Polymeric system with nano-in-micro architecture for controlled release of low molecular weight water soluble drugs and method for its preparation

Abstract

The present invention relates to a polymer system with a nano-in-micro architecture (fucoidan micromatrix with PLGA nanoparticles incorporated therein) and finds application as a system for controlled delivery of low molecular weight water-soluble medicinal substances (e.g. galantamine hydrobromide, benzydamine hydrochloride, betahistine hydrochloride, etc.). The system includes polylactic-coglycolic acid (PLGA) nanoparticles in a fucoidan matrix, with the PLGA content being from 1% to 10% and fucoidan content being from 90% to 99% in the form of a fucoidan matrix with 100% PLGA nanoparticles incorporated therein, with the microparticles having an average diameter of 2 μm to 10 μm. The polymer system for controlled release of low molecular weight water-soluble drugs, when loaded with low molecular weight water soluble drugs such as galantamine, benzydamine, doxylamine, contains polylactic-co-glycolic acid from 1% to 10% and fucoidan from 90% to 99% in the form of a fucoidan matrix with PLGA nanoparticles incorporated therein, in the form of a fucoidan matrix with PLGA nanoparticles incorporated therein from 94% to 99% and a low molecular weight water-soluble drug from 1% to 6%, wherein the microparticles have an average diameter of 2 μm to 10 μm.

Description

[0001] Polymeric system with nano-in-micro architecture for controlled release of low molecular weight water soluble drugs and method for its preparation

[0002] Related Applications

[0003] This application claims priority to BG / P / 2025 / 114050 filed 21 February 2025, the entire disclosure of which is hereby incorporated herein by reference.

[0004] Field of technology

[0005] The present invention relates to a polymeric system with a nano-in-micro architecture (fucoidan micromatrix with PLGA nanoparticles incorporated therein) and finds application as a system for controlled delivery of low-molecular-weight, water-soluble drug substances (e.g., galantamine hydrobromide, benzidamine hydrochloride, betahistine hydrochloride, etc.).

[0006] Background

[0007] Innovation in pharmaceutical technology is at the forefront of healthcare and a key factor in improving quality of life. They enhance the effectiveness and safety of existing medicines by reducing the risk of adverse effects. Innovative drug delivery systems based on particle design constitute a significant part of modern pharmaceutical innovation. With such systems, it is possible to precisely regulate the rate of drug release, tailored to the specific needs of the disease and the organism, as well as to target the therapeutic agent to specific tissues and organs to potentiate its pharmacological action and limit the adverse effects of its administration. There are numerous examples of successful incorporation of therapeutic agents into structures ranging in size from a few nanometers to the micrometer scale. Not only low-molecular-weight substances but also peptides, proteins, and nucleic acids have been studied, demonstrating the potential of such structures as innovative drug delivery systems with a modified / controlled drug release profile and targeted delivery into the body.

[0008] Due to their small size, nanocarriers can transport drug substances to a specific target area while protecting them from enzymatic and chemical degradation and improving their passage through membrane barriers. On the other hand, their large surface area is the cause of low stability, a tendency to form aggregates, and rapid release of the incorporated drug. This suggests that optimizing carrier size in the micro range is a potential strategy to delay drug release, maintaining a desired plasma concentration fora longer period, and improving therapeutic control. Additionally, based on their size and surface properties (such as hydrophilicity, charge, andmucoadhesiveness), microparticles can be passively targeted to specific body sites. A new class of drug delivery systems combines the benefits of both micro- and nanoparticles, comprising a more advanced carrier with a microdimensional polymer matrix in which nanoparticles are embedded. Achieving targeted delivery and controlled drug release largely depends on the polymers used and the resulting microstructure. Besides the choice of materials, selecting an appropriate method for preparing the microcomposites is critical for their structural, morphological, and biopharmaceutical performance.

[0009] The choice of drug carriers can be made from a wide range of natural, semi-synthetic, and synthetic polymers, with key criteria including their biocompatibility, biodegradability, non-toxicity, mucoadhesiveness, good encapsulating abilities, and affordability. Advances in polymer chemistry, along with the need for polymers with specific functionalities and precise physicochemical properties, lead to a diverse array of polymer materials. Commonly used synthetic polymers for making nano- and microparticles include polylactic-co-glycolic acid, polycyanoacrylate, poly-E-caprolactone, polyanhydride, and polymethacrylate, mainly because of their confirmed ability to biodegrade within the body.

[0010] Polylactic-co-glycolic acid (PLGA) is an aliphatic polyester formed by the copolymerization of lactic and glycolic acids. It is included in many FDA-approved therapeutic devices due to its biodegradability and biocompatibility. Under physiological conditions, it degrades through the hydrolysis of ester linkages in the polymer chain. Compared to other polymers, PLGA is relatively easy to process, enabling the preparation of various structures, such as micro- and nanoparticles, suitable for different administration routes. Many research efforts have focused on optimizing the fabrication of PLGA carriers. Emulsion techniques, phase separation (coacervation), and lyophilization are commonly used to produce these carriers. Process parameters like solvent type, polymer molecular weight, copolymer composition, stirring speed and duration, and stabilizing agents are crucial for achieving optimal sustained-release structures of the loaded drugs (Hines DJ, Kaplan DL. Poly(lactic-co-glycolic) acid-controlled-release systems: experimental and modeling insights. Crit Rev Ther Drug Carrier Syst. 2013;30(3):257-76. doi: 10.1615 / critrevtherdrugcarriersyst.2O13006475.)

[0011] Along with their undeniable advantages, nanosized structures also have certain limitations, usually related to their physicochemical and biological properties. These include low drug entrapment efficiency, especially for hydrophilic therapeutic agents, rapid release of a large fraction of the drug on the particle surface ("burst effect"), neutralization by the immune system, immunogenic effects, and uncontrolled tissue distribution. These drawbacks restrict their widespread use in large-scale industrial production. Various strategies have been employed tocombine PLGA with hydrophilic polymers in order to address these issues. The goal is to enhance the functionality of PLGA systems. Building a surface coating can help overcome some barriers to targeted delivery of PLGA particles, such as their limited ability to pass through the body's barrier systems. For instance, the blood-brain barrier hinders drug delivery to the brain. Coating PLGA nanoparticles with trimethylated chitosan boosts their active transport across this barrier, thanks to its cationic ligand properties (Wang ZH, Wang ZY, Sun CS, Wang CY, Jiang TY, Wang SL. Trimethylated chitosan-conjugated PLGA nanoparticles for the delivery of drugs to the brain. Biomaterials. 2010 Feb;31(5):908-15. doi: 10.1016 / j. biomaterials.2009.09.104.). Also, PLGA micro- and nanoparticles with liposomal carrier features have been developed by coating them with a layer of soy lecithin, followed by polyethylene glycol (Chan JM, Zhang L, Yuet KP, Liao G, Rhee JW, Langer R, Farokhzad OC. PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery. Biomaterials. 2009 Mar;30(8): 1627-34. doi: 10.1016 / j. biomaterials.2008.12.013). Nanoparticles and microparticles made from PLGA and sulfated polysaccharides were prepared using a double emulsion solvent evaporation method. Sulfated polysaccharides were added to the external aqueous phase of the emulsion in amounts sufficient to give the particles a negative ^-potential. This method allows the sulfate groups to be tightly integrated into the nano- and microstructures. Polysaccharides with high sulfate levels include fucoidan, carrageenan, heparan sulfate, and ulvan (International Patent WO2020243248 dated 03.12.2020). The drug molecules can be encapsulated within the particles or attached to their surface via covalent or ionic bonds. Covalent attachment of drug molecules to the particle surface can be achieved through ester or amide bonds, which release the drug upon hydrolysis in vivo. Saren et al. developed PLGA nanoparticles coated with sequential layers of chitosan and fucoidan, based on electrostatic interactions between the negatively charged PLGA and fucoidan and the positively charged chitosan. The carrier was successfully loaded with the protein kinase inhibitor dasatinib. Its release was extended up to 120 hours, and its hemolytic potential was three times lower than that of suspension or uncoated particles containing dasatinib. This carrier system reduces the necessary drug dose and minimizes side effects (Saren BN, Mahajan S, Aalhate M, Kumar R, Chatterjee E, Maji I, Gupta U, Guru SK, Singh PK. Fucoidan-mediated targeted delivery of dasatinib-loaded nanoparticles amplifies apoptosis and endows cytotoxic potential in triplenegative breast cancer. Colloids Surf B Biointerfaces. 2024 Jan;233:113631. doi: 10.1016 / j. colsurfb.2023.113631). Notably, methods of the invention overcome the requirement for electrostatic attraction for the incorporation of PLGA nanoparticles in a microparticle matrix. The invention utilizes spray drying which is a physical method for obtaining PLGA nanoparticles incorporated in a fucoidan microparticle matrix regardless of electrostatic attraction.Additionally, chitosan-modified PLGA nanoparticles were developed to enhance the intestinal absorption of melatonin and fucoidan, and to facilitate their delivery to tumor cells. The positive charge of chitosan facilitates the binding of nanoparticles to M cells, promoting transcytosis and enhancing absorption in the intestines (Yen YW, Lee YL, Yu LY, Li CE, Shueng PW, Chiu HC, Lo CL). Due to the positive charge of chitosan, the interaction between chitosan and cells primarily relies on the electrostatic attraction between the positively charged chitosan and the negatively charged cell membranes, including those of M cells. Conversely, fucoidan interacts with cells via cell receptors through specific, receptor-mediated mechanisms. For example, fucoidan can bind to selectin and scavenger receptors, which are expressed on endothelial, epithelial and immune cells, including microglial cells and macrophages. Therefore, the invention allows for cellular targeting of the polymeric system disclosed herein through the receptor-mediated interactions between fucoidan and target cells.

