Mucoadhesive polymers for nasal drug delivery

Abstract

The present invention relates generally to mucosal protective agents, and in particular to agents acting on the nasal mucosa. To that end, the present invention provides a series of mucoadhesive polymer compositions and methods that can be used as such as blocking agents against a wide range of microbial pathogens and allergens, or as an elegant drug delivery system for active agents across the oral and / or nasal mucosa.

Description

[Technical field]

[0001] The present invention relates generally to mucoadhesive polymers, specifically hydrophilic biopolymers and naturally occurring hydrophilic polysaccharides that have mucoadhesive affinity for a variety of mucosal tissues. [Background technology]

[0002] The emergence of innovative drug delivery systems along with the implementation of non-invasive and painless administration routes will transform the pharmaceutical industry and the treatment of diseases. Drug delivery systems that can be administered through mucosa have attracted increasing interest due to the options to overcome the major limitations of oral administration, such as first-pass metabolism, P-glycoprotein efflux, and to provide high patient compliance. Furthermore, mucosal layers are ubiquitous in many organs and have relatively high substance permeability. Therefore, creating new drug delivery systems and formulations targeting mucosa, particularly mucoadhesive forms with longer administration times and increased local and systemic bioavailability of active substances, has become one of the main focuses of pharmaceutical companies' research and development departments.

[0003] Particular examples are the mucous membranes of the pharynx and nose, both of which act as very important portals of entry for pathogens such as allergens, viruses and bacteria, and also as a source of pathogen dissemination. For example, in the COVID-19 (Coronavirus Disease 2019) pandemic, a considerable body of evidence indicates that SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) titers in the pharynx and nose are very high and 1 , the receptor responsible for SARS-CoV-2 entry, hACE2 receptor in oral and nasal tissue mucosa 2 The expression in is similar.

[0004] One feature of the COVID-19 pandemic is manifested in the rapid spread of SARS-CoV in immunologically naive human populations worldwide, mainly by droplet and contact transmission. Another feature is that the clinical manifestations of COVID-19 show a wide range of symptom severity, with a higher case fatality rate in the elderly, immunocompromised patients and those with certain comorbid conditions, and, on the other hand, a significant proportion of individuals with asymptomatic or subclinical disease. This latter is estimated to account for 44% of infections worldwide.

[0005] Furthermore, with regard to viral load in the nose and mouth or nasopharynx, symptomatic and asymptomatic individuals appear to be similar in that both contain the highest viral loads in the body sites. In addition, it has been shown that in symptomatic individuals, transmission via nasal and oral secretions is highest before or immediately after the onset of symptoms. Thus, asymptomatic and early symptomatic COVID-19 individuals are in fact "silent spreaders" that unknowingly contribute to the exponential spread of the disease.

[0006] Therefore, in addition to traditional mitigation strategies such as vaccination, social distancing, testing, and travel restrictions to prevent viral transmission and infection, if any, other approaches should use drugs that block or weaken viral entry via the nasal and oral openings or that can reduce the viral load in the nasal and oral cavities. This type of strategy may be equally applicable at the individual and population level and may be particularly relevant for populations and subpopulations that cannot tolerate vaccination or when vaccination is not available. It remains ever more relevant given the continuous emergence of new SARS-CoV-2 variants (alpha, beta, delta, omicron, etc.) and the resulting uncertainties regarding the efficacy of existing vaccines.

[0007] From a broad perspective, the oral and nasal mucosa constitute the structural and functional interface between the outside and inside of the human body, acting as the first barrier against the continuous flow of inhaled pathogens, allergens, and other substances. An important structural component of the epithelial barrier that plays a crucial role in maintaining its functionality is the so-called tight junction (TJ), a cell-cell junction complex located on the apical side of the epithelial cells. There is an increasing body of evidence showing that dysfunction of the oral and nasal mucosal barrier, and in particular dysfunction of TJ, underlies many allergic diseases, such as asthma, atopic dermatitis, and nasal allergy, as well as reactions to allergens and environmental pollutants. All this leads to the idea that drugs or methods that protect and maintain the functionality of the epithelial barrier may be advantageous in preventing or attenuating these conditions.

[0008] Considering two drug delivery routes, nasal and oral drug delivery, nasal delivery route has some obvious advantages.As mentioned, nasal delivery allows avoidance of liver first-pass metabolism.The nasal cavity has a relatively large surface area, and the epithelium and submucosa of the nasal cavity are characterized by high vascularization and high substance permeability, all of which promote rapid drug absorption.In addition, nasal delivery provides a convenient option for self-medication.

[0009] Mucoadhesive polymers, especially hydrophilic biopolymers and polysaccharides from natural sources, have attracted more and more attention as vehicles and active substances for oral and nasal drug delivery. One example is carrageenan, a natural sulfated polysaccharide extracted from red algae, which has been associated with antiviral properties. At the same time, carrageenan itself has been found to be highly inflammatory and has been found to perform poorly in terms of spray coverage and mucoadhesion. To overcome these problems, carrageenan is usually used in mixtures with other biocompatible polysaccharides, such as gellan gum. 3 Another algal polysaccharide is alginate, and in certain instances mucoadhesive drug delivery systems use it as a carrier for conventional drugs. 4Certain hybrid mucoadhesive delivery systems using polymers in conjunction with drug-loaded lipid nanoparticles to adapt the system to individualized dosing are described in US201922411 and WO19246384.

[0010] Overall, despite the obvious advantages of mucoadhesive polymers, some concerns still exist about the toxicity of the polymers, even biocompatible mucoadhesive polymers, as well as the mucoadhesive, spreading, and coating properties of the polymers. From a broader perspective, there is an unmet need to find solutions for effective and safe systemic drug delivery, specifically the delivery of drugs related to restoring and maintaining the functionality and integrity of the oral and nasal epithelial mucosal barrier. Conditions such as the COVID-19 pandemic and damage from allergies and air pollution ultimately reinforce the need to provide such solutions.

[0011] References 1.Zou L et al.SARS-CoV-2 viral load in upper respiratory specimens of infected patients.N.Engl.J.Med.382(12),1177-1179(2020). 2.Hamming I et al.Tissue distribution of ACE2 protein,the functional receptor for SARS coronavirus.A first step in understanding SARS pathogenesis.J.Pathol.203(2),631-637(2004). 3.Robinson TE et al.Low acyl gellan as an excipient to improve the sprayability and mucoadhesion of iota carrageenan in a nasal spray to prevent infection with SARS-COV-2.Front.Med.Tech.3, article 687681(2021). 4.Patil SB and Sawant KK.Development, optimization and in vitro evaluation of alginate mucoadhesive microspheres of carvedilol for nasal delivery.J.Microencapsul.26(5):432-443(2009). Summary of the Invention

[0012] The epithelial barrier is the first line of defense against exposure to harmful pathogens, allergens, and other foreign particles. The integrity of epithelial tissue or epithelial mucosa plays a crucial role in both innate and adaptive mucosal immunity. Epithelial cells are responsible for the activation of functional molecules that impede pathogen invasion (e.g., proinflammatory cytokines, growth factors, and chemokines) as well as antimicrobial substances and peptides (AMPs, e.g., lysozyme, defensins, lactoferrin, S-100 proteins). Mucociliary clearance is responsible for trapping microorganisms and particles in the mucus secreted by glandular and ciliated cells in the oral and nasal cavities. Alterations in the homeostasis of any of these systems play a key role in inflammatory and infectious diseases in the upper respiratory tract.

[0013] The nasal epithelial barrier is further characterized by the apical junctional complex (AJC) that allows interconnections between epithelial cells (TJs, adherens junctions, desmosomes, hemidesmosomes). TJ disorders are a major contributor to the pathogenesis of, for example, allergic rhinitis (AR), a common disorder that affects up to 40% of the world's population and persists throughout life. Further examples are asthma, atopic dermatitis, nasal allergies, and reactions to allergens and environmental pollutants.

[0014] In COVID-19 infection, the virus mainly enters through the nasal cavity, where it multiplies and destroys the cells of the nasal mucosa, thereby allowing systemic spread of the virus and triggering of local and systemic inflammatory processes. When symptoms appear, the pathophysiology of the disease is already established. And if infection and inflammation persist, this can result in secondary end-stage disease, including respiratory failure, systemic shock, and potentially multiple organ failure.

[0015] Therefore, to effectively address infections, allergies and disorders of the upper respiratory tract, more direct approaches, if any, should be taken to prevent or hinder the causative pathogens from contacting or entering the nasal or oral cavity, thereby minimizing the risk of subsequent infection or allergic reactions. For viruses, and especially for COVID-19, a key objective is to minimize the viral load in the nasal cavity to prevent transmission of the virus to other individuals and its spread in the population.

[0016] Mucoadhesives, by themselves or in combination with antiviral, anti-inflammatory or anti-allergic drugs, are attractive candidates for such preventive approaches offering a convenient and economical method of protection against pathogens and allergens that can be easily applied at individual and population level.

[0017] Within this framework, the present invention provides a particularly advantageous biocompatible mucoadhesive composition, which when applied to cells or mucosal surfaces, transforms into a continuous, durable, non-toxic thin film capable of acting as an effective protective barrier against a variety of pathogens, allergens and air pollutants. The relevance and efficacy of this protection has been demonstrated by a series of experiments in various viral infection and allergen exposure models.

[0018] In other words, the composition of the present invention itself has been shown to be an effective and safe mucosal protectant for two highly prevalent conditions, viral load and allergen exposure, without the addition of any active substances.More generally, due to the convenience, biocompatibility and ability to incorporate additional therapeutic active substances of the composition, the composition can provide a safe and straightforward solution to prevent both pathogen transmission and overexposure to harmful pollutants at the individual and population levels.

[0019] More specifically, the present invention provides a composition comprising a combination of a sulfated polysaccharide and a hydrophobic or hydrophilic polymer partially crosslinked by a divalent cation. It has been demonstrated herein that certain compositions consisting of this component have unique and surprising physical properties of improved gel / liquid consistency, rheological behavior and deformability into thin films, and further surprising biological properties of effective mucoadhesion, mucoprotection and general lack of toxicity.

[0020] Starting with physical properties, the compositions of the present invention have been shown to have a substantially constant viscosity at room temperature (RT) in terms of viscosity measured by a viscometer, and a rheological behavior under shear force.The viscosity of these compositions is also lower (up to 20%) than the viscosity of similar solutions that contain the same concentration of polymer but are not partially crosslinked.The rheological behavior (or viscosity behavior) of these compositions under various shear forces is also surprisingly constant, and is substantially more constant (<25% deviation) than the behavior of similar non-crosslinked solutions measured under the same conditions (Example 5).

[0021] These two core physical properties, low and constant viscosity and relative resistance to various shear forces at RT, account for the major structural advantages of the compositions of the present invention - improved gel / liquid consistency or spreadability / sprayability when present alone, and the ability or deformability of the compositions to transform into a continuous and durable thin film when in contact with a cell surface.

[0022] The integrity, durability and protective properties of the film were demonstrated in a series of experiments in various in vitro viral infection and allergen exposure models. Due to their film-forming ability, the compositions of the present invention proved to be highly effective mucosal protectants against various types of viruses, including several types of coronaviruses and influenza viruses (Examples 2-3). These compositions were also found to be effective against a relatively wide range of aeroallergens, including many common determinants of allergic reactions and allergen-associated inflammation. In relation to allergen exposure, the protective effect of the compositions was also substantially more pronounced and synergistic compared to other tested compositions (non-crosslinked solutions and single polymer compositions) (Example 4). Moreover, the compositions were also demonstrated to be non-toxic over a wide range of pharmacologic applicable concentrations (Example 1).

