Micro-nano system for peritoneal dialysis

Abstract

The invention relates to a micro-nano system for peritoneal dialysis. The components of the micro-nano system comprise large-mass substances, such as macromolecules, polymers and tiny structures formed by specific substances. The large-mass substances have the advantage of high combining capacity with wastes / toxins in the dialysate. The micro-nano system is dissolved or suspended in the dialysate, and large-mass substances in the micro-nano system extract and enrich waste in the peritoneal dialysate during peritoneal dialysis, so that the capacity of the dialysate is enhanced.

Description

TECHNICAL FIELD

[0001] The present invention relates to micro- and nano-systems for peritoneal dialysis, in particular to the application of macromolecules. BACKGROUND

[0002] Peritoneal dialysis utilizes the peritoneum of the human abdomen for the exchange of fluid and solutes between blood and dialysate. It is used to remove metabolic waste products and / or toxins from the body of a patient. See Wikipedia https: / / en.wikipedia.org / wiki / Peritoneal_dialysis) Peritoneal dialysis solutions for therapy have been approved by FDA, CDE of China, EMA and other authorities and are widely used.

[0003] During peritoneal dialysis, clean dialysate is introduced into the peritoneal cavity through a catheter and receives dialyzed waste products and / or toxins. Unlike the urinary system, dialysis relies on passive diffusion of waste products and / or toxins from the peritoneal blood vessels into the dialysate. The prerequisite for passive diffusion is that the concentration of waste products and / or toxins in the peritoneal dialysis solution is lower than the concentration in the body. This requires a large amount of peritoneal dialysis solution to be infused into the abdomen of the patient and frequently changed Figure 1 ).

[0004] For example, according to the FDA's recommendations, patients receiving continuous ambulatory peritoneal dialysis treatment usually have 4 changes of dialysate per day. Patients receiving automated peritoneal dialysis treatment usually have 4-5 nightly cycles and 2 daytime cycles of dialysis and solution change. The amount of infusion is usually several liters. For patients, a large amount and frequent infusion and drainage are both inconvenient and uncomfortable. In addition, frequent infusion and drainage can also cause clinical problems such as infection.

[0005] The present invention is a specific micro- and nano-system that can enhance the stronger holding capacity of peritoneal dialysis solution for waste products and / or toxins Figure 2 , so as to reduce the daily amount of dialysate. SUMMARY

[0006] The term "macromolecule" refers to a substance with a molecular weight greater than 1000 daltons. For example, RNA chains, peptide chains.

[0007] The term "polymer" refers to a substance composed of two or more identical groups connected by chemical bonds. Polymers include homopolymers and copolymers. For example, 1-Hydroxyethylidene Diphosphonic Acid, polylactic acid.

[0008] The term "microstructure formed by specific substances" refers to substances with a size in the micron, nanometer level formed by organic or inorganic substances through polymerization, crystallization, precipitation, bonding, etc. For example, porous nanoparticles formed by silicon dioxide.

[0009] The term "macromaterials" includes the above-mentioned macromolecules, polymers, and microstructures formed by specific substances. Their characteristic is that they have multiple groups of the same or similar structure and function. For example, multiple negatively charged groups in polymers, multiple sites with adsorption capacity exposed in microstructures formed by specific substances.

[0010] The term "micro- and nanosystems" is a system with appropriate dimensions (in microns and nanometers). Their size is between 10 nanometers and 1000 microns. It includes, but is not limited to, liposomes, nanoparticles, polymer nanoparticles, mesoporous nanoparticles, colloids, and others.

[0011] The micro- and nanosystems of the present application take advantage of the affinity of the macromaterials they contain for specific substances (such as metabolic waste, toxins) to extract and concentrate waste and / or toxins from the peritoneal dialysis solution, thus reducing the concentration of waste and / or toxins in the dialysis solution and improving the dialysis capacity of the dialysis solution. Figure 2 ).

[0012] The advantages of these macromaterials are: Compared to small molecules (such as citric acid, ammonium sulfate), their larger structure allows them to be stably present in the micro- and nanosystems and not easily migrate and leak from the micro- and nanosystems to the external dialysis solution.

[0013] Compared to small molecules (such as citric acid, ammonium sulfate), they have multiple groups or sites, making them more capable of extracting, fixing, and concentrating waste or toxins in the dialysis solution, and more easily forming stable complexes with waste and / or toxins and remaining inside the micro- and nanosystems.

[0014] When these micro- and nanomaterials are dissolved / suspended in the dialysis solution, during the dialysis process, the waste and / or toxins in the dialysis solution can reach the macromaterials through the surface of the micro- and nanomaterials (including the surface liposome membrane, the surface micropores) and be adsorbed and fixed by the macromaterials.

[0015] The adsorption mechanism can include the mutual attraction between hetero-charges. For example: The mutual attraction between negatively charged macromaterials (such as polyphosphates) and positively charged waste and / or toxins (such as urea) Figure 3 ); The mutual attraction between positively charged macromaterials (such as polyarginine) and negatively charged waste and / or toxins (such as uric acid) Figure 4 ); The mutual attraction between hydrophobic functional molecules (such as nanocarbon) and proteins, lipids Figure 5 ).

