec. 30, 2015, the disclosure of each of which is incorporated by reference their its entirety herein.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16067053 | Jun 2018 | US |
| Child | 17404858 | US |