[0012] Fucoidan / chitosan layered PLGA nanoparticles with melatonin loading for inducing intestinal absorption and addressing triple-negative breast cancer progression. I nt J Biol Macromol. 2023 Oct 1 ;250: 126211. doi: 10.1016 / j.ijbiomac.2023.126211). In another study, chitosan / fucoidan nanoparticles reduced drug toxicity, enhanced epithelial permeability, and improved delivery of celecoxib to COX-2 overexpression sites within tumors (Mabrouk, Aya A., et al. "Novel celecoxib-loaded chitosan-fucoidan nanoparticles as potential immunotherapy for oral squamous cell carcinoma: Mechanistic insights." Journal of Drug Delivery Science and Technology 81 (2023): 104228). The reduction in toxicity is likely due to the fucoidan incorporated into the particles.

[0013] Among the most commonly used natural polymers for producing nano- and microparticles are alginate, chitosan, fucoidan, cellulose, gelatin, gliadin, pullulan, and others. Fucoidan is a water-soluble heteropolysaccharide made up of L-Fucose and sulfate groups. It has been found in the cell walls of various brown algae species such as Laminaria digitata, Ascophyllum nodosum, and Fucus vesiculosus. Fucoidan is known for its anticoagulant, antiviral, anti-inflammatory, antioxidant, and anticancer properties. Fucoidan-based drug delivery systems offer several advantages, including high drug incorporation efficiency, low toxicity, controlled release, and protection of therapeutic agents from enzymatic degradation in the gastrointestinal tract and other parts of the body. When introduced into the body, fucoidan not only acts as an inert carrier of drug substances but also facilitates its therapeutic effects. Currently developed fucoidan-based carriers include nanoparticles, emulsions, films, nanocapsules, and hydrogels. Fucoidan can be combined with other hydrophilic biopolymers (e.g., chitosan, zein, collagen, casein) to create drug delivery systems with specific properties. For instance, fucoidan binds to amino groups of chitosan, forming nanoparticles with high potency and bioavailability after oral administration(Tran PHL, Duan W, Tran TTD. Fucoidan-based nanostructures: A focus on its combination with chitosan and the surface functionalization of metallic nanoparticles for drug delivery. _ Int J Pharm. > 2020 Feb 15; 575: 118956. doi: 10.1016 / j. ijpharm.2019.118956. 118956). Hydrogen bonding between polymers is also an alternative method for forming fucoidan-based complexes. Casein / fucoidan composite nanoparticles have been prepared through self-association of casein and fucoidan due to electrostatic attraction (Patent BG 4536 U 1 dated 16.10.16.10.2023). Chitosan / fucoidan nanoparticles, which rely on electrostatic interactions, have also been developed as carriers for lipophilic drugs (Patent KR 102363434 B1, dated 10.02.2022). Using an emulsion solvent evaporation method, fucoidan / PLGA nanoparticles loaded with docetaxel have been produced. These particles are spherical, stable, and well-dispersed without aggregation in aqueous media; however, their yield is relatively low, at around 18%. Due to their higher negative ^-potential and hydrophilicity, the drug-loaded nanoparticles showed anticancer activity after incubation with MDA-MB-231 triple-negative breast cancer cells (Lai YH, Chiang CS, Hsu CH, Cheng HW, Chen SY. Development and Characterization of a Fucoidan-Based Drug Delivery System by Using Hydrophilic Anticancer Polysaccharides to Simultaneously Deliver Hydrophobic Anticancer Drugs. Biomolecules. 2020 Jun 28;10(7):970. doi: 10.3390 / biom10070970.). This demonstrates that the combination of PLGA and fucoidan can be used as an effective drug delivery system.

[0014] Fan et al. build a multilayer polyelectrolyte shell of poly-L-ornithine and fucoidan on PLGA nanoparticles. The shell was formed through static adsorption after the sequential addition of nanoparticles to polyelectrolyte solutions of the two polymers. TEM micrographs reveal that the PLGA nanoparticles have a spherical shape, and after self-assembly of the polyelectrolyte materials, the surface becomes slightly uneven, confirming the formation of the film shell. This innovative particle design allows penetration of the carrier into the cells along with controlled release of the incorporated drugs (Fan, Jingqian, et al. "Synthesis and characterization of innovative poly(lactide-co-glycolide)-(poly-L-ornithine / fucoidan) core-shell nanocarriers by layer-by-layer self-assembly." RSC advances 7.52 (2017): 32786-32794).

[0015] Miranda-Linares et al. developed nanomicrostructures based on the biopolymers alginate and pectin, encapsulating lemon and rosemary oils and a-tocopherol. The synthesized structures were further incorporated into a matrix of mannitol (Miranda-Linares, V., Quintanar-Guerrero, D., Del Real, L.,A., Zambrano-Zaragoza, M.L., Spray-drying method for the encapsulation of a functionalized ingredient in alginate-pectin nano- and microparticles loaded with distinct natural actives: Stability and antioxidant effect, Food Hydrocolloids (2019), doi: https: / / doi.Org / 10.1016 / j.foodhyd.2019.105560.).An alginate / chitosan based nanoparticle microcomposite system has been developed to enhance the stability of omega-3 rich oils (flaxseed or fish oil). The microspheres were synthesized by emulsifying oil in water (o / w), gelling and microencapsulation, and loaded with curcumin as a natural antioxidant (Hamed SF, Hashim AF, Abdel Hamid HA, Abd-Elsalam KA, Golonka I, Musiat W, El-Sherbiny IM. Edible alginate / chitosan-based nanocomposite microspheres as delivery vehicles of omega-3 rich oils. Carbohydr Polym. 2020 Jul 1 ;239:116201. doi: 10.1016 / j.carbpol.2020.116201. epub 2020 Apr 8. PMID: 32414429.).

