RU2846110C1 - Sulphanilamide delivery system and a method for its preparation - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: group of inventions relates to chemistry and pharmaceutics, specifically to a sulphonyl amide delivery system and a method for production thereof. Proposed delivery system comprises: sulphanilamide – 3.8-32.9 wt. %; hyaluronic acid with molecular weight from 1.0 to 2.0 MDa (polysaccharide-based polymer matrix) – 65.7-95.4 wt. %; distilled water and dimethyl sulphoxide – balance, where the weight ratio of said hyaluronic acid and sulphanilamide is from 25:1 to 2:1. Disclosed method comprises dissolving said hyaluronic acid in an equidistant mixture of distilled water and dimethyl sulphoxide and then adding sulphanilamide, then obtained solution is poured into Petri dishes and held for 12-24 hours at room temperature for stabilization and deaeration, and then dried in air at temperature 30-45 °C to constant weight.

EFFECT: group of inventions provides the prolonged non-explosive release of sulphanilamide for 12 hours and simplifies the synthesis process.

2 cl, 1 dwg, 1 ex

Description

The invention relates to medicine and the pharmaceutical industry, namely to the development of a delivery system for the antimicrobial drug sulfanilamide, widely used for the treatment of microbial infections, especially for the treatment of infected wounds.

Sulfanilamide delivery systems are known in various forms: fibers, hydrogel, capsules, etc.

The article “Biological Properties of Sulfanilamide-Loaded Alginate Hydrogel Fibers Based on Ionic and Chemical Crosslinking for Wound Dressings” published in the International Journal of Biological Macromolecules in issue 157 of 2020 (pp. 522-529) describes the composition and method for producing sodium alginate-based fibers with embedded sulfanilamide. Calcium chloride and glutaraldehyde are used as crosslinking agents, which ensures the required slow release of sulfanilamide.

The disadvantages of the proposed sulfanilamide delivery system are the lack of targeted action, the complexity of the fiber production method, and the use of toxic glutaraldehyde in the synthesis process.

The article “Effect of monomer composition on the properties of biodegradable poly(NIPAAm-AA-PCLdA) copolymeric hydrogels” (Journal of Applied Polymer Science, 2013, issue 128, pp. 230-238) presents a method for the preparation of a biodegradable hydrogel based on N-isopropylacrylamide, acrylic acid, and the crosslinking agent poly(caprolactone) diacrylate.

The disadvantages of this delivery system are the labor-intensive nature of the hydrogel synthesis process, insufficiently high yield of the target product, and the explosive nature of the release of sulfanilamide.

Also known (see “Fabrication and characterization of the novel bionanocomposite poly(ester-imide-sulfonamide)s/Ag film coated on glass bead for inactivation of E. coli”, Polymer Bulletin, 2022, issue 79, pp. 7589-7611) is an antibacterial polymer coating in the form of a film based on polyetherimide with the addition of metallic silver.

The disadvantages of the proposed polymer film are the complex and expensive scheme for synthesizing the target product, as well as the chemical binding of the sulfanilamide to the polymer matrix, which complicates its release.

The closest to the proposed invention are sulfanilamide nanocapsules in kappa-carrageenan, proposed in Russian patent 2657767, IPC A61K 9/51, A61K 31/63, A61K 47/36, A61J 3/07, B82B 3/00, published 15.06.2018, (2017). The sulfanilamide delivery system in the form of capsules includes sulfated polysaccharide kappa-carrageenan as a matrix, surfactant E472c, and 1,2-dichloroethane as a cross-linking agent.

The method for producing capsules is as follows: sulfanilamide is added in portions to a suspension of sulfated polysaccharide kappa-carrageenan in ethanol, containing the drug E472c as a surfactant at a core:shell weight ratio of 1:1, or 1:3, or 5:1, the mixture is stirred, then 1,2-dichloroethane is added, the resulting suspension of nanocapsules is filtered and dried.

The disadvantages of such a system are the complexity, labor intensity and duration of the process of its production, the use of ethanol in the suspension, which requires special conditions for the synthesis, the low content of sulfanilamide in the proposed system, and the use of 1,2-dichloroethane, which is a particularly toxic chemical reagent. Another disadvantage is the lack of targeted action of the proposed nanocapsules.

The task that the proposed invention is aimed at solving is to reduce the amount of constituent reagents and the toxicity of the delivery system and ensure its targeted effect.

The set task is solved by achieving a technical result consisting in simplifying the synthesis process and ensuring prolonged release of sulfanilamide for 12 hours without an explosive nature.