[0023] All these properties make the compositions of the invention particularly suitable for topical and mucosal administration, and in particular for application onto the oral and / or nasal mucosa.

[0024] More generally, the invention forms the basis of two types of products. (1) OTC products in which the composition is used by itself or in combination with an OTC-approved active agent (e.g., xylometazoline, ibuprofen, decongestants, etc.) to provide a safe and effective coating of mucosal tissues (e.g., oral and / or nasal mucosa) against exposure to pathogens, allergens, and other airborne fomites. (2) Prescription-based drugs and methods for using the compositions in combination with conventional drugs to treat existing infections and / or inflammation, and, in the case of viruses, to reduce transmission to other hosts.

[0025] Both types of products can be provided in a variety of conventional forms, for example as sprays for inhalation or microparticles for oral or nasal application.

[0026] The advantages of these compositions stem from the biocompatibility and availability of the core components, sulfated polysaccharides, hydrophobic and hydrophilic polymers, and divalent cations. A variety of such polymers are available from natural sources, plants, animals, and microorganisms. Notable examples are sulfated polysaccharides produced by various types of marine algae, such as galactans, ulvans, fucans, and fucoidans, with particular examples being agaran and carrageenan, galactans. Examples of biocompatible hydrophilic polymers are dextran, alginate, chitosan, agarose, pullulan polysaccharides, and albumin, gelatin, collagen, and lectin proteins, all of which are available from natural sources. An example of a crosslinking divalent cation is Ba. 2+ , Ca 2+ , Co 2+ , Cu 2+ , Fe 2+ , Mg 2+ and Zn 2+ It is.

[0027] More specific examples include carrageenan and Ca at concentrations of about 0.005% to 1%, about 0.1% to 3%, and about 0.0001% to 1% (w / w), respectively. 2+ A composition comprising a combination of alginic acid partially crosslinked with

[0028] The composition may further comprise buffers, excipients, preservatives, flavors and odorants so as to be compatible and optimally adapted for administration by spray coating or by inhalation via the oral and / or nasal routes.

[0029] As a pharmaceutical composition, the composition may further incorporate conventional therapeutically active substances according to the specific clinical indication. Attractive candidates may be drugs for treating a group of widespread subclinical and clinical conditions commonly referred to as oral, nasal or upper airway mucosal barrier dysfunction.

[0030] In a broad sense, the present invention applies to any condition associated with an alteration in the homeostasis of epithelia or mucosal barriers or a loss of the integrity and functionality of epithelia or mucosal barriers. The present invention further applies to conditions associated with disturbances in the physical continuity, cellular structure, functionality of mediators of innate and adaptive immunity, and other features of the epithelial environment. Particular examples of such conditions are microbial (viral and / or bacterial) infections, and aeroallergen-induced allergies and inflammation, for which the compositions of the present invention, alone or in combination with other antiviral, antibiotic and / or anti-inflammatory agents, can provide effective and safe protection.

[0031] In yet another aspect, the composition of the present invention provides a new drug delivery system for introducing systemic drugs via administration onto various mucosal tissues. To date, the most common routes of systemic drug administration are oral, enteral, or parenteral, each of which has certain advantages and disadvantages. The present invention provides an alternative route of drug administration by mucoadhesion and permeation through various mucosal tissues, including urogenital, rectal, oral and nasal mucosa, pulmonary and other mucosa.

[0032] This embodiment may further include additional technologies that allow for targeted and / or controlled release of active agents to either the epithelium or the systemic environment, including micronization and nanoparticle and encapsulation technologies to improve drug safety and efficacy.

[0033] The approach proposed in the present invention can be particularly useful for the formulation of highly lipophilic active substances. Approximately 60%-70% of known drugs, and even a high percentage of current drug candidates, are highly lipophilic. Lipophilic active substances generally suffer from low oral bioavailability, poor gastrointestinal (GI) permeability and absorption, GI efflux and first-pass hepatic metabolism. Epithelial mucosa, especially oral and nasal mucosa, are naturally rich in vascularization and have relatively high permeability independent of hepatic first-pass metabolism. Thus, lipophilic drugs using these routes are likely to have better drug bioavailability and absorption. Solubility and bioavailability can be further improved by incorporating certain permeation enhancers, solubilizers, emulsifiers and surfactants into the compositions of the present invention.

[0034] In other words, the compositions of the present invention may have better drug retention properties due to their superior mucoadhesive, covering and protective properties, and as a result, improved absorption and assimilation of the drug into mucosal tissues, which can be further enhanced by additional formulation, nanoparticle and encapsulation techniques, and the use of patches or thin films for local and systemic drug delivery.

[0035] An interesting application in relation to local or systemic delivery can be the oral and / or nasal delivery of vaccines, including antiviral vaccines and vaccines for other disorders. Being relatively non-invasive and "needle-free", such vaccines can be easily incorporated into a variety of individual and population-based prevention strategies.

[0036] Yet another interesting application of the compositions of the present invention is in tissue regeneration and the bioengineering of tissue grafts. Due to the biocompatibility and physical, chemical and other properties of the compositions, these compositions can act as universal "all-purpose" materials in the form of matrices and / or injectable hydrogels to provide physical support for tissue and organ regeneration and to aid cell assembly at specific sites. The flexibility of the compositions of the present invention to incorporate additional materials, active substances and drugs makes them particularly attractive candidates for this application.

[0037] For example, matrices / gels made from these compositions can further include active substances, drugs, growth factors, hormones, enzymes, nucleic acids, and other agents that provide morphological and biochemical instructions for specific cell population, proliferation, and functionality. Depending on the required indication, the matrices / gels can further include encapsulated cells of various types and origins. A particular example is stem cells of various types that, upon appropriate trigger, can cause the cells to populate, proliferate, and / or differentiate at a specific application site.

[0038] In the context of nerve or heart, the composition of the present invention can assist in the structural and functional recovery of damaged tissues by delivering mechanical and functional support to change cell fate in favor of nerve or heart regeneration and repair infarcted heart, injured spinal cord or neurodegenerated brain tissue. When viewed as a tool for nerve repair or regeneration, the composition of the present invention can be combined with an auxiliary device and incorporated into neurological surgical procedures.

[0039] Finally, the present invention provides a wide range of products, methods and uses based on biocompatible mucoadhesive compositions in the form of sprays, gels, matrices or thin films for use independently or in combination with other drugs or delivery devices as mucosal protective antiviral and / or anti-inflammatory agents, agents supporting tissue regeneration and repair, and local and systemic drug delivery. [Brief description of the drawings]

[0040] In order to better understand the subject matter and to demonstrate how it may be carried out in practice, embodiments will now be described by way of non-limiting examples with reference to the following drawings, in which: [Figure 1]Figures 1A-1D show the lack of cytotoxicity (safety) of the compositions of the present invention by comparing the effects of compositions containing alginate / carrageenan combinations in non-crosslinked (#16) and partially crosslinked forms (#21, #26 at 1.47% and 0.02% CaCl2, respectively) with an untreated control (UT) in MRC-5 (A), MDCK (B), A549 (C) and Vero (D) cells. No cytotoxicity was observed in any of the models tested. [Diagram 2] 2A-2B show the antiviral mucosal protective effects of compositions of the invention in an in vitro human coronavirus (229E) model comparing compositions (A) and (B) containing single polymers (#4 alginate, #5 carrageenan) and uncrosslinked (#15, #16 with 0.12% and 0.24% carrageenan, respectively) and partially crosslinked (#25, #26 with 0.12% and 0.24% carrageenan, respectively) forms and partially crosslinked alginate (#27) (B) versus untreated cells and cells exposed to virus (UT+virus). Compositions containing partially crosslinked polymers were significantly more effective against 229E than compositions containing single and non-crosslinked polymers. [Diagram 3] Figure 3 shows the antiviral mucosal protective effect of compositions containing non-crosslinked (#16) and partially crosslinked (#26) polymers at various concentrations (x1, x0.8, x0.6, x0.4, x0.2) against another coronavirus SARS-CoV-2 (Omicron variant, B.1.1.529.BA.1) comparing the effect of compositions containing non-crosslinked (#16) and partially crosslinked (#26) polymers at various concentrations (x1, x0.8, x0.6, x0.4, x0.2) versus UT and UT + virus controls. Compositions containing partially crosslinked polymers were more effective against SARS-CoV-2, including those with a low concentration of polymer (x0.2). [Figure 4]Figures 4A-4B show the antiviral mucosal protective efficacy of compositions against human influenza virus (H1N1) comparing the efficacy of compositions (A) and (B) containing single non-crosslinked polymers (#4, #5) and a composition (B) containing combinations of non-crosslinked (#15, #16) and partially crosslinked (#25, #26) polymers and partially crosslinked alginate (#27) versus UT and UT+virus controls. Compositions containing partially crosslinked polymers were found to be equally effective against H1N1 and more effective than non-crosslinked and other components. [Diagram 5] Figure 5 shows the effect of cross-linking degree in the same H1N1 model, comparing the effect of compositions containing alginate-carrageenan polymers with various cross-linking degrees (0.0.2%, 0.01%, 0.005%, 0.001%, 0.0001% CaCl2 #26) and non-cross-linked polymer (#16) versus UT and UT + virus controls. Compositions containing combinations of polymers with cross-linking with CaCl2 in the range of 0.005% to 0.02% had the highest antiviral mucosal protective effect (>90% cell viability), and were more effective than the non-cross-linked composition even in the range of 0.0001% to 0.02%. [Figure 6] Figure 6 shows the anti-inflammatory mucoprotective effect of compositions in an in vitro allergen challenge model using house dust mite Der p1 allergen and IL-8 markers, comparing the effect of compositions containing two concentrations (x1, x0.5) of single polymers (#3 iota carrageenan, #4 alginate, #5 carrageenan) and non-crosslinked (#15, #16) and partially crosslinked (#25, #26) alginate / carrageenan vs. UT and UT+virus controls. In this model, compositions containing partially crosslinked polymer combinations showed synergistic effects compared to non-crosslinked and single polymer compositions. [Figure 7] Figures 7A-7B show the anti-inflammatory mucoprotective effect against the additional allergens dust mite allergen Der f1 and pollen allergen Phl p1, comparing the effect of compositions containing non-crosslinked (#16) and partially crosslinked (#26) polymers versus UT and UT + virus controls. Again in this model, compositions containing the partially crosslinked polymer combinations were more effective. [Figure 8] Figure 8 shows the same effect of Car b1 using the same experimental model and different concentrations of another pollen allergen Car b1 (60 μg / ml, 30 μg / ml, 15 μg / ml). In all test groups, the effect was consistent with a classical dose-response, with the composition containing the partially crosslinked polymer showing the highest anti-inflammatory mucoprotective effect (lowest IL-8). [Figure 9] 9 compares the long-term (21 day) viscosity (at 25° C.) of compositions containing non-crosslinked (#16) and partially crosslinked (#26) polymers, demonstrating one of the distinguishing properties of the compositions of the present invention, as evidenced by their low viscosity and persistence at RT. While both types of compositions had relatively constant viscosity at RT over the test period, the partially crosslinked composition had a lower viscosity and better sprayability, coverage, and spreadability, suggesting its convertibility into a uniform, continuous thin film. [Figure 10] Figure 10 shows the characteristics of sustained or constant viscosity under various shear forces, comparing the viscosity of compositions containing single polymers (#4 alginate, #5 carrageenan) and combinations of non-crosslinked (#15) and partially crosslinked (#25, #26) polymers and partially crosslinked alginate (#27) at various shear rates (0.1, 1 and 10 s-1). The viscosity of the compositions containing partially crosslinked polymers was resistant to shear forces, indicating the deformability of the compositions into uniform and durable thin films at room temperature. [Figure 11] FIG. 11 is a schematic diagram of an additional embodiment of a composition including an optional polymer, a crosslinker, and a preservative. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] It should be noted that the present invention is not limited to the particular methodologies and experimental conditions described herein, and the terminology used herein is for illustrative purposes only and is not intended to be limiting.