[0016] A similar approach was suggested by Zhang et al. for delivering curcumin to the colon. Hyaluronic acid / zein complex nanoparticles were loaded with curcumin and then incorporated into alginate / chitosan microspheres using electrospray technology. The release of curcumin was delayed in simulated gastric fluid, while in conditions resembling the colon, the dissolution was faster. An additional advantage of these nanocomposite microparticles is their longer retention and affinity for colonic tissues (Zhang C, Wang X, Xiao M, Ma J, Qu Y, Zou L, Zhang J. Nano-in-micro alginate / chitosan hydrogel via electrospray technology for oral curcumin delivery to effectively alleviate ulcerative colitis. Materials & Design Volume 221 , September 2022, 110894).

[0017] Another group is developing a composite structure, nano-in-micro particles for nasal administration, GCPQ--L-DOPA, through spray drying. When applied nasally to rats, the N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ)-based composite with nanoparticle-encapsulated levodopa exhibited prolonged retention in the nasal cavity and efficient delivery into brain tissue, thereby avoiding systemic side effects.

[0018] Microparticles incorporating solid lipid nanoparticles were developed by Li et al. as carriers for the pulmonary delivery of thymopentin. A spray-drying method using mannitol and leucine as structure-forming excipients was applied (Li, Y. Z., Sun, X., Gong, T., Liu, J., Zuo, J., & Zhang, Z. R. (2010). Inhalable microparticles as carriers for pulmonary delivery of thymopentin-loaded solid lipid nanoparticles. Pharmaceutical research, 27(9), 1977-1986. https: / / doi.orq / 10.1007 / s11095-010-0201 -z). A similar method was proposed by Grenha et al. for the preparation of lipid / chitosan nanocomplexes, incorporated into microspheres as a multi-component delivery system for therapeutic proteins (Grenha, A., Remufian-Lopez, C., Carvalho, E. L., & Seijo, B. (2008). Microspheres containing lipid / chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 69(1), 83-93). The same collective also proposed another development based on chitosan nanoparticles incorporated into mannitol microparticles (Al-Qadi, et al. "Microencapsulated chitosan nanoparticles for pulmonaryprotein delivery: In vivo evaluation of insulin-loaded formulations". Journal of Controlled Release, vol. 157, n.° 3, 2012, pp. 383-90, https: / / doi.Org / 10.1016 / J.JCONREL.2011.08.008.).

[0019] Spindler et al. propose a nano-in-microparticle-type development based on PLGA nanoparticles synthesized by a precipitation method and incorporated into a chitosan micromatrix. The resulting microparticles have homogeneous size distribution and high incorporation efficiency (Spindler, L. M., Feuerhake, A., Ladel, S., Gunday, C., Flamm, J., Gunday-Tureli, N., Tureli, E., Tovar, G. E. M., Schindowski, K., & Gruber-Traub, C. (2021). Nano-in-Micro-Particles Consisting of PLGA Nanoparticles Embedded in Chitosan Microparticles via Spray-Drying Enhances Their Uptake in the Olfactory Mucosa. Frontiers in pharmacology, 12, 732954. htps: / / doi.org / 10.3389 / fDhar.2021.732954).

[0020] In a review article, Haggag et al. extensively review the literature on the pharmaceutical applications of fucoidan, including as a structure-forming polymer for the construction of drug delivery systems. Developments based on fucoidan alone or in combination with other biopolymers to produce nanosized drug carriers (nanoparticles, liposomes, nanogels) and fucoidan microspheres (fucospheres) are reported (Haggag YA, Abd Elrahman AA, Ulber R, Zayed A. Fucoidan in Pharmaceutical Formulations: A Comprehensive Review for Smart Drug Delivery Systems. Marine Drugs. 2023; 21(2):112. https: / / doi.org / 10.3390 / md21020112). There is a lack of information on innovative drug carriers of the nano-in-microstructure type, such as the systems described in the current decision. Another review article (Zayed A, Al-Saedi DA, Mensah EC, Kanwugu ON, Adadi P, Ulber R. Fucoidan's Molecular Targets: A Comprehensive Review of Its Unique and Multiple Targets Accounting for Promoting Bioactivities Supported by In Silico Studies. Marine Drugs. 2024; 22(1):29. https: / / doi.org / 10.3390 / md22010029) reviews the pharmacological properties of fucoidan, focusing on elucidating the mechanisms of action of fucoidan at the molecular level without addressing its application in pharmaceutical technology as a carrier in drug delivery systems.

[0021] A solution is described in patent application US 2024 / 0374529 A1, which involves a complex with amphiphilic properties consisting of a fucoidan polysaccharide shell and a hydrophobic PLGA core. This patent application is essentially a pharmaceutical composition based on a nanoprecipitate (a PLGA nanoparticle coated with a fucoidan shell), whereas the current solution described here relates to a matrix system in the form of a micro-sized matrix containing nanoparticles of PLGA.

[0022] Solutions are also documented in patent applications CN106038512A and CN106038512B, which describe nanocarriers created through a layer-by-layer deposition method. These nanocarriers consist of a PLGA nano core and a shell formed by the self-assembly of apolycationic electrolyte and a polyanionic electrolyte (fucoidan), unlike the current solution, which is a nano-in-micro particle microcomposite.

[0023] The above information shows that, so far, no nanocomposite microsphere system has been created for delivering low molecular weight water-soluble drugs using polymers like PLGA and fucoidan (nanoparticles of PLGA embedded in a fucoidan matrix).

[0024] Description of the Figures

[0025] The present invention will be further described by way of example only, with reference to the accompanying figures.

[0026] Figure 1 is a SEM micrograph of a system with nano-in-micro architecture (polylactic-co-glycolic acid nanoparticles incorporated in a fucoidan matrix).

[0027] Figure 2 is a SEM micrograph of a system with nano-in-micro architecture (PLGA nanoparticles incorporated in a fucoidan matrix) containing galantamine hydrobromide.

[0028] Figure 3 demonstrates the release profile of galantamine from a nano-in-micro architecture system.

[0029] Figure 4 is a SEM micrograph of a system with a nano-in-micro architecture (nanoparticles of PLGA incorporated in a fucoidan matrix) containing doxylamine.

[0030] Figure 5 shows the release profile of doxylamine from a system with nano-in-micro architecture.

[0031] Figure 6 is a SEM micrograph of a system with nano-in-micro architecture (nanoparticles of PLGA incorporated in a fucoidan matrix) containing benzidamine.

[0032] Figure 7 shows the release profile of benzidamine from a system with nano-in-micro architecture.

[0033] Summary of the Invention and Detailed Description

[0034] In order to achieve controlled release of low-molecular-weight water-soluble drug substances such as galantamine hydrobromide, betahistine dihydrochloride, benzidamine hydrochloride, and doxylamine hydrochloride, etc., the present invention facilitates their incorporation into a drugdelivery system with a nano-in-micro architecture. This system is prepared using a double emulsion solvent evaporation method, followed by spray drying. Fucoidan is known to exhibit affinity for certain cell surface receptors, such as selectin and scavenger receptors, which are present on endothelial, epithelial, and immune cells, such as microglial cells and macrophages. This property, as reported in the scientific literature, may enhance the ability of the polymeric system disclosed herein to associate with and deliver active agents to these cell types. In some embodiments, the polymeric system for use disclosed herein targets endothelial, epithelial, and immune cells such as microglial cells and macrophages.

[0035] In one aspect, the disclosure relates to a polymeric system for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.