Prolonged release of sulfanilamide over 12 hours without an explosive nature is achieved by the fact that the sulfanilamide delivery system, including sulfanilamide and a polymer matrix based on a polysaccharide, is characterized in that the polymer matrix based on a polysaccharide is hyaluronic acid with a molecular weight (MM) from 1.0 to 2.0 MDa, while the mass ratio of said hyaluronic acid and sulfanilamide is from 25:1 to 2:1, where the delivery system also contains distilled water and dimethyl sulfoxide and has the following composition:

hyaluronic acid with MM from 1.0 to 2.0 MDa 65.7-95.4 wt.% sulfanilamide 3.8-32.9 wt.% distilled water and dimethyl sulfoxide rest

The synthesis process is simplified by the fact that the method for obtaining the sulfanilamide delivery system includes dissolving hyaluronic acid with an MM of 1.0 to 2.0 MDa in an equal-volume mixture of distilled water and dimethyl sulfoxide and adding sulfanilamide to this mixture, before drying the resulting solution in air at a temperature of 30-45°C to a constant weight, the solution is poured into Petri dishes and kept for 12-24 hours at room temperature for stabilization and deaeration.

The use of a natural non-sulfated polysaccharide, hyaluronic acid, which has its own receptors on the surface of cells, as a polymer matrix for sulfanilamide ensures its targeted effect.

Dissolution of sulfanilamide in a polymer matrix based on hyaluronic acid polysaccharide in an equal volume mixture of distilled water and dimethyl sulfoxide, followed by stabilization, deaeration and drying ensures the simplicity of the technological process for obtaining the proposed delivery system and the absence of its toxicity.

The kinetics of sulfanilamide release is not explosive and provides the desired prolonged release over 12 hours.

The essence of the method for manufacturing the delivery system is as follows. A sample of hyaluronic acid is dissolved in an equal-volume mixture of distilled water and dimethyl sulfoxide using a magnetic or overhead stirrer, then sulfanilamide is added in an amount corresponding to the mass ratio of hyaluronic acid and sulfanilamide from 25:1 to 2:1, continuing to stir until it is completely dissolved. After preparing the solution, the surface area of the resulting solution is increased, for example, by pouring the solution into Petri dishes, it is kept for 12-24 hours at room temperature for stabilization and deaeration and dried in air at a temperature of 30 to 45 °C to a constant mass.

As a result, the resulting system has the following composition:

hyaluronic acid with MM from 1.0 to 2.0 MDa 65.7-95.4 wt.% sulfanilamide 3.8-32.9 wt.% distilled water and dimethyl sulfoxide the rest

EXAMPLE

Four 0.9 g portions of hyaluronic acid with a molecular weight of 1.3 MDa were dissolved in 100 ml measuring cups containing 25 ml of distilled water and 25 ml of dimethyl sulfoxide. Dissolution was carried out using a multi-place magnetic stirrer at room temperature and a stirring speed of 200 rpm. A pre-prepared portion of sulfanilamide was added to each of the resulting polymer solutions in the following quantities: 0.045 g (sample "1:20"), 0.06 g (sample "1:15"), 0.09 g (sample "1:10"), 0.18 g (sample "1:5") and stirring of the solution was continued until the sulfanilamide was completely dissolved. The polymer solutions were poured into four 100 mm diameter polystyrene Petri dishes, left at room temperature for 24 h for stabilization and deaeration, and dried in a drying oven at 40°C for 72 h. The resulting films weighed 0.954 g, 0.972 g, 1.003 g, and 1.095 g.

The kinetics of sulfanilamide release into a phosphate buffer solution (pH 7.4) from the resulting delivery system is shown in the figure. The sulfanilamide release regime was similar regardless of the sulfanilamide content in the sample. Sulfanilamide was gradually released into the model medium over 12 hours.

Claims (3)

1. A sulfanilamide delivery system comprising a sulfanilamide and a polymer matrix based on a polysaccharide, characterized in that the polymer matrix based on a polysaccharide is hyaluronic acid with a molecular weight (MW) from 1.0 to 2.0 MDa, wherein the mass ratio of said hyaluronic acid and sulfanilamide is from 25:1 to 2:1, wherein the delivery system also contains distilled water and dimethyl sulfoxide and has the following composition: hyaluronic acid with MM from 1.0 to 2.0 MDa 65.7-95.4 wt.% sulfanilamide 3.8-32.9 wt.% distilled water and dimethyl sulfoxide rest 2. A method for producing a sulfanilamide delivery system according to claim 1, characterized in that hyaluronic acid with an MM of 1.0 to 2.0 MDa is dissolved in an equal volume mixture of distilled water and dimethyl sulfoxide and then sulfanilamide is added, then the resulting solution is poured into Petri dishes and kept for 12-24 hours at room temperature for stabilization and deaeration, after which it is dried in air at a temperature of 30-45°C to a constant weight.