[0042] In its broadest sense, the present invention provides compositions comprising a composite material comprising one or more sulfated polysaccharide polymers and one or more hydrophobic or hydrophilic polymers or copolymers partially crosslinked by one or more positively charged ions.

[0043] The term "sulfated polysaccharide polymer" is used broadly herein to refer to a class of compounds generally characterized by long chains of negatively charged monosaccharides cross-linked by glycosidic bonds, bearing one or more sulfate groups. The term, as used herein, encompasses monomers and heteromers, as well as linear and branched forms. The term further encompasses natural, synthetic and semi-synthetic sulfated polysaccharides, as well as any artificial modification of a natural polysaccharide, including sulfation (including sulfurylation).

[0044] The term "hydrophobic / hydrophilic polymer" is used broadly herein to refer to any type of charged and uncharged polymer, water-soluble and water-insoluble polymer, and hydrophobic polymers associated or conjugated with surfactants and other amphiphiles. The term further encompasses natural, synthetic and semi-synthetic hydrophilic and hydrophobic polymers, as well as manmade modifications of natural polymers.

[0045] The term "copolymer" refers to a combined polymer made from two or more different polymers.

[0046] The term "crosslinked / partially crosslinked" is used broadly herein to refer to any type of non-covalent bond between a sulfated polysaccharide polymer and a hydrophobic or hydrophilic polymer or copolymer.

[0047] In some embodiments, the sulfated polysaccharide polymer and the hydrophobic or hydrophilic polymer or copolymer are crosslinked or partially crosslinked by ionic bonds. The extent or degree of crosslinking, the number of groups interconnecting the two polymers, or the density of the crosslinking can vary.

[0048] The degree of crosslinking (DC) is generally expressed by the proportion of crosslinking groups in a polymer composite (mole percent or mole fraction). A high DC means more bonds per polymer length (or a higher density of gel components); for example, fluids have a DC close to zero, elastomers have a low DC, and resins have a high DC.

[0049] The compositions of the present invention may be in semi-solid form, such as liquids, semi-fluids, gels, resins, etc. In some embodiments, the compositions may be in solid form.

[0050] In some embodiments, the sulfated polysaccharide polymers and hydrophobic or hydrophilic polymers or copolymers may be crosslinked or partially crosslinked with one or more positively charged ions with DC values ​​within the range of at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% mole percent.

[0051] The term "positively charged ion" as used herein broadly refers to any ion, atom, or group of atoms that has one or more positive charges (also cations). This term is used herein to refer to Na + , K + , Ca 2+ , Mg 2+ , Cu 2+ , Zn 2+ And Fe 2+ and Fe 3+ Metal ions such as monovalent, divalent, trivalent and polyvalent ions or NH4 + and H3O + This includes polyatomic ions such as:

[0052] In some embodiments, the sulfated polymer and the hydrophobic or hydrophilic polymer can be partially crosslinked with at least one divalent cation.

[0053] In a further embodiment, the divalent cation is Ba 2+ , B.E. 2+ , Ca 2+ , Co2+ , Mg 2+ , Cu 2+ , Ni 2+ , Fe 2+ and / or Zn 2+ can be selected from:

[0054] In some embodiments, the bridging cation is Ca 2+ It is.

[0055] One of the important features of the compositions of the present invention is that they have a substantially constant viscosity at room temperature.The term "substantially constant viscosity" means herein that the viscosity or rheological behavior of these compositions remains relatively unchanged / stable or constant within a deviation of less than 25% or up to 25%, or more specifically, less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, measured by various methods (e.g., viscometer, rheometer) and under various conditions (e.g., shear force, time).

[0056] Viscosity is measured in newton seconds per square meter, pascals per second, or SI units (SI(μ) = pascals per second (Pa*s -1 )=1kgm ‐1 s ‐1 ) can be expressed as

[0057] In some embodiments, the term "viscosity" as used herein refers to the viscosity measured by a viscometer.

[0058] In some embodiments, the term "viscosity" as used herein means rheological behavior and refers to the viscosity under various shear forces (and shear rates) as measured by a rheometer.

[0059] Thus, in some embodiments, the viscosity of the compositions of the present invention is about 1 mPa*s as measured by a viscometer. -1~about 50mPa*s -1 in the range of, more specifically, about 1 to 5 mPa*s -1 , about 5~10mPa*s -1 , about 10~15mPa*s -1 , about 15~20mPa*s -1 , about 20~25mPa*s -1 , about 25~30mPa*s -1 , about 30~35mPa*s -1 , about 35~40mPa*s -1 , about 40~45mPa*s -1 , about 45~50mPa*s -1 or any other range derived above, of a substantially constant viscosity at room temperature.

[0060] In some embodiments, the viscosity is about 1 to 50 mPa*s -1 , about 5~45mPa*s -1 , about 10~40mPa*s -1 , about 15~35mPa*s -1 , about 20~30mPa*s -1 may be in the range.

[0061] In some embodiments, the viscosity is about 1 to 50 mPa*s -1 , about 1~45mPa*s -1 , about 1~40mPa*s -1 , about 1~35mPa*s -1 , about 1~30mPa*s -1 , about 1~25mPa*s -1 , about 1~20mPa*s -1 , about 1~15mPa*s -1 , about 1~10mPa*s -1 , about 1~5mPa*s -1 may be in the range.

[0062] The viscosity depends on the concentration and / or degree of cross-linking of the polymeric components (sulfated polysaccharides and hydrophobic or hydrophilic polymers) and the cross-linking agents (positively charged ions).

[0063] One of the salient features of the compositions of the present invention is that the viscosity as measured by a viscometer remains substantially constant within the above ranges for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 days.

[0064] Another distinguishing feature is that the viscosity, as measured by a viscometer, of the compositions of the present invention is less than the viscosity of a similar solution of the same combination and concentration of polymers but without the positively charged ions or without crosslinking.

[0065] In some embodiments, the viscosity may be up to 20% lower than the viscosity of a solution containing the same concentrations of the same polymers but without the positively charged ions, or may be up to 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% lower than the viscosity of a solution containing the same combination of the same polymers but without the positively charged ions, when measured under the same conditions.

[0066] In other words, crosslinking or partial crosslinking confers a lower viscosity or more liquid, liquefied state to the composition, which is counterintuitive and surprising, and is a characteristic of the composition when present alone, prior to contact with a cell or mucosal surface. This structural feature may have significant advantages with respect to ease of application, spreadability, and sprayability of the compositions of the invention, particularly in the context of topical application or application onto the oral and / or nasal mucosa.

[0067] Yet another distinguishing feature of the compositions of the present invention is that, upon contact with cells or mucosal surfaces, the compositions are transformable (deformable) into a thin film that has surprising continuity, durability and integrity, as well as the ability to provide adequate and uniform coverage. This structural feature of transformability into a thin film is a characteristic of the compositions after contact with cells or mucosal surfaces, and is essentially responsible for the mucoadhesive and mucoprotective biological benefits of these compositions.

[0068] Thus, in some embodiments, the composition may be in a liquid, semi-fluid, or sprayable form prior to contacting the cell or mucosal surface.

[0069] In some embodiments, the composition may be in a liquid, semi-fluid, or sprayable form prior to contacting the cell or mucosal surface.

[0070] In some embodiments, the composition is capable or capable of transforming into a uniform and continuous film upon contact with a cell or mucosal surface.

[0071] In some embodiments, the cell or mucosal surface can be an epithelial mucosa. The term "epithelial mucosa," as used herein, encompasses the oral and nasal mucosa, and further encompasses the mucosal linings of the eyelids, cornea, trachea, lungs, stomach and intestines, ureters, urethra, and bladder, reproductive tract, and anal canal.

[0072] Thus, in some embodiments, the composition is capable of transforming into a uniform and continuous thin film upon contact with the oral and / or nasal mucosa.

[0073] The film-forming ability of the compositions of the present invention is rooted in the unique rheological behavior of the compositions, manifested by a substantially constant viscosity under varying shear forces as measured with a rheometer.

[0074] In some embodiments, the viscosity is about 0.1 s -1 ~about 10s -1 Approximately 100 mPa*s at shear rates in the range -1 ~about 800mPa*s -1 in the range of, more specifically, up to 0.1s -1 , 1s -1 , or 10s -1 At a shear rate of about 100 to 200 mPa*s -1 , about 200~300mPa*s -1 , about 300~400mPa*s -1 , about 400~500mPa*s -1 , about 500~600mPa*s -1 , about 600~700mPa*s-1 , about 700~800mPa*s -1 or any other range derivable above.

[0075] In some embodiments, the viscosity is up to 0.1 s -1 , 1s -1 , or 10s -1 Approximately 100 to 800 mPa*s at a shear rate of -1 , about 150~750mPa*s -1 , about 200~700mPa*s -1 , about 250~650mPa*s -1 , about 300~600mPa*s -1 , about 350~550mPa*s -1 , about 400~500mPa*s -1 may be in the range.

[0076] In some embodiments, the viscosity is up to 0.1 s -1 , 1s -1 , or 10s -1 Approximately 100 to 800 mPa*s at a shear rate of -1 , about 100~750mPa*s -1 , about 100~700mPa*s -1 , about 100~650mPa*s -1 , about 100~600mPa*s -1 , about 100~550mPa*s -1 , about 100~500mPa*s -1 , about 100~450mPa*s -1 , about 100~400mPa*s -1 , about 100~350mPa*s -1 , about 100~300mPa*s -1 , about 100~200mPa*s -1 may be in the range.

[0077] In some embodiments, the viscosity is from about 0.1 to about 10 s -1Maximum deviation of 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less at shear rates in the range of 0.1 s -1 , 1s -1 , or 10s -1 The deviation may be in the range of about 1% to 25%, about 1% to 20%, about 1% to 15%, about 1% to 10%, or about 1% to 5% at the shear rate.

[0078] This feature makes the compositions of the present invention essentially different from similar non-crosslinked solutions containing the same combinations and concentrations of polymers, which exhibit significant variations in viscosity under the same conditions, and compositions containing a single polymer, which have completely different rheological behavior.

[0079] As has been mentioned, in some embodiments, the compositions of the present invention can be provided as liquid and semi-liquid formulations and sprays, which may be particularly useful for topical application and application onto the oral and nasal mucosa.