[0036] In some embodiments, the PLGA content is from 1% to 10%.

[0037] In some embodiments, the fucoidan content is from 90% to 99% in the form of the fucoidan matrix.

[0038] In some embodiments, the microparticles have an average diameter of 2 pm to 10 pm.

[0039] In some embodiments, the polymeric system disclosed herein further comprises a low-molecular-weight water-soluble drug substance.

[0040] In some embodiments, the water-soluble drugs are selected from the group consisting of: galantamine, benzidamine or doxylamine.

[0041] In some embodiments, the PLGA nanoparticles are incorporated in the fucoidan matrix from 94% to 99% and the drug substances from 1% to 6%.

[0042] In some embodiments, the fucoidan matrix consists of fucoidan.

[0043] In some embodiments, the matrix disclosed herein does not comprise chitosan. In some embodiments, the polymeric system disclosed herein does not comprise chitosan.

[0044] In some embodiments, the polymeric system disclosed herein is formulated as a powder formulation. In some embodiments, the polymeric system disclosed herein is formulated as a solid dosage form, such as a tablet or capsule.The polymeric system disclosed herein is suitable for nasal and / or oral administration. The size of the microparticles ensures optimal deposition in the nasal cavity without the risk of entering the lungs.

[0045] In some embodiments, the polymeric system disclosed herein is suitable for nasal administration. In some embodiments, the polymeric system disclosed herein is formulated as a powder formulation and is suitable for nasal administration. In some embodiments, the polymeric system disclosed herein is suitable for oral administration. In some embodiments, the polymeric system disclosed herein is formulated as a solid dosage form, such as a tablet or capsule, and is suitable for oral administration.

[0046] In a further aspect, the disclosure relates to a method for obtaining a polymeric system for controlled release of low-molecular-weight water-soluble drug substances, characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle, the method comprising:

[0047] i) generating PLGA nanoparticles by double emulsion solvent evaporation; and ii) incorporating the PLGA nanoparticles into a fucoidan microparticle by spray-drying.

[0048] The methods disclosed herein do not require electrostatic interaction between the PLGA nanoparticles and the fucoidan matrix. Spray drying provides a physical method for the incorporation of the PLGA nanoparticles into the fucoidan matrix. Incorporation is achieved by physical encapsulation of the PLGA nanoparticles during the spray drying process, during which the polymeric system solidifies to form a solid particle comprising PLGA nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle. This approach ensures homogenous distribution and structural stability of the polymeric system disclosed herein despite the opposing negative charges of PLGA and fucoidan.

[0049] In some embodiments, the spray drying is performed at an inlet temperature of 120°C to 180°C.

[0050] In some embodiments, the spray drying is performed at an inlet temperature of 140°C and 170°C.

[0051] In some embodiments, the spray drying is performed with a spray nozzle with an orifice size of 0.7 to 1.4 mm.In some embodiments, generating PLGA nanoparticles by double emulsion solvent evaporation comprises:

[0052] a) dissolving PLGA in dichloromethane to obtain a solution having a concentration of 0.1% to 1% wt / vol;

[0053] b) adding a lipophilic emulsifier to the solution of step a;

[0054] c) emulsifying purified water in the solution of step b to obtain a primary emulsion; d) dispersing the primary emulsion of step c in an external aqueous phase comprising an emulsifier to obtain a double emulsion; and,

[0055] e) evaporating the dichloromethane to obtain a suspension of solid polymer nanoparticles; and,

[0056] wherein incorporating the PLGA nanoparticles into a fucoidan microparticle by spray-drying comprises:

[0057] a) dissolving fucoidan in the suspension obtained in step e; and

[0058] b) spray drying the suspension obtained in step ii,a).

[0059] In some embodiments, generating PLGA nanoparticles by double emulsion solvent evaporation comprises:

[0060] a) dissolving PLGA in dichloromethane, at a temperature of 15 °C to 40 °C in an ultrasonic bath to obtain a solution having a volume of 5 mLto 10 mL and a concentration of 0.1 % wt / vol to 1.0 % wt / vol;

[0061] b) adding a lipophilic emulsifier Span 85 at a concentration of 0.5% wt / vol to 2.0% wt / vol to the solution prepared in step a);

[0062] c) emulsifying purified water in a volume of 1 mL to 5 mL in the PLGA solution in dichloromethane containing Span 85 prepared in step b) under high-speed homogenization at a speed of 10,000 rpm to 25,000 rpm for 1 min to 5 min to obtain a primary emulsion (W / O);

[0063] d) dispersing the primary emulsion obtained in step c) in an external aqueous phase comprising Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol under high-speed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form a double emulsion (W / O / W); ande) stirring with an electromechanical stirrer at a speed of 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymer nanoparticles is obtained; and

[0064] incorporating the PLGA nanoparticles into a fucoidan microparticle by spray-drying comprises:

[0065] a) dissolving fucoidan in the suspension obtained in step e) to obtain a polymer solution having a concentration of 0.25 % wt / vol to 3.5 % wt / vol; and

[0066] b) subjecting the suspension obtained in step ii. a) to spray drying under the following conditions: (a) inlet temperature from 120°C to 180°C, optionally between 140°C and 170°C; (b) gas flow rate from 400 L / h to 600 L / h; (c) solution feed rate from 4 mUmin to 10 mL / min; (d) spray nozzle with orifice size of 0.7 to 1.4 mm; and (e) aspiration from 15 m3 / h to 35 m3 / h.

[0067] In some embodiments, the PLGA nanoparticles comprise a low-molecular-weight water-soluble drug substance.

[0068] In some embodiments, the method comprises:

[0069] i) generating PLGA nanoparticles comprising a low-molecular-weight water-soluble drug substance by double emulsion solvent evaporation; and

[0070] ii) incorporating the PLGA nanoparticles comprising a low-molecular-weight water- soluble drug substance into a fucoidan microparticle by spray-drying.

[0071] In some embodiments, generating PLGA nanoparticles comprising a low-molecular-weight water-soluble drug substance by double emulsion solvent evaporation comprises:

[0072] a) dissolving PLGA in dichloromethane to obtain a solution having a concentration of 0.1% to 1% wt / vol;

[0073] b) adding a lipophilic emulsifier to the solution of step a;

[0074] c) dissolving a low-molecular-weight water-soluble drug substance in purified water; d) emulsifying the solution of step c in the solution of step b to obtain a primary emulsion;

[0075] e) dispersing the primary emulsion of step d in an external aqueous phase comprising polysorbate 20 emulsifier to obtain a double emulsion; and,

[0076] f) evaporating the dichloromethane to obtain a suspension of solid polymer nanoparticles comprising a low-molecular-weight water-soluble drug substance; and,incorporating the PLGA nanoparticles comprising a low-molecular-weight water-soluble drug substance into a fucoidan microparticle by spray-drying comprises:

[0077] a) dissolving fucoidan in the suspension obtained in step f; and

[0078] b) spray drying the suspension obtained in step ii.a).