[0016] To implement the present application, it is necessary to employ a large mass substance with multiple identical or similar groups or sites, for example: Polymers with two or more negatively charged acid groups, such as polystyrene sulfonate sodium; Polymers with multiple positively charged amino groups, such as chitin; Nanomaterials of smaller scale with multiple adsorption sites, such as porous silica nanoparticles.

[0017] To implement the present application, the micro / nano system of the present application is used together with peritoneal dialysis solution. For example, the micro / nano system of the present application can be mixed with peritoneal dialysis solution and then infused, or they can be infused sequentially. The micro / nano system of the present application extracts and enriches waste and / or toxins in the micro / nano system by virtue of its strong affinity for waste and / or toxins in the dialysis solution, thereby keeping the dialysis solution clean.

[0018] In a preferred embodiment, the large mass substance of the present application can be a macromolecule, such as a protein, a peptide, etc. These macromolecules have multiple functional groups, such as the multiple negatively charged groups of RNA.

[0019] In a preferred embodiment, the large mass substance of the present application can be a polymer, such as trimeric phosphoric acid, chitin, polystyrene sulfonate sodium. These macromolecules have multiple functional groups, such as the positively charged groups of chitin.

[0020] In a preferred embodiment, the large mass substance of the present application can be a microstructure formed by a specific substance. For example, silica forms porous silica nanoparticles. These microstructures have multiple sites or functional groups, such as the negatively charged silica nanoparticles. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 Common dialysis process. Waste and / or toxins enter the dialysis solution by passive diffusion.

[0022] Figure 2 Dialysis process using micro / nano system. Waste in the peritoneal dialysis solution is extracted into the micro / nano system and stored, and the dialysis solution remains relatively clean.

[0023] Figure 3 Micro / nano system containing negatively charged large mass substances concentrates waste and / or toxins in the micro / nano system.

[0024] Figure 4 Micro / nano system containing positively charged large mass substances concentrates waste and / or toxins in the micro / nano system.

[0025] Figure 5Micro / nano systems containing microstructures formed by specific substances extract waste into the micro / nano system. DETAILED DESCRIPTION

[0026] The following examples are intended to further illustrate the present application and should not be construed as limiting the patent.

[0027] Example 1, Preparation of micro / nano systems containing polymers Dissolve 2 g of chitosan in 100 mL of a 2.5% acetic acid (w / w) solution in deionized water, stirring at 80 o C for 1 hour until the chitosan is completely dissolved. Then add 50 mL of the chitosan solution to 50 mL of ethyl acetate and stir for 30 minutes until an emulsion is formed. Then add a solution of Polystyrene Sulfonate (PSS) to the emulsion and mix for another 30 minutes. Add a 1M solution of NaOH to the chitosan-PSS emulsion and stir for 1 hour to allow it to coagulate. After coagulation for 1 hour, collect the chitosan beads and then wash repeatedly with distilled water to remove the ethyl acetate. See Kam Sheng Lau et al., Polymers, 15, 1269, 2023.

[0028] Example 2, Preparation of micro / nano systems with microstructures formed by specific substances - silica nanoparticles Take 40 mL of an aqueous solution containing 0.5% cetyltrimethylammonium bromide, 5% ethanol, 25% cyclohexane, and 0.1% NH4OH, and emulsify by stirring thoroughly. While stirring, add 2 mL of tetraethoxysilane and 0.5 mL of 3-aminopropyltriethoxysilane, and react at room temperature for 3 hours. Add 2 mL of tetraethoxysilane and continue to react for another 3 hours to obtain porous silica nanoparticles. Then add the porous silica nanoparticles to an equal amount of chitosan solution (pH 6) and stir for 2 hours. See Xingdang Bo et al., Journal of Sol-Gel Science and Technology 93:324-331, 2020.

[0029] Example 3, Use of micro / nano systems in dialysis Inject the micro / nano systems of the present application (e.g., in Examples 1, 2) into the dialysate solution bag and mix well. Then follow the dialysis procedure to infuse the dialysate into the patient's body for dialysis.

Claims

1. A micro / nano system for peritoneal dialysis, whose components contain high-mass substances that can extract and enrich waste and toxic substances in the dialysis fluid.

2. The micro / nano system according to claim 1, wherein the high-mass substances in its components are macromolecules.

3. The micro / nano system according to claim 1, wherein the high-mass component is a polymer.

4. The micro / nano system according to claim 1, wherein the high-mass substances in its components are microstructures formed by specific substances, including but not limited to crystals, colloids, nanoparticles, etc.

5. The micro / nano system according to claims 2, 3, and 4, wherein the high-mass material in its constituent components has multiple negatively or positively charged groups.

6. The micro / nano system according to claims 2, 3, and 4, wherein the high-mass substances in its components have lipophilic (or hydrophobic) groups or active adsorption sites.

7. Compositions of various micro / nano systems according to claims 2, 3, 4, 5, and 6.

Images