[0080] In some embodiments, the formulation may comprise microparticles or nanoparticles or droplets. Compositions of this type may be useful for application by inhalation and assisted by inhalation devices.

[0081] In some embodiments, the droplets or particles can have a size in the range of more than 1 μm or in the range of about 1-10 μm, about 10-20 μm, about 20-30 μm, about 30-40 μm, about 40-50 μm, about 50-60 μm, about 60-70 μm, about 70-80 μm, about 90-100 μm, or in the range of less than 1 μm or in the range of about 1-100 nm, about 100-200 nm, about 200-300 nm, about 300-400 nm, about 400-500 nm, about 500-600 nm, about 600-700 nm, about 700-800 nm, about 800-900 nm, about 900-1000 nm.

[0082] In some embodiments, the droplets or particles offer the additional features of increased surface area, drug loading and porosity, which can encapsulate various types of active agents to facilitate local and / or systemic delivery and absorption of these active agents.

[0083] In some embodiments, the compositions can be provided in solid or semi-solid films or resins. Compositions of this type may be useful for local or topical application for localized or systemic drug delivery.

[0084] All these properties make the compositions of the present invention highly adaptable to various formulation techniques and drug delivery systems, either by themselves or in combination with other active substances or drugs to achieve additional therapeutic value.Non-limiting examples of such formulations are gels / sprays and inhalants for oral and / or nasal application, mucoadhesive films and resins for application onto mucosal tissues, adhesive films and resins for localized topical or surgical application.

[0085] With respect to the polymers, in many embodiments, the sulfated polysaccharide polymers and hydrophobic or hydrophilic polymers included in the compositions of the present invention may be characterized as biocompatible polymers. The term "biocompatible" broadly refers to any material that is non-harmful to living tissue.

[0086] In some embodiments, the polymer may be a natural polymer, modified natural polymer or synthetic polymer obtained from plants, animals and various microorganisms, or any combination thereof. Examples are sulfated polysaccharides obtained from algae or marine invertebrates (e.g., carrageenan, fucan), and glycosaminoglycans obtained from animals (e.g., heparin), plant polysaccharides (e.g., starch, cellulose, pectin), and polysaccharides from other sources such as bacteria (e.g., dextrans) and the exoskeletons of arthropods and cell walls of fungi (e.g., chitin).

[0087] In some embodiments, the at least one sulfated polysaccharide polymer may be selected from natural or modified sulfated polysaccharides such as galactan, ulvan, fucan, fucoidan, heparin, sulfated glucosamine, sulfated chitosan, chitin and / or chondroitin and sulfated dextran, or any combination thereof.

[0088] In some embodiments, the at least one sulfated polysaccharide polymer may be a linear and / or non-linear sulfated polysaccharide.

[0089] In some embodiments, the at least one sulfated polysaccharide polymer can belong to the carrageenan family of biopolymers.

[0090] The term "carrageenan" as used herein generally refers to a sulfated linear polysaccharide of D-galactose and 3,6-anhydro-D-galactose, which can be extracted, for example, from red seaweed of the Rhodophyceae family. The term encompasses all types of carrageenan, including three main types, kappa (k), iota (i), and lambda (λ), which differ, for example, in chemical and physical properties, methods of manufacture and other properties, and ability to interact with other biopolymers and form thin films.

[0091] Iota carrageenan forms strong gels when combined with calcium salts. It contains 28-30% sulfate esters. It is soluble in water and has an elastic texture.

[0092] Kappa carrageenan, the most common form of carrageenan, is considered food grade. Kappa carrageenan contains 25-30% sulfate esters. Kappa carrageenan produces a strong gel when combined with potassium salts and forms a brittle gel when mixed with locust bean gum.

[0093] The two forms differ in that the lambda carrageenan is soluble in cold water, whereas the above form is soluble in hot water. Lambda carrageenan is applied to impart high viscosity properties to the product.

[0094] The chemical structures of iota, kappa and lambda carrageenans are shown below.

[0095] TIFF2024532611000001.tif72170

[0096] In some embodiments, the at least one sulfated polysaccharide polymer can be iota carrageenan, kappa carrageenan, and / or lambda carrageenan.

[0097] With regard to the hydrophilic and hydrophobic polymers or copolymers, in some embodiments, the compositions can comprise at least one polymer selected from poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanoes, polyoxalates, poly(α-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), mixtures and copolymers thereof.

[0098] In some embodiments, the composition can comprise at least one polymer selected from stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propane and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, copolymers of polyurethane and poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of α-amino acids, copolymers of α-amino acids and caproic acid, copolymers of α-benzyl glutamate and polyethylene glycol, copolymers of succinic acid and poly(glycol), polyphosphazenes, polyhydroxyalkanoates, lactide / glycolide copolymers, polyanhydrides, and combinations thereof.

[0099] In some embodiments, the composition can include at least one polymer selected from polysaccharides, gums, and combinations thereof. Gums herein refer to complex branched heteropolysaccharides that are neutral or charged (anionic or cationic). Notable examples are gum arabic and xanthan gum.

[0100] In some embodiments, the composition can comprise a natural or synthetic hydrophilic polymer selected from polyethylene oxide (PEO), pullulan, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HPC), hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl copolymers, starch, gelatin, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof.

[0101] In some embodiments, the at least one hydrophilic polymer can be a cationic, anionic and / or neutral hydrophilic polymer or a mixture thereof.

[0102] In some embodiments, the at least one hydrophilic polymer can be a polycationic polymer or mixtures thereof, which as used herein refers to a molecule or complex that carries one or more positive charges at various sites.

[0103] In some embodiments, the polycationic polymer can be polyethyleneimine, polybrene, and / or poly(amidoamine) (PAMAM).

[0104] In some embodiments, the hydrophilic polymer can be a polysaccharide and / or a protein.

[0105] In some embodiments, the at least one natural hydrophilic polymer can be a mixture selected from polysaccharides obtained from natural sources, plants, algae, animals, fungi and various microorganisms, namely dextran, alginate, chitosan, agarose and / or pullulan.

[0106] In some embodiments, the at least one natural hydrophilic polymer can be a protein selected from albumin, gelatin, collagen, lectin, legumin and / or vicilin, or a combination thereof.

[0107] In some embodiments, the at least one naturally occurring hydrophilic polymer can be alginic acid or an alginate.

[0108] The term "alginate" (or alginic acid or algin) is used herein generally to refer to a naturally occurring anionic polymer, typically obtained from brown algae. The term encompasses a range of polymers with linear structure heteropolysaccharides composed of D-mannuronic acid and L-guluronic acid, with different viscosities. The term further encompasses alginates from different sources, with different MG content, and with different physical properties. Another source of alginate is bacterial biosynthesis (Azotobacter and Pseudomonas), which differs in chemical structure and physical properties from alginates derived from seaweed.

[0109] The chemical structure of a typical alginic acid is shown below.

[0110] TIFF2024532611000002.tif50170

[0111] The term further includes various alginates with metals, such as sodium, potassium, calcium, and physical magnesium alginate. These salts can contain various types of alginates or mixtures thereof. The molecular weight of commercially available sodium alginate ranges, for example, from 32,000 to 400,000 g / mol.

[0112] In general, the compositions of the present invention can include sulfated polysaccharide polymers, hydrophobic or hydrophilic polymers and positively charged crosslinking ions, as well as various combinations of more than one chemical entity from each of these groups.

[0113] In some embodiments, the composition comprises at least one of carrageenan and Ca 2+ The composition may include at least one alginate that is crosslinked or partially crosslinked by

[0114] In some embodiments, the carrageenan can be at a concentration ranging from about 0.005% to 1%, or from about 0.005% to 0.01%, from about 0.01% to 0.05%, from about 0.05% to 0.1%, from about 0.1% to 0.2%, from about 0.2% to 0.3%, from about 0.3% to 0.4%, from about 0.4% to 0.5%, from about 0.5% to 0.6%, from about 0.6% to 0.7%, from about 0.7% to 0.8%, from about 0.8% to 0.9%, from about 0.9% to 1% (w / w).

[0115] In some embodiments, the alginate can be at a concentration ranging from about 0.1% to 3% (w / w), or from about 0.1% to 0.5%, about 0.5% to 1%, about 1% to 1.5%, about 1.5% to 2%, about 2% to 2.5%, or about 2.5% to 3% (w / w).

[0116] In some embodiments, Ca 2+ can be at a concentration in the range of about 0.0001%-1% (w / w), or in the range of about 0.0001%-0.0005%, about 0.0005%-0.001%, about 0.001%-0.005%, about 0.005%-0.01%, about 0.01%-0.05%, about 0.05%-0.1%, about 0.1%-0.5%, or about 0.5%-1% (w / w).

[0117] In some embodiments, carrageenan can be at a concentration ranging from about 0.1% to 0.3% (w / w), or up to about 0.1%, about 0.125%, about 0.15%, about 1.75%, about 0.2%, about 0.225%, about 0.25%, about 0.275%, about 0.3% (w / w).

[0118] In some embodiments, alginate can be at a concentration ranging from about 1% to 3% (w / w), or up to about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3% (w / w).

[0119] In some embodiments, Ca 2+can be at a concentration ranging from about 0.0001% to 0.005% (w / w), up to about 0.0001%, about 0.0005%, about 0.001%, about 0.0015%, about 0.002%, about 0.0025%, about 0.003%, about 0.0035%, about 0.004%, about 0.0045%, about 0.005% (w / w).

[0120] In some embodiments, carrageenan can be at a concentration ranging from about 0.2% to 0.3% (w / w), or up to about 0.2%, about 0.225%, about 0.25%, about 0.275%, about 0.3% (w / w).

[0121] In some embodiments, alginate can be at a concentration ranging from about 1% to 3% (w / w), or up to about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3% (w / w).

[0122] In some embodiments, Ca 2+ can be at a concentration ranging from about 0.01% to 0.03% (w / w), or at a concentration of up to about 0.01%, about 0.0125%, about 0.015%, about 0.0175%, about 0.02%, about 0.0225%, about 0.025%, about 0.0275%, about 0.03% (w / w).

[0123] Compositions of this type are applicable to oral and / or nasal sprays / gels and inhalation products.

[0124] In yet other embodiments, the composition comprises Ca in a concentration ranging from about 1% to 2% (w / w), or up to about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2% (w / w). 2+ Higher concentrations of Ca such as 2+ may include.

[0125] Compositions of this type are applicable to solid forms and inhalation products.

[0126] The compositions of the present invention may further include various solvents, buffers, excipients, adjuvants, permeation enhancers, plasticizers, thickeners, rheology modifiers, alcohols, bulking agents, preservatives, colorants, dyes, sweeteners, flavors and / or odorants, or combinations thereof.

[0127] In some embodiments, the solvent can be selected from water, alcohol, acetone, methylene chloride, and combinations thereof.

[0128] The compositions of the invention can be used as the basis of a pharmaceutical composition, with the active agent provided in a therapeutically effective amount, and pharma- ceutically acceptable buffers and / or excipients.

[0129] In some embodiments, the sulfated polysaccharide polymer and the hydrophobic or hydrophilic polymer can act as active agents when provided in a therapeutically effective amount.