[0079] In some embodiments, generating PLGA nanoparticles comprising a low-molecular-weight water-soluble drug substance by double emulsion solvent evaporation comprises:

[0080] a) dissolving PLGA in dichloromethane, at a temperature of 15 °C to 40 °C in an ultrasonic bath to produce a solution having a volume of 5 mL to 10 mL and having a concentration of 0.1% wt / vol to 1.0% wt / vol;

[0081] b) adding a Span 85 lipophilic emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol to the solution prepared in Step a;

[0082] c) dissolving a low-molecular-weight water-soluble drug substance in purified water at a temperature of 25 °C to 35 °C to produce a solution of 1 mL to 5 mL in volume and at a concentration of 0.1 % wt / vol to 1.0 % wt / vol;

[0083] d) emulsifying the solution of step c in the PLGA solution in dichloromethane containing Span 85 obtained in step b under high-speed homogenization at 10,000 rpm to 25,000 rpm for 1 min to 5 min to obtain a primary emulsion;

[0084] e) dispersing the primary emulsion obtained in step d in an external aqueous phase comprising Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol under high-speed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form the double emulsion; and

[0085] f) stirring with an electromechanical stirrer at a speed of 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymeric nanoparticles comprising a low-molecular-weight water-soluble drug substance is obtained; and,

[0086] incorporating the PLGA nanoparticles comprising a low-molecular-weight water-soluble drug substance into a fucoidan microparticle by spray-drying comprises

[0087] a) dissolving fucoidan in the suspension obtained in step f and obtaining a polymer solution having a concentration of 0.25% wt / vol to 3.5% wt / vol; and

[0088] b) subjecting the suspension obtained in step ii.a) to spray drying under the following conditions: (a) an inlet temperature of 120°C to 180°C, optionally 140°C to 170°C; (b) a gas flow rate of 400 L / h to 600 L / h; (c) a solution feed rate of 4 mL / min to 10 mL / min;(d) spray nozzle with orifice size of 0.7 to 1.4 mm; (e) an aspiration rate of 15 m3 / h to 35 m3 / h.

[0089] In a further aspect, the disclosure relates to a polymeric system obtained by a method disclosed herein.

[0090] In a further aspect, the disclosure relates to the polymeric system disclosed herein for use in medicine.

[0091] In a further aspect, the disclosure relates to a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the polymeric system disclosed herein.

[0092] In some embodiments, the polymeric system disclosed herein is formulated as a powder formulation. In some embodiments, the polymeric system disclosed herein is formulated as a solid dosage form, such as a tablet or capsule.

[0093] The polymeric system disclosed herein is suitable for nasal and / or oral administration. The size of the microparticles ensures optimal deposition in the nasal cavity without the risk of entering the lungs.

[0094] In some embodiments, the polymeric system disclosed herein is suitable for nasal administration. In some embodiments, the polymeric system disclosed herein is formulated as a powder formulation and is suitable for nasal administration. In some embodiments, the polymeric system disclosed herein is suitable for oral administration. In some embodiments, the polymeric system disclosed herein is formulated as a solid dosage form, such as a tablet or capsule, and is suitable for oral administration.

[0095] In a further aspect, the disclosure relates to a kit for preparing microparticles for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.

[0096] In a further aspect, the disclosure relates to use of the kit disclosed herein for the generation of a polymeric system for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.In a further aspect, the disclosure relates to use of PLGA and fucoidan in preparing a polymeric system for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.

[0097] In some embodiments, the PLGA content is from 1% to 10%.

[0098] In some embodiments, the fucoidan content is from 90% to 99% in the form of the fucoidan matrix.

[0099] In some embodiments, the microparticles have an average diameter of 2 pm to 10 pm.

[0100] In some embodiments, the polymeric system further comprises a low-molecular-weight water-soluble drug substance.

[0101] In some embodiments, the low-molecular-weight water-soluble drugs are selected from the group consisting of: galantamine, benzidamine or doxylamine.

[0102] In some embodiments, the PLGA nanoparticles are incorporated in the fucoidan matrix from 94% to 99% and the drug substances from 1% to 6%.

[0103] In some embodiments, the fucoidan matrix consists of fucoidan.

[0104] In some embodiments, the matrix disclosed herein does not comprise chitosan. In some embodiments, the polymeric system disclosed herein does not comprise chitosan.

[0105] In the present development, a system with a nano-in-micro architecture (polylactic-co-glycolic acid nanoparticles incorporated in a fucoidan matrix) and one loaded with low-molecular-weight water-soluble drug substances, along with methods fortheir preparation, are provided.

[0106] The nano-in-micro architecture system is prepared by a double emulsion solvent evaporation method and subsequent spray drying and contains PLGA from 1% to 10% and fucoidan from 90% to 99% in the form of a matrix of fucoidan with 100% PLGA nanoparticles incorporated therein, the microparticles having an average diameter of 2 pm to 10 pm.

[0107] The present work proposes a method to prepare a system with nano-in-micro architecture (PLGA nanoparticles incorporated in a fucoidan matrix) in the following sequence of steps:

[0108] Step 1. Dissolve PLGA in dichloromethane at 15 °C to 40 °C in an ultrasonic bath to obtain a solution of 5 mL to 10 mL with a concentration of 0.1% wt / vol to 1.0% wt / vol.Step 2. Add Span 85, lipophilic emulsifier, to the solution prepared in Step 1 at a concentration of 0.5% wt / vol to 2.0% wt / vol.

[0109] Step 3. Preparation of primary emulsion W / O: Purified water, in a volume of 1 mL to 5 mL, is emulsified in the PLGA solution in dichloromethane containing Span 85 prepared in Step 2 under high-speed homogenization at 10,000 rpm to 25,000 rpm for 1 min to 5 min.

[0110] Step 4. Disperse the primary emulsion obtained in Step 3 into an external aqueous phase containing Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol, under highspeed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form the double emulsion (W / O / W).

[0111] Step 5. Stir with an electromechanical stirrer at 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymer nanoparticles forms.

[0112] Step 6. Dissolve fucoidan in the suspension obtained in Step 5 to create a polymer solution with a concentration of 0.25% wt / vol to 3.5% wt / vol.

[0113] Step 7. The suspension from Step 6 is spray-dried under the following conditions:

[0114] (a) Inlet temperature from 20°C to 180°C;

[0115] (b) a gas flow rate of 400 L / h to 600 L / h;

[0116] (c) a solution flow rate of 4 mL / min to 10 mL / min;

[0117] (d) spray membrane with orifice size of 0.7 to 1.4 mm;

[0118] (e) an aspiration rate of 15 m3 / h to 35 m3 / h.

[0119] In some embodiments, the spray membrane is a spray nozzle.

[0120] In some embodiments the inlet temperature is from 120°C to 180°C.

[0121] In preferred embodiments, the inlet temperature is from 140°C and 170°C.

[0122] The system with nano-in-micro architecture loaded with low-molecular-weight, water-soluble drug substances is prepared using a double emulsion solvent evaporation method, followed by spray drying. It contains 1% to 10% PLGA, 90% to 99% fucoidan, and 1% to 10% of the low molecular weight, water-soluble drug substance, forming a matrix of fucoidan with incorporated PLGA nanoparticles. These PLGA nanoparticles consist of 94% to 99%, with the low molecular weight water-soluble drug substance present in the nanoparticles at 1% to 6%. In some embodiments, the PLGA nanoparticles consist of 95% to 99% with the low molecular weight water-soluble drug substance present in the nanoparticles at 1% to 6%. The microparticles have an average size of 2 pm to 10 pm.The present work proposes a method to prepare a system with nano-in-micro architecture (PLGA nanoparticles incorporated in a fucoidan matrix) loaded with low molecular weight water soluble drug substances in the following sequence of steps:

[0123] Step 1. Dissolution of PLGA in dichloromethane, at a temperature of 15 °C to 40 °C in an ultrasonic bath to produce a solution with a volume of 5 mL to 10 mL and a concentration of 0.1% wt / vol to 1.0% wt / vol.

[0124] Step 2. Add Span 85, lipophilic emulsifier, to the solution prepared in Step 1 at a concentration of 0.5% wt / vol to 2.0% wt / vol.

[0125] Step 3. Dissolve a low-molecular-weight water-soluble drug substance in purified water at a temperature of 25°C to 35°C to produce a solution of 1 mL to 5 mL with a concentration of 0.1% wt / vol to 1.0% wt / vol.

[0126] Step 4. Preparation of primary emulsion O / W: The solution prepared in Step 3 was emulsified into the PLGA solution in dichloromethane containing Span 85 obtained in Step 2 under highspeed homogenization at 10,000 rpm to 25,000 rpm for 1 min to 5 min.

[0127] Step 5. Disperse the primary emulsion obtained in Step 4 into an external aqueous phase containing Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol, under highspeed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form the double emulsion (W / O / W).

[0128] Step 6. Stir with an electromechanical stirrer at 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymer nanoparticles forms.

[0129] Step 7. Dissolve fucoidan in the suspension obtained in Step 6 to create a polymer solution with a concentration of 0.25% wt / vol to 3.5% wt / vol.

[0130] Step 8. The suspension from Step 7 is spray-dried under the following conditions:

[0131] (a) Inlet temperature from 20°C to 180°C;

[0132] (b) gas flow rate from 400 L / h to 600 L / h;

[0133] (c) a solution flow rate of 4 mL / min to 10 mL / min;

[0134] (d) spray membrane with orifice size of 0.7 to 1.4 mm;

[0135] (e) an aspiration rate of 15 m3 / h to 35 m3 / h.

[0136] In some embodiments, the spray membrane is a spray nozzle.

[0137] In some embodiments the inlet temperature is from 120°C to 180°C.

[0138] In preferred embodiments, the inlet temperature is from 140°C and 170°C.

[0139] Definitions

[0140] Y1The term “treating” or “treatment”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or slowing or delaying the progression or reoccurrence of, the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treating” also refers to prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.

[0141] As used herein, the indefinite articles “a” and “an” and the definite article “the” include plural as well as singular referents, unless the context clearly dictates otherwise.

[0142] The term “low-molecular-weight drug substance” is well known in the art. Unless otherwise stated, the term refers to compounds which can easily enter cells, including but not limited to organic and synthetic small molecules. In some embodiments, the term “low molecular weight” refers to an organic compound with a molecular weight of less than or equal to 900 Daltons. The term “water-soluble drug substance” refers to a drug substance which can dissolve completely in water to form a solution.

[0143] The term “drug substance” refers to a component of a medicine which is capable of inducing a biological effect, such as a therapeutic effect. In some embodiments, a “drug substance” refers to an organic compound or a synthetic compound. In some embodiments, the “drug substance” is a drug or a prodrug.

[0144] The term “nanoparticle” refers to a particle between 1 and 1000 nanometers (nm) in diameter. Ranges, as defined herein should be understood to be inclusive of the end values (i.e. the highest and lowest values stated) as well as all values in between said end values. For example, the term “from 1% to 6%” is inclusive of 1%, 2%, 3%, 4%, 5% and 6% and all values in-between such as 1.5%, 2.5%, 3.5%, 4.5% and 5.5%.

[0145] The term “fucoidan matrix” refers to a continuous fucoidan structure. The term “microparticles” refers to composite structures in which fucoidan forms a matrix in which the PLGA nanoparticles are embedded.

[0146] Examples

[0147] The invention is illustrated by the following non-limiting examples. The following examples are offered by way of illustration, and not by way of limitation.Example 1: System of polylactic-co-glycolic acid nanoparticles incorporated in a fucoidan matrix

[0148] A system of PLGA nanoparticles incorporated into a fucoidan matrix is prepared using the proposed method for creating a nano-in-micro architecture.

[0149] PLGA nanoparticles are prepared using the double emulsion solvent evaporation method. An aqueous phase of 4 mL was emulsified into 8 mL of PLGA solution in dichloromethane containing 1% emulsifying agent (Span 85) while stirring with a high-speed homogenizer at 21,000 rpm for 3 minutes. The primary emulsion was then dispersed into 50 mL of an external aqueous phase containing 1% Polysorbate 20 as the emulsifying agent, under high-speed homogenization at 25,000 rpm for 5 minutes to form the double emulsion. Stirring was continued at 800 rpm until dichloromethane had completely evaporated, resulting in a nanoparticle suspension.

[0150] Fucoidan was dissolved in the nanoparticle dispersion to create a 3% concentration solution. The resulting dispersion was sent to a spray dryer using a peristaltic pump at a rate of 5 mL / min, with continuous stirring provided by an electromagnetic stirrer at 500 rpm. The injection was performed through a 0.7 mm nozzle at a drying gas inlet temperature of 140°C. For separation and collection of the dry particles, the pulverization process was carried out at 95% aspiration.

[0151] The composition of the resulting particles was: a matrix of fucoidan with incorporated PLGA nanoparticles 100%. The particles have an average size of 4.38 pm (Fig. 1).

[0152] Example 2: System of polylactic-co-glycolic acid nanoparticles incorporated in a fucoidan matrix containing a low molecular weight water soluble drug galantamine hydrobromide

[0153] A system of PLGA nanoparticles incorporated into a fucoidan matrix containing galantamine hydrobromide is prepared using the proposed method to create a nano-in-micro architecture.

[0154] PLGA nanoparticles are prepared using the double emulsion solvent evaporation method. An aqueous solution of galantamine at a concentration of 0.5% with a volume of 4 mL was emulsified into 8 mL of PLGA solution in dichloromethane containing 1% emulsifying agent (Span 85) while stirring with a high-speed homogenizer at 21,000 rpm for 3 minutes. The primary emulsion was then dispersed into 50 mL of an external aqueous phase containing 1% Polysorbate 20 as the emulsifying agent, under high-speed homogenization at 25,000 rpm for 5 minutes to form thedouble emulsion. Stirring was continued at 800 rpm until dichloromethane had completely evaporated, resulting in a nanoparticle suspension.

[0155] Fucoidan was dissolved in the nanoparticle dispersion to create a 3% concentration solution. The resulting dispersion was sent to a spray dryer using a peristaltic pump at a rate of 5 mL / min, with continuous stirring provided by an electromagnetic stirrer at 500 rpm. The injection was performed through a 0.7 mm nozzle at a drying gas inlet temperature of 140°C. For separation and collection of the dry particles, the pulverization process was carried out at 95% aspiration.

[0156] The composition of the obtained particles was as follows: a fucoidan matrix with incorporated PLGA nanoparticles - 96.6%, and galantamine - 3.4%. The particles have an average size of 6.44 pm (Fig. 2 and Fig. 3). The release profile (Fig. 3) shows a gradual, prolonged release of the active substance overtime, confirming the system's ability to provide controlled drug release from the composite particles.

[0157] Example 3: System of polylactic-co-glycolic acid nanoparticles incorporated in a fucoidan matrix containing a low molecular weight water soluble drug doxylamine succinate

[0158] A system of PLGA nanoparticles incorporated into a fucoidan matrix containing doxylamine succinate is prepared using the proposed method to create a nano-in-micro architecture.

[0159] PLGA nanoparticles are prepared using the double emulsion solvent evaporation method. An aqueous solution of doxylamine succinate at a concentration of 0.5% in a volume of 4 mL was emulsified in 8 mL of a 0.25% solution of PLGA in dichloromethane containing 1% emulsifying agent (Span 85) under stirring with a high-speed homogenizer at 21,000 rpm for 3 minutes. The primary emulsion was then dispersed into 50 mL of an external aqueous phase containing 1% Polysorbate 20 as the emulsifying agent, under high-speed homogenization at 25,000 rpm for 5 minutes to form the double emulsion. Stirring was continued at 800 rpm until dichloromethane had completely evaporated, resulting in a nanoparticle suspension.