[0130] The term "therapeutically effective amount" or "dose" (or pharmacologically, pharmacologiclly, or physiologically effective amount or dose) broadly relates to the amount or dose of a composition or active agent required to provide a desired level of physiological or clinically measurable response. The term dose can further relate to the number of dosage forms or the number of administrations to exert a desired effect. The effect can be evaluated or measured by specific clinical indicators of the relevant condition, recognized molecular or biochemical markers, and other parameters. In this case, these terms can be translated to an amount or dose of a pharmaceutical composition that can be associated with a measurable mucosal protective effect, specifically a measurable reduction in infection or viral load of a mucosal tissue, or a reduction in an inflammatory response by one or more recognized inflammatory markers.

[0131] In some embodiments, the pharmaceutical composition may further comprise at least one additional active or therapeutic agent. With regard to additional therapeutically active agents, the pharmaceutical compositions of the present invention may incorporate various types of drugs and therapeutically active agents depending on the indication, method of application and use.

[0132] In many embodiments, the pharmaceutical composition can incorporate therapeutic agents that provide protection to oral and nasal mucosal barrier function. The concept of "mucosal barrier function" has been discussed above. Essentially, this term encompasses any dysregulation of oral and / or nasal epithelium or mucosal barrier homeostasis, including physical destruction of epithelial tissue and / or certain molecular structures such as TJs, unregulated secretion of proinflammatory cytokines, growth factors and chemokines responsible for innate and adaptive immunity, insufficient secretion of antimicrobial peptides and dysregulation of mucociliary clearance of ciliated epithelial cells responsible for trapping microorganisms and microparticles.

[0133] Due to the mucoadhesive and mucoprotective properties of the compositions of the present invention and their ability to prevent or reduce excessive exposure of mucous membranes to harmful infectious pathogens and allergens, the compositions of the present invention can contribute to the restoration of the oral and / or nasal mucosal barrier and its functionality.

[0134] In some embodiments, the pharmaceutical compositions may be applied to treat, alleviate and / or prevent microbial infections of the oral and / or nasal passages, which herein include bacterial and viral infections.

[0135] The most common example is bacterial infections causing dental cavities, mainly infections caused by Streptococcus mutans and Streptococcus sobrinus, and Lactobacillus. Another example is acute rhinosinusitis (ABRS) of the nasal cavity and sinuses caused by Streptococcus pneumonia. ABRS is usually secondary to viral infections. Yet another example is acute upper respiratory tract infections (URI), namely sinusitis, epiglottitis, laryngitis, and bronchitis, caused by group A or C beta-hemolytic streptococci, Corynebacterium diphtheriae (diphtheria), Neisseria gonorrhoeae (gonorrhea), and Chlamydia pneumoniae (chlamydia).

[0136] In some embodiments, the compositions may be applied to treat, alleviate and / or prevent meningococcal meningitis, a bacterial meningitis caused by Streptococcus pneumoniae that is typically found in the airways, sinuses and nasal passages. Indicators of this condition include sudden high fever, severe headache, seizures, stiff neck, nausea and sensitivity to light, among others.

[0137] In some embodiments, the compositions can include agents that target bacterial infections, in other words, the compositions can include different types of antibiotics and combinations of antibiotics with different ranges of antibacterial activity. Non-limiting examples are as follows: 1. Penicillin and its derivatives such as amoxicillin 2. Cephalosporins, such as Cephalexin (Keflex) 3. Macrolides such as erythromycin (E-Mycin), clarithromycin (Biaxin), and azithromycin (Zithromax) 4. Fluoroquinolones, such as ciprofloxacin (Cipro), levofloxacin (Levaquin), and ofloxacin (Floxin) 5. Sulfonamides such as Co-trimoxazole (Bactrim) and Trimethoprim (Proloprim) 6. Tetracycline (Sumycin, Panmycin) and Doxycycline (Vibramycin) 7. Aminoglycosides such as gentamicin (Garamycin) and tobramycin (Tobrex)

[0138] Sinusitis is a specific example, as it can be caused by viruses, bacteria, and / or fungi, as well as aeroallergens.

[0139] In some embodiments, the compositions can be applied to treat, reduce and / or prevent infections caused by human respiratory viruses. This group includes a wide range of viruses that have a general tendency to replicate in cells of the respiratory tract and are usually transmitted to other hosts by respiratory secretions. The term "respiratory viruses" as used herein encompasses various types of influenza viruses, respiratory syncytial virus (RSV), parainfluenza viruses, metapneumoviruses, rhinoviruses, coronaviruses, adenoviruses, and bocaviruses.

[0140] In some embodiments, the compositions may be applied to treat, alleviate and / or prevent viral infections of the oral and / or nasal passages.

[0141] In some embodiments, the compositions can be applied in combination with known antiviral drug treatments. Many antiviral drugs are currently available, including amantadine (Symmetral), ribavirin (Virazole), and palivizumab (Synagis), the latter two of which are indicated for the treatment of RSV. Oral amantadine is effective in both treating and preventing influenza A. Additional drugs are in various stages of research and development (R&D) and regulatory approval.

[0142] In some embodiments, the compositions can be used to treat, alleviate and / or prevent the common cold, mild influenza, tonsillitis, laryngitis, and sinus infections. Currently, four drugs approved by the FDA for the treatment of influenza are oseltamivir phosphate (Tamiflu), zanamivir (Relenza), peramivir (Rapivab) and baloxavir marboxil (Xofluza).

[0143] In some embodiments, the compositions may be applied alone or in combination with arbidol (an FDA approved drug for influenza) to treat, reduce and / or prevent infection with influenza A and B viruses, which are the primary causative pathogens of seasonal influenza epidemics (seasonal influenza).

[0144] In some embodiments, the compositions may be applied to treat, alleviate and / or prevent aseptic viral meningitis, primarily caused by enteroviruses.

[0145] More broadly, the compositions may be applied to treat, alleviate and / or prevent any type of infection caused by, related or associated with influenza virus, respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, coronavirus, adenovirus, and bocavirus.

[0146] In some embodiments, the compositions may be applied to treat, mitigate and / or prevent infection caused by SARS-CoV-2, including known SARS-CoV-2 and more recent SARS-CoV-2 variants.

[0147] In some embodiments, the compositions can be applied together with additional antiviral drugs that interfere with viral entry and life cycle (broad spectrum antiviral activity), such as nucleoside / nucleotide analogues (e.g., remdesivir), protease inhibitors (disulfiram, lopinavir, and ritonavir and darunavir) and several small molecules designed based on specific viral structures.

[0148] In some embodiments, the compositions can include antiviral drugs that target specific viruses.

[0149] In some embodiments, the compositions can further include penicillin VK, amoxicillin, penicillin G benzathine, cefadroxil, erythromycin, broad spectrum augmentin (amoxicillin and clavulanic acid).

[0150] In some embodiments, the compositions can include a combination of antibiotics and antivirals to treat, reduce and / or prevent primary and secondary infections.

[0151] In some embodiments, the composition can include an anti-viral vaccine containing either an inactivated or attenuated virus or a portion of the viral genome. A precursor COVID-19 vaccine in the form of a nasal spray has recently been tested in animals.

[0152] In some embodiments, the compositions may be applied to treat and / or prevent aeroallergen-induced allergies and / or inflammation. Aeroallergens, as used herein, refer broadly to a wide range of airborne substances or inhaled allergens, such as pollen, spores, and biological or non-biological airborne particles that can trigger an allergic response.

[0153] In clinical terms, in some embodiments, the compositions may be applied to treat, reduce and / or prevent coughing, wheezing and sudden respiratory illnesses resulting from an aeroallergen-driven Th2 immune response.

[0154] In some embodiments, the compositions may be applied to treat, alleviate active asthma and / or prevent the risk of contracting asthma.

[0155] In some embodiments, the compositions can be applied to prevent occupational hazards. Occupational allergens include hundreds of chemicals present in almost every industry, such as metals, epoxy and acrylic resins, rubber additives, and chemical intermediates.

[0156] In some embodiments, the composition can further include steroidal and nonsteroidal anti-inflammatory agents. Examples are the various types of corticosteroids (cortisone, hydrocortisone, prednisone, prednisolone, dexamethasone) and the various types of NSAIDs, such as aspirin, ibuprofen, naproxen, meloxicam, celecoxib, etc.

[0157] In some embodiments, the composition can further include an anti-allergy drug. Notable examples are antihistamines. Nasal drops can include decongestants such as oxymetazoline, tetrahydrozoline, and various types of corticosteroids (budesonide, fluticasone furoate, fluticasone propionate, mometasone, triamcinolone). Inhalants can include corticosteroids such as beclomethasone, budesonide, ciclesonide, fluticasone, mometasone, including long-acting bronchodilators, and additional drugs that target specific disorders of mucosal barrier function.

[0158] Broadly speaking, the compositions of the present invention can be incorporated into several types of products. (1) Compositions by themselves or in combination with OTC-approved or homeopathic active substances for the protection of the nasal and oral mucosa from exposure to potential infectious and non-infectious agents and pathogens. (2) prescription-based products that contain compositions and FDA-approved drugs that target clinical conditions associated with oral and nasal mucosal barrier dysfunction. (3) A drug delivery system comprising the composition that acts as a carrier for FDA-approved drugs for various clinical disorders and clinical and subclinical conditions.

[0159] For example, in some embodiments, the present invention can provide oral and nasal sprays / gels comprising one or a combination of the above compositions.

[0160] In some embodiments, the present invention may provide an oral or nasal inhalant comprising one or a combination of the above compositions. The inhalant may be in the form of particles or droplets, preferably greater than 10 μm.

[0161] In some embodiments, the spray / gel or inhalant may help protect the oral and / or nasal mucosa from impairment of mucosal barrier function.

[0162] In some embodiments, the spray / gel or inhalant may further comprise at least one therapeutic agent that targets impaired mucosal barrier function.

[0163] In yet another aspect, the invention can provide a kit comprising one or a combination of the compositions of the invention (e.g. oral or nasal spray / gel or inhalant) and a device for oral or nasal delivery, and instructions for use. The kit concept refers to the compartmentalization of the spray / gel or inhalant in a specific container or dosage form.

[0164] In some embodiments, the composition can be incorporated into a device.

[0165] In another aspect, the present invention can provide an oral or nasal drug delivery system comprising one or a combination of the above compositions, with or without an additional therapeutic agent.

[0166] Yet another important objective of the present invention is to provide a drug delivery system that targets various clinical disorders and clinical and subclinical conditions. The agents or drugs delivered by such systems are usually referred to as systemically acting agents or drugs. The term "systemically acting agents or drugs" is used broadly herein to refer to agents that act outside the point of application or administration of the agent or drug and target other parts of the body via circulation. This term is used herein to include agents that act on the cardiovascular system, respiratory system, gastrointestinal system, or nervous system. At the molecular level, this term is used herein to include enzyme inhibitors, receptor antagonists or agonists, proton pump and ion channel inhibitors, and reuptake inhibitors.

[0167] In some embodiments, the additional systemic drug can be selected from antibiotics, antifungals, antivirals, neuroleptics, analgesics, hormones, anti-inflammatory agents, nonsteroidal anti-inflammatory agents, antirheumatic agents, anticoagulants, beta blockers, diuretics, antihypertensive agents, antiatherosclerotic agents, antidiabetic agents, antiasthmatic agents, decongestants, and / or cold medications.

[0168] Candidate agents can be selected from a comprehensive list of FDA approved drug categories, examples of which are set forth in ANNEX A. A more specific list of relevant clinical disorders and conditions is set forth in ANNEX B.