[0160] Fucoidan was dissolved in the nanoparticle dispersion to create a 3% concentration solution. The resulting dispersion was sent to a spray dryer using a peristaltic pump at a rate of 5 mL / min, with continuous stirring provided by an electromagnetic stirrer at 500 rpm. The injection was performed through a 0.7 mm nozzle at a drying gas inlet temperature of 140°C. For separation and collection of the dry particles, the pulverization process was carried out at 95% aspiration.

[0161] The composition of the obtained particles was as follows: fucoidan matrix with incorporated PLGA nanoparticles - 94,36 % and doxylamine succinate - 5,64 %. The particles have an averagesize of 7.04 pm (Fig. 4 and Fig. 5). The release profile of doxylamine from the composite microparticles demonstrates an extended release without a pronounced initial burst effect. This behaviour is characteristic of systems exhibiting diffusion-controlled drug release (Fig. 5).

[0162] Example 4: System of polylactic-co-glycolic acid nanoparticles incorporated in a fucoidan matrix containing a low molecular weight water-soluble drug benzidamine hydrochloride

[0163] A system of PLGA nanoparticles incorporated into a fucoidan matrix containing benzidamine hydrochloride is prepared using the proposed method to create a nano-in-micro architecture.

[0164] PLGA nanoparticles are prepared using the double emulsion solvent evaporation method. An aqueous solution of benzidamine at a concentration of 0.5 % in a volume of 4 mL was emulsified in 8 mL of a 0.25% solution of PLGA in dichloromethane containing 1% emulsifying agent (Span 85) under stirring with a high-speed homogenizer at 21,000 rpm for 3 minutes. The primary emulsion was then dispersed into 50 mL of an external aqueous phase containing 1 % Polysorbate 20 as the emulsifying agent, under high-speed homogenization at 25,000 rpm for 5 minutes to form the double emulsion. Stirring was continued at 800 rpm until dichloromethane had completely evaporated, resulting in a nanoparticle suspension.

[0165] Fucoidan was dissolved in the nanoparticle dispersion to create a 3% concentration solution. The resulting dispersion was sent to a spray dryer using a peristaltic pump at a rate of 5 mL / min, with continuous stirring provided by an electromagnetic stirrer at 500 rpm. The injection was performed through a 0.7 mm nozzle at a drying gas inlet temperature of 140°C. For separation and collection of the dry particles, the pulverization process was carried out at 95% aspiration.

[0166] The composition of the obtained particles was as follows: a matrix of fucoidan with incorporated PLGA nanoparticles -98 % and benzidamine hydrochloride -2 %. The particles have an average size of 7.21 pm (Fig. 6 and Fig. 7). As shown in Fig 7, the release of benzydamine proceeds gradually in time, with a sustained release profile consistent with a diffusion-controlled mechanism within the polymer matrix (Fig. 7).

[0167] Scope of the Invention

[0168] The subject matter disclosed herein may be embodied in various forms and should not be construed as being limited solely to the specific embodiments described. These embodiments are presented to ensure that the disclosure is thorough and complete, thereby fully conveying the scope and nature of the invention to those skilled in the relevant art. The principles andfeatures described may be applied to other variations and applications without departing from the spirit and scope of the invention.

[0169] The invention is not to be limited in scope by the specific embodiments described herein.

[0170] Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0171] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

[0172] Exemplary clauses

[0173] Clause 1: A polymeric system for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture consisting of polylactic-co-glycolic acid (PLGA) nanoparticles, incorporated in a fucoidan matrix, the PLGA content being from 1 % to 10 % and the fucoidan content from 90 % to 99 % in the form of a fucoidan matrix with 100 % PLGA nanoparticles incorporated therein, with the microparticles having an average diameter of 2 pm to 10 pm.

[0174] Clause 2: Polymeric controlled release system for low-molecular-weight water-soluble pharmaceuticals according to clause 1 , characterized in that it comprises polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the PLGA content is from 1 % to 10 %, and of fucoidan from 90% to 99% in the form of a matrix of fucoidan with PLGA nanoparticles incorporated therein from 94% to 99% and low-molecular-weight water-soluble drug substances such as galantamine, benzidamine, doxylamine from 1% to 6%, wherein the microparticles have an average diameter of 2 pm to 10 pm.

[0175] Clause 3: A method for obtaining a system with nano-in-micro architecture (PLGA nanoparticles incorporated in a fucoidan matrix), characterized in that it comprises the following steps: step 1 - dissolving PLGA in dichloromethane, at a temperature of 15 °C to 40 °C in an ultrasonic bath to obtain a solution having a volume of 5 mL to 10 mL and a concentration of 0,1 % wt / vol to 1,0 % wt / vol; step 2- adding to a lipophilic emulsifier Span 85 at a concentration of 0,5 % wt / vol to2,0 % wt / vol to the solution prepared in step 1; step 3 - obtaining a primary emulsion W / O: Purified water in a volume of 1 mL to 5 mL is emulsified in the PLGA solution in dichloromethane containing Span 85 prepared in step 2 under high-speed homogenization at a speed of 10,000 rpm to 25,000 rpm for 1 min to 5 min; step 4 - dispersing the primary emulsion obtained in step 3 in an external aqueous phase comprising Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol under high speed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form the double emulsion (W / O / W); step 5 -stirring with an electromechanical stirrer at a speed of 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymer nanoparticles is obtained; step 6 - dissolving fucoidan in the suspension obtained in step 5 and obtaining a polymer solution having a concentration of 0.25 % wt / vol to 3.5 % wt / vol; step 7 - subjecting the suspension obtained in step 6 to spray drying under the following conditions: (a) inlet temperature from 20°C to 180°C, with a suitable temperature between 140°C and 170°C; (b) gas flow rate from 400 L / h to 600 L / h; (c) solution feed rate from 4 mL / min to 10 mL / min; (d) spray membrane with orifice size of 4,0 to 7,0 pm; (e) aspiration from 15 m3 / h to 35 m3 / h.

[0176] Clause 4: A method for obtaining a system having a nano-in-micro architecture (PLGA nanoparticles incorporated in a fucoidan matrix) according to clause 3, characterized in that it comprises loading the system with low-molecular-weight water-soluble drug substances in the following sequence of steps: step 1 - dissolving PLGA in dichloromethane, at a temperature of 15 °C to 40 °C in an ultrasonic bath to produce a solution having a volume of 5 mL to 10 mL and having a concentration of 0.1% wt / vol to 1.0% wt / vol.; Step 2 -add to a Span 85 lipophilic emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol to the solution prepared in Step 1 ; Step 3 - dissolving a low-molecular-weight water-soluble drug substance in purified water at a temperature of 25 °C to 35 °C to produce a solution of 1 mL to 5 mL in volume and at a concentration of 0.1 % wt / vol to 1.0 % wt / vol; Step 4 - producing a primary emulsion W / O: The solution prepared in Step 3 was emulsified in the PLGA solution in dichloromethane containing Span 85 obtained in Step 2 under high-speed homogenization at 10,000 rpm to 25,000 rpm for 1 min to 5 min.; Step 5 - dispersing the primary emulsion obtained in Step 4 in an external aqueous phase comprising Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol under high speed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form the double emulsion (W / O / W); step 6 - stirring with an electromechanical stirrer at a speed of 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymeric nanoparticles is obtained; step 7 - dissolving fucoidan in thesuspension obtained in step 6 and obtaining a polymer solution having a concentration of 0.25% wt / vol to 3.5% wt / vol; step 8 - subjecting the suspension obtained in step 7 to spray drying under the following conditions: (a) an inlet temperature of 20°C to 180°C, wherein 140°C to 170°C is suitable; (b) a gas flow rate of 400 L / h to 600 L / h; (c) a solution feed rate of 4 mL / min to 10 mL / min; (d) spray membrane with orifice size of 4,0 to 7,0 pm; (e) an aspiration rate of 15 m3 / h to 35 m3 / h.

Claims

CLAIMS1. A polymeric system for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture comprising polylactic-co- glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.

2. The polymeric system of claim 1 , wherein the PLGA content is from 1% to 10%.

3. The polymeric system of claim 1 or 2, wherein the fucoidan content is from 90% to 99% in the form of the fucoidan matrix.

4. The polymeric system of any one of claims 1-3, wherein the microparticles have an average diameter of 2 pm to 10 pm.

5. The polymeric system according to any one of claims 1-4, further comprising a low- molecular-weight water-soluble drug substance.

6. The polymeric system of claim 5, wherein the low-molecular-weight water-soluble drugs are selected from the group consisting of: galantamine, benzidamine or doxylamine.

7. The polymeric system of claims 5 or 6, wherein PLGA nanoparticles are incorporated in the fucoidan matrix from 94% to 99% and the drug substances from 1% to 6%.

8. A method for obtaining a polymeric system for controlled release of low-molecular- weight water-soluble drug substances, characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle, the method comprising: i) generating PLGA nanoparticles by double emulsion solvent evaporation; and ii) incorporating the PLGA nanoparticles into a fucoidan microparticle by spray-drying.

9. The method of claim 8, wherein the spray drying is performed at an inlet temperature of 120°C to 180°C.

10. The method of any one of claims 8 or 9, wherein the spray drying is performed with a spray nozzle with an orifice size of 0.7 to 1.4 mm.

11. The method of any one of claims 8-10, wherein step i) comprises:a) dissolving PLGA in dichloromethane to obtain a solution having a concentration of 0.1% to 1% wt / vol;b) adding a lipophilic emulsifier to the solution of step a;c) emulsifying purified water in the solution of step b to obtain a primary emulsion; d) dispersing the primary emulsion of step c in an external aqueous phase comprising an emulsifier to obtain a double emulsion; and,e) evaporating the dichloromethane to obtain a suspension of solid polymer nanoparticles; and,wherein step ii) comprises:a) dissolving fucoidan in the suspension obtained in step e; andb) spray drying the suspension obtained in step ii,a).

12. The method of any one of claims 8-11 , wherein step i) comprises:a) dissolving PLGA in dichloromethane, at a temperature of 15 °C to 40 °C in an ultrasonic bath to obtain a solution having a volume of 5 mL to 10 mL and a concentration of 0.1% wt / vol to 1.0 % wt / vol;b) adding a lipophilic emulsifier Span 85 at a concentration of 0.5% wt / vol to 2.0% wt / vol to the solution prepared in step a);c) emulsifying purified water in a volume of 1 mL to 5 mL in the PLGA solution in dichloromethane containing Span 85 prepared in step b) under high-speed homogenization at a speed of 10,000 rpm to 25,000 rpm for 1 min to 5 min to obtain a primary emulsion (W / O);d) dispersing the primary emulsion obtained in step c) in an external aqueous phase comprising Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol under high-speed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form a double emulsion (W / O / W); ande) stirring with an electromechanical stirrer at a speed of 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymer nanoparticles is obtained; andwherein step ii) comprises:a) dissolving fucoidan in the suspension obtained in step e) to obtain a polymer solution having a concentration of 0.25 % wt / vol to 3.5 % wt / vol; andb) subjecting the suspension obtained in step ii. a) to spray drying under the following conditions: (a) inlet temperature from 120°C to 180°C, optionally between 140°C and 170°C; (b) gas flow rate from 400 L / h to 600 L / h; (c) solution feed rate from 4 mL / min to 10 mL / min; (d) spray nozzle with orifice size of 0.7 to 1.4 mm; and (e) aspiration from 15 m3 / h to 35 m3 / h.

13. The method of claims 8-12, wherein the PLGA nanoparticles comprise a low-molecular- weight water-soluble drug substance.

14. The method of claim 13, the method comprising:i) generating PLGA nanoparticles comprising a low-molecular-weight water- soluble drug substance by double emulsion solvent evaporation; andii) incorporating the PLGA nanoparticles comprising a low-molecular-weight water-soluble drug substance into a fucoidan microparticle by spray-drying.

15. The method of claim 14, wherein step i) comprises:a) dissolving PLGA in dichloromethane to obtain a solution having a concentration of 0.1 % to 1 % wt / vol ;b) adding a lipophilic emulsifier to the solution of step a;c) dissolving a low-molecular-weight water-soluble drug substance in purified water;d) emulsifying the solution of step c in the solution of step b to obtain a primary emulsion;e) dispersing the primary emulsion of step d in an external aqueous phase comprising polysorbate 20 emulsifier to obtain a double emulsion; and,f) evaporating the dichloromethane to obtain a suspension of solid polymer nanoparticles comprising a low-molecular-weight water-soluble drug substance; and, wherein step ii) comprises:a) dissolving fucoidan in the suspension obtained in step f; andb) spray drying the suspension obtained in step ii.a).

16. The method of claim 15, wherein step i) comprises:a) dissolving PLGA in dichloromethane, at a temperature of 15 °C to 40 °C in an ultrasonic bath to produce a solution having a volume of 5 mL to 10 mL and having a concentration of 0.1% wt / vol to 1.0% wt / vol;b) adding a Span 85 lipophilic emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol to the solution prepared in Step a;c) dissolving a low-molecular-weight water-soluble drug substance in purified water at a temperature of 25 °C to 35 °C to produce a solution of 1 mL to 5 mL in volume and at a concentration of 0.1 % wt / vol to 1.0 % wt / vol;d) emulsifying the solution of step c in the PLGA solution in dichloromethane containing Span 85 obtained in step b under high-speed homogenization at 10,000 rpm to 25,000 rpm for 1 min to 5 min to obtain a primary emulsion;e) dispersing the primary emulsion obtained in step d in an external aqueous phase comprising Polysorbate 20 emulsifier at a concentration of 0.5% wt / vol to 2.0% wt / vol under high-speed homogenization at a speed of 20,000 rpm to 35,000 rpm for 1 min to 5 min to form the double emulsion; andf) stirring with an electromechanical stirrer at a speed of 600 rpm to 1000 rpm until the dichloromethane is completely evaporated and a suspension of solid polymeric nanoparticles comprising a low-molecular-weight water-soluble drug substance is obtained; and,wherein step ii) comprisesa) dissolving fucoidan in the suspension obtained in step f and obtaining a polymer solution having a concentration of 0.25% wt / vol to 3.5% wt / vol; andb) subjecting the suspension obtained in step ii.a) to spray drying under the following conditions: (a) an inlet temperature of 120°C to 180°C, optionally 140°C to 170°C; (b) a gas flow rate of 400 L / h to 600 L / h; (c) a solution feed rate of 4 mL / min to 10 mL / min; (d) spray nozzle with orifice size of 0.7 to 1.4 mm; (e) an aspiration rate of 15 m3 / h to 35 m3 / h.

17. A polymeric system obtained by the method according to any one of claims 8-16.

18. The polymeric system according to one of claims 1-7 for use in medicine.

19. The polymeric system according to claim 17 for use in medicine.

20. A method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the polymeric system according to any one of claims 1-7.

21. A method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the polymeric system according to claim 17.

22. A kit for preparing microparticles for controlled release of low-molecular-weight water- soluble drug substances characterized by a nano-in-micro comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.

23. Use of the kit according to claim 22 for the generation of a polymeric system for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.

24. Use of PLGA and fucoidan in preparing a polymeric system for controlled release of low-molecular-weight water-soluble drug substances characterized by a nano-in-micro architecture comprising polylactic-co-glycolic acid (PLGA) nanoparticles incorporated in a fucoidan matrix, wherein the fucoidan matrix forms a microparticle.

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