[0169] In some embodiments, the additional therapeutic agent may be selected from beneficial oils, nutraceuticals, vitamins, dietary or food supplements, nutrients, antioxidants, superfoods, natural extracts of animal and plant origin, probiotic microorganisms, or any combination thereof.

[0170] In terms of structure, the composition may include therapeutic agents belonging to the group of carbohydrates, lipids, proteins, peptides, enzymes, nucleic acids, oligonucleotides or complex molecules containing these.

[0171] In some embodiments, the composition can include an agent that belongs to the group of small molecules, which generally refer to organic compounds with low molecular weight (<900 Daltons) that may modulate biological processes.

[0172] In some embodiments, the compositions can include single and double stranded DNA or RNA, siRNA, plasmids, linear or circular DNA or RNA, or combinations thereof.

[0173] Another object of the present invention is to provide a method for systemic or local drug delivery through epithelial mucosa by administering one or more of the above compositions or delivery systems to the epithelial mucosa of a subject. The term "administering to epithelial mucosa" as used herein means oral, nasal, ocular, pulmonary, and other mucosal tissues.

[0174] In some embodiments, the methods of the present invention can include co-administering one or more therapeutic agents to a subject, which can be simultaneous or sequential using enteral, parenteral, topical or any other route, as per the particular indication and need of the subject.

[0175] In some embodiments, the methods may be applied to protect oral and nasal barrier function in a subject by oral or nasal administration of one or a combination of the above compositions.

[0176] In some embodiments, the methods can be applied to treat, alleviate, and prevent microbial oral and / or nasal infections in a subject by orally or nasally administering a therapeutically effective amount of any of the above compositions.

[0177] In some embodiments, the methods may be applied to treat, reduce and prevent aeroallergen-induced allergy and / or inflammation in a subject by oral or nasal administration of a therapeutically effective amount of any of the above compositions.

[0178] The invention may further be manifested in the form of the use of any of the above compositions for the manufacture of a medicament for treating aeroallergen-induced allergy and / or inflammation or microbial oral or nasal infections.

[0179] From yet another perspective, the mucoadhesive compositions of the present invention can be utilized in the bioengineering of functional tissue grafts. Due to their biocompatibility and physical, chemical and biological properties, the compositions of the present invention can act as universal "all-purpose" materials in the form of matrices or injectable hydrogels that can be used to provide physical support for the regeneration of tissues and more complex organs, and to aid the assembly of cells to specific sites. The flexibility of the compositions of the present invention to incorporate additional materials, active substances and drugs makes them particularly attractive candidates for this type of application.

[0180] In some embodiments, matrices made from the compositions of the present invention can further include active agents, drugs, growth factors, hormones, enzymes, nucleic acids, oligos and other agents that provide biochemical and topographical direction to cell assembly and function.

[0181] In some embodiments, such matrices can further include encapsulated cells of various types and origins depending on the required indication, specific examples being stem cells of various origins, which upon appropriate triggers can populate, develop and differentiate into specific cells at the site of application.

[0182] In other words, the compositions of the present invention can be used to assist structural and functional recovery of damaged tissues by providing mechanical support and inducing cell fates for nerve or cardiomyocyte regeneration to repair the infarcted heart, injured spinal cord, and neurodegenerated brain.

[0183] When viewed as a tool for nerve repair or regeneration, the compositions of the present invention may further comprise auxiliary devices and be incorporated into neurological surgical procedures.

[0184] Wherever the term "about" appears in this text, it means a deviation of up to ±10% from the stated value and / or range, and more specifically a deviation of up to ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9% or ±10% therefrom. EXAMPLES

[0185] Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.Several embodiments of the present invention are now described by way of example with reference to respective drawings.

[0186] Materials and Methods cell MRC-5 human normal lung fibroblast cells (ATCC CCL-171) were cultured in EMEM medium containing 10% FBS, 2 mM L-glutamine, and 1% penicillin-streptomycin (Biological Industries).

[0187] MDCK canine normal kidney cells (ATCC NBL-2) were cultured in EMEM medium containing 1% FBS, 2 mM L-glutamine, and 1% penicillin-streptomycin (Biological Industries).

[0188] A549 human alveolar basal epithelial adenocarcinoma cells (ATCC CCL-185) were cultured in EMEM medium containing 10% FBS, 2 mM L-glutamine, and 1% penicillin-streptomycin (Biological Industries).

[0189] Vero E6 African green monkey kidney cells (ATCC CRL-1586) were cultured in EMEM medium containing 5% FBS, 2 mM L-glutamine, and 1% penicillin-streptomycin (Biological Industries).

[0190] virus Human coronavirus 229E was diluted 1:15 in the respective medium and introduced into cultured MRC-5 cells (infectious dose 2 μL / well).

[0191] Influenza virus H1N1 was diluted 1:10 in each medium and transfected into MDCK cells (infectious dose 3 μL / well).

[0192] SARS-CoC-2 omicron mutant (strain B.1.1.529.BA.1) was diluted 1:10 in culture medium and transfected into Vero E6 cells (infectious dose 30 μL / well).

[0193] Allergens Recombinant Dermatophagoides pteronyssinus dust mite allergen Der p1 (20-320 amino acid sequence containing six His C-terminal tags, total Mw = 34.5 kDa, pI = 5.6) was diluted in assay medium and transfected into A549 cells (final concentration 50 μg / ml).

[0194] Recombinant Dermatophagoides farina Der f1 (amino acid sequence 1-320 with six His fused to the C-terminus, total Mw = 36 kDa, pI = 5.88) was diluted in assay medium and transfected into A549 cells (final concentration 25 μg / ml).

[0195] Recombinant Gramineous group pollen allergen Phl p1 (glycosylated polypeptide chain produced in SF9, calculated molecular weight = 29 kDa, expressed with an N-terminal 10xHis tag and purified by chromatographic methods) was diluted in assay medium and transfected into A549 cells (final concentration 25 μg / ml).

[0196] Recombinant hornbeam (Carpinus betulus) pollen allergen Car b1 isoform (non-glycosylated polypeptide chain produced by Escherichia coli, calculated molecular weight = 18 kDa, expressed with an N-terminal 10xHis tag and purified by chromatographic methods) was diluted in assay medium and introduced into A549 cells (final concentrations of 15 μg / ml, 30 μg / ml and 60 μg / ml).

[0197] Pretreatment and Processing Procedures 1. Seed the cells (1x10) in medium in a 96-well plate. 4 cells / well) and allowed to attach for 16–24 h at 37 °C, 5% CO2. 2.30 μL of test item (listed in Table 1) was added to the cells and incubated at 37 °C, 5% CO2 for 30 min.

[0198] TIFF2024532611000003.tif101170

[0199] 3. Cells were preincubated on ice for 15 minutes in the presence of 60-140 μL of assay medium and 30 μL of test virus or 10 μL of activated allergen with 5 mM L-cysteine. 4. Cells were incubated with the test virus or allergen for 72 hours at 37°C, 5% CO2, washed and incubated under the same conditions for a further 72 hours. 5. At the end of the incubation period, cells were treated as per the respective assay protocol.

[0200] XTT-based cell proliferation assay 1. The reaction solution was prepared from 0.1 mL of activation solution and 5 mL of XTT reagent (Cell Proliferation Kit, Biological Industries) according to the manufacturer's protocol. 2. The cells were washed and 50 μL of XTT reagent was added in fresh medium. 3. Measure the OD at 450 nm and normalize the results to vehicle-treated cells (OD = 0.5-1.5) and subtract the non-specific OD at 620 nm (% cell viability).

[0201] IL-8 detection by ELISA assay 1. At the end of the incubation period, the assay medium was collected and stored (-20°C) for the IL-8 ELISA assay. 2. A 25 μL aliquot of the supernatant was tested as per the manufacturer's instructions.

[0202] Example 1: Cytotoxicity studies of several animal cell lines The cytotoxicity of the compositions of the present invention was investigated in various in vitro cell models (MRC-5, MDCK, A549 and Vero cells). Cells were treated with compositions containing various ratios of alginate / carrageenan / CaCl2 (Table 2) corresponding to different degrees of cross-linking (#26 partial, #21 complete, #16 no cross-linking) and compared to cell viability of untreated cells (UT).

[0203] TIFF2024532611000004.tif43170

[0204] Toxicity results are shown in Figures 1A-1D (mean ± SE for each group). Overall, the compositions showed no or minimal cytotoxicity (less than 5% decrease in % cell viability) in all cell types examined, with no significant effect on the degree of CaCl2 crosslinking.

[0205] Example 2: Protective effect of the composition against coronavirus The mucosal protective effect of the compositions of the invention against the spread and infection of various coronavirus strains (229E and Omicron lineage B.1.1.529.BA.1) was investigated in an in vitro cell model (MRC-5 and Vero cells, respectively). In the 229E model, virus-infected cells were treated with compositions containing various concentrations of alginate / carrageenan / CaCl2 (#25, #26, #27 partial and #4, #5, #15, #16 no cross-linking) and various concentrations of carrageenan (#16, #26 high, #4, #15, #25 low and #5, #27 no carrageenan) (see Table 3). In the Omicron model, virus-infected cells were treated with serial dilutions (0.2-1) of partially cross-linked and non-cross-linked compositions (#26 and #16, respectively). Treated cells were compared to uninfected and untreated cells (UT) and virus-infected cells (UT+virus).

[0206] TIFF2024532611000005.tif72170

[0207] The results for the 229E and Omicron models are shown in Figures 2A-2B and 3, respectively (mean ± SE for each group), and the corresponding statistical analyses of the study groups (Tukey HSD) are shown in Tables 4-5, respectively.

[0208] TIFF2024532611000006.tif81170

[0209] TIFF2024532611000007.tif77170

[0210] In the 229E model, compositions containing partially cross-linked alginate-carrageenan combinations (#25, #26) had significantly more antiviral mucosal protective effects than compositions containing non-cross-linked polymers (#4, #15, #16) or no carrageenan (#5, #27). Compositions containing low and high concentrations of carrageenan (#25 vs. #26) had similar effects.

[0211] In the SARS-CoV-2 Omicron model, the effect of compositions containing partially cross-linked polymers was not concentration-dependent and remained significant with lower concentrations of the tested compositions (#26x0.2 vs. #26x1). Furthermore, even at lower concentrations, the partially cross-linked compositions were more effective than compositions containing non-cross-linked polymers (#26x0.2 vs. #16x0.2).

[0212] Overall, compositions containing partially cross-linked alginate-carrageenan polymers were shown to have significant antiviral mucosal protective effects against several coronavirus strains, including the currently circulating omicron variant.

[0213] Example 3: Protective effect of the composition against influenza virus The antiviral mucosal protective effect of the compositions against human influenza virus (H1N1) was further investigated in an in vitro cell model. MDCK cells were treated with the same compositions (Table 3). Cell viability was assessed as described above. The results are shown in Figures 4A-4B (mean ± SE for each group) and the corresponding statistical analysis of the study groups (Tukey HSD) is shown in Table 6.

[0214] TIFF2024532611000008.tif77170

[0215] The results show that compositions containing combinations of partially crosslinked polymers (#25, #26) had significant antiviral mucosal protective effects against H1N1 virus compared to compositions containing non-crosslinked or single polymers (#4, #5, #15, #16, #27). More generally, the results suggest that the antiviral mucosal protective effects of these compositions are not limited to coronaviruses, and that these compositions may be protective against influenza, and potentially other respiratory viruses, as well.

[0216] The antiviral mucosal protective effect of the compositions was further investigated with respect to the degree of cross-linking. To this end, H1N1-infected MDCK cells were treated with the alginate-carrageenan combination (#26) and compositions containing different concentrations of CaCl2 (0.0001-0.02%) corresponding to different degrees of cross-linking. The results are shown in Figure 5 (mean ± SE for each group) and the corresponding statistical analysis (Tukey HSD) is shown in Table 7.

[0217] TIFF2024532611000009.tif80170

[0218] The results show that compositions containing high concentrations of CaCl2 (#26 0.005%-0.02% CaCl2) had significant antiviral mucosal protective effects compared to compositions containing low concentrations of CaCl2 (#26 0.001%-0.0001% CaCl2) or compositions without CaCl2 (#16). Overall, the results suggest that the degree of partial cross-linking of the two polymers contributes to the desired antiviral mucosal protective effects.

[0219] Example 4: Protective effect of the composition against allergens The mucosal protective effect of the compositions in the presence of common allergens and allergen-induced inflammation was further investigated using in vitro cell models (house dust mite allergens Der p1 and Der f1 and pollen allergens Phl p1 and Car b1), respectively, and interleukin (IL-8) as a molecular marker of inflammation. The test compositions are listed in Table 8.

[0220] TIFF2024532611000010.tif70170

[0221] A549 cells were treated with compositions containing various concentrations of alginate / carrageenan / CaCl2 (#25, #26 partially and #4, #5, #15, #16 not cross-linked) and various concentrations of lambda (#16, #26 high, #4, #15, #25 low and #5 no carrageenan) or iota carrageenan (#3) using two concentrations of the test composition (x1 or x0.5) and compared with treated and untreated (UT) cells and cells exposed to allergen (UT+A). The results are shown in Figure 6 and the corresponding statistical analysis (Tukey HSD) is shown in Table 9.

[0222] TIFF2024532611000011.tif77170

[0223] The results show that compositions containing partially cross-linked polymer combinations (#25, #26) had significant mucosal protective anti-inflammatory effects against Der p1 allergen compared to compositions containing non-cross-linked or single polymers (#4, #5, #15, #16, #27). The magnitude of these differences was surprising, suggesting that the alginate / carrageenan / CaCl2 partially cross-linked combination may have a synergistic effect on anti-allergic mucosal protection.

[0224] The results further demonstrated concentration-dependence and specificity of the tested effects, revealing higher IL-8 expression at higher concentrations of the composition compared to the same composition at lower concentrations (x1 vs. x0.5).

[0225] Additional allergens were further investigated using the allergen exposure model (dust mite allergen Der f1 and pollen allergens Phl p1 and Car b1). Der f1 and Phl p1 allergens were tested in A549 cells treated with either a composition containing a partially cross-linked polymer (#26) or a composition containing a non-cross-linked polymer (#16) and compared to treated and untreated cells (UT) and cells exposed to the allergen (UT+A). Car b1 allergen was tested in the same model using different Car b1 concentrations (15 μg / ml, 30 μg / ml, 60 μg / ml). The results are shown in Figures 7A-7B and 8 (mean ± SE for each group) and the corresponding statistical analysis (Tukey HSD) is shown in Tables 10-12.

[0226] TIFF2024532611000012.tif46170

[0227] TIFF2024532611000013.tif44170

[0228] TIFF2024532611000014.tif78170

[0229] The results indicate that the anti-inflammatory mucosal protective effect of the compositions is not limited to a specific allergen or class of allergens, but is broadly applicable to a wide variety of antigens, examples of which are several dust mite and pollen antigens. For all tested antigens, the compositions containing partially cross-linked polymers were more effective than the compositions containing non-cross-linked polymers (#26 vs. #16).

[0230] Overall, the present studies in both types of models, viral infection and allergen exposure, point to the surprising ability of compositions containing combinations of partially crosslinked polymers to confer robust and effective antiviral and anti-inflammatory mucosal protective effects.

[0231] Example 5: Sprayable form and convertibility into durable thin films The physical properties of the compositions and especially their ability to form thin films at room temperature were also investigated by measuring the viscosity of the composition containing the non-crosslinked polymer (#16) and the composition containing the partially crosslinked polymer (#26) (diluted 1:1) over a long period of time (21 days) using a viscometer (MRC, pedal No. 2, 60 RPM, room temperature). The results are shown in Figure 9.

[0232] The results showed that while both types of compositions had a sustained or constant viscosity at room temperature over the test period, the partially crosslinked compositions had a lower viscosity (up to 20%), suggesting better sprayability, coverage and the ability to easily spread and transform into a uniform, continuous thin film. This surprising physical property of the partially crosslinked compositions being lower in viscosity makes these compositions particularly advantageous for topical, and especially nasal, administration, as a result of optimal sprayability and coverage without the risk of clogging.

[0233] Compositions containing single polymers (#4, #5, #27) and combinations of partially crosslinked polymers (#25, #26) or non-crosslinked polymers (#15) were subjected to various shear rates (0.1, 1, 10 s ) using a rheometer (NETZSCH Kinexus Pro, Malvern, discs 21, 61 mm, room temperature). -1 The durability and reliability of the formed thin films were further investigated by measuring the viscosity under various shear forces at room temperature, including testing at 1000 V. The results are shown in FIG.

[0234] The results show that the viscosity of the compositions containing the partially crosslinked polymer combinations (#25, #26) was relatively resistant to shear forces (maximum deviation of about 25%) when compared to other compositions whose viscosities varied dramatically under the same conditions. This study further demonstrates the advantageous physical properties of the partially crosslinked compositions and their ability to form reliable, durable, continuous thin films at room temperature.

[0235] Overall, these studies reveal several surprising and advantageous properties of the partially crosslinked compositions, manifested by a relatively constant or persistent viscosity over extended periods of time at room temperature, which is also lower (at least 20%) than the viscosities of non-crosslinked and other compositions, and which is resistant to a variety of shear forces (within the range of about 25%). This surprising and advantageous property of superior viscosity translates into the ability of these compositions to form (or be transformable into) sprayable, uniform, continuous and reliable thin films, which in turn are responsible for the dramatic mucosal protective effects of these compositions.

[0236] Example 6: Inhaled and Nasal Product Development Current efforts are focused on the development of inhalation and nasal products. Figure 11 provides a schematic diagram of further embodiments of the compositions disclosed in the present invention, including additional optional polymer, crosslinker and preservative combinations. Further embodiments include compositions in the form of particulate matter, with the particles or droplets being in a particular size range (e.g., greater than 10 μm) that is optimal for nasal and inhalation applications. This type of composition is currently undergoing testing as per the specific requirements of FDA and EMEA for nasal and inhalation products.

[0237] Specific Embodiments In the embodiment of the composition according to the invention, the following is meant: In some embodiments, the compositions can be applied for delivery to epithelial mucosa.

[0238] In some embodiments, the epithelial mucosa can be the oral and / or nasal mucosa.

[0239] In some embodiments, the composition comprises at least one sulfated polysaccharide polymer and at least one hydrophobic or hydrophilic polymer partially crosslinked with at least one positively charged ion, and upon contact with the mucosa, the composition is transformable into a continuous thin film.

[0240] In some embodiments, the composition can have an essentially persistent viscosity under a range of shear forces.

[0241] In some embodiments, the composition is heated to about 0.1 to 10 s at room temperature. -1 When measured at a shear rate of about 100 to 1000 mPa*sec -1 The viscosity of the mixture may be 0.1 to 100 μm.

[0242] In some embodiments, the composition can include microparticles or nanoparticles.

[0243] In some embodiments, the at least one sulfated polysaccharide polymer and the at least one hydrophobic or hydrophilic polymer can be synthetic, semi-synthetic and / or modified natural polymers.

[0244] In some embodiments, the at least one sulfated polysaccharide polymer and the at least one hydrophobic or hydrophilic polymer can be natural polymers obtained from plant, animal and / or microbial sources.

[0245] In some embodiments, the at least one sulfated polysaccharide polymer may be selected from galactan, ulvan, fucan, fucoidan, heparin, sulfated glucosamine, sulfated chitosan, chitin and / or chondroitin and sulfated dextran, or combinations thereof.

[0246] In some embodiments, the at least one sulfated polysaccharide polymer can be at least one carrageenan or a combination thereof.

[0247] In some embodiments, the at least one carrageenan can be selected from iota carrageenan, kappa carrageenan, and / or lambda carrageenan.

[0248] In some embodiments, the at least one hydrophobic or hydrophilic polymer can be selected from poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanoes, polyoxalates, poly(α-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyaminoacids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), mixtures and copolymers thereof.

[0249] In some embodiments, the at least one hydrophobic or hydrophilic polymer in the composition can be selected from stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propane and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, copolymers of polyurethane and poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of α-amino acids, copolymers of α-amino acids and caproic acid, copolymers of α-benzyl glutamate and polyethylene glycol, copolymers of succinic acid and poly(glycol), polyphosphazenes, polyhydroxyalkanoates, lactide / glycolide copolymers, polyanhydrides, and combinations thereof.

[0250] In some embodiments, the at least one hydrophilic polymer can be a natural or synthetic hydrophilic polymer selected from polyethylene oxide (PEO), pullulan, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HPC), hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl copolymers, starch, gelatin, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof.

[0251] In some embodiments, the at least one hydrophilic polymer can be a natural polymer that is a polysaccharide or a protein.

[0252] In some embodiments, the polysaccharide may be selected from dextran, alginate, chitosan, agarose, and / or pullulan.

[0253] In some embodiments, the protein may be selected from albumin, gelatin, collagen, lectin, legumin, and / or vicilin.

[0254] In some embodiments, the polysaccharide can be alginic acid or an alginate.

[0255] In some embodiments, the at least one positively charged ion can be a divalent cation.

[0256] In some embodiments, the divalent cation is Ba 2+ , B.E. 2+ , Ca 2+ , Co 2+ , Mg 2+ , Cu 2+ , Ni 2+, Fe 2+ and / or Zn 2+ can be selected from:

[0257] In some embodiments, the at least one sulfated polysaccharide polymer can be carrageenan and the at least one hydrophilic polymer can be Ca 2+ The alginate may be partially cross-linked with

[0258] In some embodiments, the carrageenan can be at a concentration ranging from about 0.005% to about 1%, the alginic acid can be at a concentration ranging from about 0.1% to about 3%, and the Ca 2+ can be at a concentration ranging from about 0.0001% to about 1% (w / w).

[0259] In some embodiments, the carrageenan can be at a concentration ranging from about 0.1% to about 0.3%, the alginic acid can be at a concentration ranging from about 1% to about 3%, and the Ca 2+ can be at a concentration ranging from about 0.0001% to about 0.05% (w / w).

[0260] In some embodiments, the carrageenan can be at a concentration ranging from about 0.2% to about 0.3%, the alginic acid can be at a concentration ranging from about 2.0% to about 2.9%, and the Ca 2+ can be at a concentration ranging from about 0.0001% to about 0.02% (w / w).

[0261] In some embodiments, the composition can further comprise a solvent, a buffer, an excipient, an adjuvant, a permeation enhancer, a plasticizer, a thickener, a rheology modifier, an alcohol, a bulking agent, a preservative, a colorant, a dye, a sweetener, a flavoring and / or an odorant, or a combination thereof.

[0262] In some embodiments, the composition further comprises at least one additional therapeutic agent.

[0263] In some embodiments, the composition can be a pharmaceutical composition comprising a therapeutically effective amount of any one of the above compositions and a pharma- ceutically acceptable buffer, carrier, or excipient.

[0264] In some embodiments, the pharmaceutical compositions may be adapted for inhalation, optionally in particle or droplet form.

[0265] In some embodiments, the pharmaceutical compositions may be adapted for oral and / or nasal administration, optionally in the form of a spray and / or gel.

[0266] In some embodiments, the pharmaceutical composition can further comprise at least one additional therapeutic agent.

[0267] In some embodiments, the composition can further comprise at least one additional therapeutic agent for preventing or treating a disorder associated with oral and / or nasal mucosal barrier dysfunction.

[0268] In some embodiments, the compositions can be used to protect oral and nasal mucosal barrier function.

[0269] In some embodiments, the compositions can be used to treat, alleviate and / or prevent microbial oral and / or nasal infections.

[0270] In some embodiments, the microbial oral and / or nasal infection can be a viral and / or bacterial infection.

[0271] In some embodiments, the composition can further comprise at least one antibiotic and / or antiviral agent.

[0272] In some embodiments, the antiviral agent can be an antiviral vaccine.

[0273] In some embodiments, the compositions may be used to treat, reduce and / or prevent aeroallergen-induced allergies and / or inflammation.

[0274] In some embodiments, the composition may further comprise at least one anti-allergy and / or anti-inflammatory agent.

[0275] In some embodiments, the compositions may be used in the regeneration of tissue and / or in the bioengineering of tissue grafts, which means: In some embodiments, the tissue is neural or cardiac tissue.

[0276] In the kit embodiment, this means: In some embodiments, a kit can comprise any one of the compositions or pharmaceutical compositions described above, and a device for oral or nasal delivery or inhalation, and instructions for use.

[0277] In the context of the drug delivery system, this means: In some embodiments, the drug delivery system can include any one of the compositions described above and at least one additional therapeutic agent.

[0278] In some embodiments, the at least one therapeutic agent can be an agent for preventing or treating a disorder or condition associated with oral and / or nasal mucosal barrier dysfunction.

[0279] In some embodiments, the at least one therapeutic agent can be an agent for preventing or treating other types of clinical disorders or clinical or subclinical conditions.

[0280] In some embodiments, the at least one therapeutic agent can be selected from antibiotics, antifungals, antivirals, neuroleptics, analgesics, hormones, anti-inflammatory agents, nonsteroidal anti-inflammatory agents, antirheumatic agents, anticoagulants, beta blockers, diuretics, antihypertensive agents, antiatherosclerotic agents, antidiabetic agents, antiasthmatic agents, decongestants, and / or cold medications.

[0281] In an embodiment of the method for oral or nasal delivery, this means that: In some embodiments, the methods can include oral and / or nasal administration of a therapeutically effective amount of any one of the above compositions or drug delivery systems.

[0282] In some embodiments, the methods further comprise co-administering at least one additional therapeutic agent.

[0283] In some embodiments, the methods can be applied to protect oral and nasal mucosal barrier function.

[0284] In some embodiments, the methods can be applied to treat, alleviate and prevent microbial oral and / or nasal infections.

[0285] In some embodiments, the method can further include co-administering at least one antibiotic and / or antiviral agent, which administering is by oral, enteral, parenteral, or nasal route.

[0286] In some embodiments, the methods may be applied to prevent, reduce or treat aeroallergen-induced allergy and / or inflammation.

[0287] In some embodiments, the method can further include co-administering at least one anti-allergic and / or anti-inflammatory agent, which administering is by oral, enteral, parenteral, or nasal route.

[0288] In some embodiments, the methods may be applied to tissue regeneration and / or the bioengineering of tissue grafts.

[0289] In some embodiments, the method can further include a surgical procedure.

[0290] In the context of use, this means the following: In some embodiments, the compositions described above can be used to manufacture a medicament for preventing, alleviating or treating aeroallergen-induced allergy or inflammation.

[0291] In some embodiments, the medicament can be for preventing, alleviating or treating a microbial oral and / or nasal infection.

[0292] In some embodiments, the medicament can be for treating a systemic disorder.

[0293] ANNEX A FDA Catalog of Drug Categories Painkillers, including non-narcotic and narcotic analgesics Antacids Antianxiety drugs Antiarrhythmic drugs Antibiotics Antibiotics, including natural, synthetic and broad-spectrum antibiotics Anticoagulants and thrombolytics for arterial or venous thrombosis Anticonvulsants Antidepressants including mood enhancing antidepressants, tricyclics, monoamine oxidase inhibitors, and SSRIs Antidiarrheal preparations and antidiarrheal drugs that contain agents that slow down the rate of intestinal muscle contractions Antiemetics Antifungal drugs, including those for infections that affect hair, skin, nails, and mucous membranes Antihistamines Antihypertensive drugs, including diuretics, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors Anti-inflammatory agents Antineoplastic drugs Antipsychotics are also powerful tranquilizers Antipyretics Antiviral drugs, including treatment and temporary protection against viral infections Barbiturates (see Sleeping pills) Beta-blockers Bronchodilators Cold medicines for aches, pains and fevers associated with colds Corticosteroids in the context of immunosuppression, malignancy, or deficiency Cough suppressants, including narcotic and non-narcotic depressants Cytotoxic drugs as anti-cancer and immunosuppressants Decongestants Diuretics Expectorants Hormones, including synthetic equivalents and natural hormone extracts Hypoglycemic drugs (oral) Immunosuppressants Laxatives Muscle relaxants, including those that reduce muscle spasms and mild tranquilizers Sedatives Sex hormones (female) for menstrual and menopausal disorders, oral contraceptives, and to treat female and male cancers Sex hormones (male), including those used for androgen deficiency in hypopituitarism or testicular disorders, as well as to treat cancer, and anabolic steroids Sleeping pills Tranquilizers, including strong and mild tranquilizers vitamin

[0294] ANNEX B FDA Listing of Disease / Condition Coverage Addiction Maintaining abstinence from alcohol and / or drugs in alcohol- or drug-dependent individuals Neonatal Abstinence Syndrome (NAS) no smoking allergy Hereditary angioedema type I / II Analgesic / anesthesia / anti-inflammatory anesthesia anxiolysis Reduce fever pain chronic Breakthrough pain associated with malignant tumors Mild moderate Post-surgery severe Reversal of neuromuscular blockade Sedation Initially intubated and mechanically ventilated pediatric patients in the intensive care setting Skeletal muscle relaxation to facilitate rapid induction and routine endotracheal intubation cardiovascular disease Acute coronary disease congenital heart disease Congestive heart failure Heart failure due to generalized left ventricular systolic dysfunction Dilated cardiomyopathy (DCM) and symptomatic chronic heart failure High blood pressure whole body Postoperative hypertension Pulmonary hypertension Primary / Secondary After surgery Raynaud's phenomenon Tachyarrhythmia dermatology Alopecia areata Aphthous ulcers Candidiasis (skin, oropharynx) Dermatopathy (steroid-responsive dermatitis) Dermatitis (atopic dermatitis) ichthyosis vulgaris Idiopathic urticaria (chronic) Mild to moderate plaque psoriasis Molluscum contagiosum Onychomycosis of the toenails Oral mucositis Pediculosis humanis capitis (head lice and their eggs) Severe refractory nodular acne Skin and skin structure infections Ringworm head Lower leg feet Endocrine Acromegaly gigantism bone mineral density (BMD) BMD in patients with anorexia nervosa BMD in patients with osteogenesis imperfecta BMD in postmenarcheal adolescents with secondary amenorrhea Central precocious puberty (CPP) Delayed puberty in boys with primary and secondary hypogonadism. diabetes Type 1 Type 2 Growth Retardation in Children with AIDS Impairment of pituitary growth hormone secretion gynecomastia Homozygous familial hypercholesterolemia (HoFH) Hypercholesterolemia (heterozygous familial hypercholesterolemia) Hyperparathyroidism (renal failure secondary to hyperparathyroidism) Management of hypocalcemia in patients undergoing hemodialysis McCune-Albright Syndrome obesity whole body Hypothalamus osteogenesis imperfecta (OI) Tetrahydrobiopterin (BH4-)-responsive phenylketonuria (PKU) Testicular toxicosis gastroenterology antiemetic Treatment and prevention of nausea and vomiting associated with emetogenic chemotherapy Prevention of Postoperative Nausea and Vomiting Clostridium difficile-associated diarrhea (CDAD) Constipation (general) Crohn's disease Diarrhea (acute) Erosive esophagitis Gastroesophageal reflux disease (GERD) Irritable bowel syndrome (IBS) IBS-D Nephropathy cystinosis Short bowel syndrome (SBS) Ulcerative colitis (UC) ulcer Hematology / Coagulation Deep vein thrombosis (DVT) Iron deficiency in patients undergoing chronic hemodialysis Iron overload due to transfusion-dependent anemia (chronic) Sickle cell disease Thrombocythemia Thrombocytopenia Thromboembolism Immunomodulatory drugs immunosuppression Preventing organ rejection after kidney transplantation Infectious disease (viral) Cytomegalovirus (CMV) Hepatitis B virus (HBV) chronic Hepatitis C virus (HCV) chronic Herpes simplex virus (HSV) Human immunodeficiency virus (HIV) infection Preventing HIV infection in exposed newborns Perinatal transmission of HIV infection Influenza A / B Perinatal transmission of HIV infection Cold and flu related symptoms Varicella zoster virus (VZV) COVID-19 (SARS-CoV-2) Infectious diseases (non-viral) acute pyelonephritis Aspergillosis (invasive) Candidiasis Cerebrospinal fluid (CSF) shunt infection Community-acquired pneumonia (CAP) Concomitant intraabdominal infection (cIAI) Concurrent UTI acute pyelonephritis Mycosis (invasive) Associated fever and neutropenia Helicobacter pylori infection (H. pylori) malaria Meningitis (bacterial) Mold infection (rare mold) Otitis media (OM) (recurrent) / OM treatment failure Pneumonia (bacteremia) Resistant infections or infections unresponsive to first-line antibiotics Skin and skin structure infections tuberculosis Neurology Congenital and non-congenital neurological conditions Epilepsy Duchenne muscular dystrophy Insomnia in people with ADHD Intractable epileptic seizures associated with Dravet syndrome Migraine Multiple sclerosis (MS) Relapsing forms of MS Narcolepsy Cataplexy in Narcolepsy Neuroblastoma High-risk resistant or recurrent neuroblastoma Neuromuscular disorders Epileptic seizures General Lennox-Gastaut Syndrome (LGS) portion With or without secondary generalized seizures spasticity management Obstructive Sleep Apnea (OSA) (excessive sleepiness in OSA) Tourette Syndrome ADHD in Tourette's patients Oncology Allogeneic bone marrow transplantation chemotherapy toxicity protection Chronic graft-versus-host disease (GVHD) CNS Malignancies and Solid Tumors Giant cell tumor of bone and osteosarcoma Hematological tumors Central nervous system lymphoma Low-grade lymphoma High-grade lymphoma Recurrent, progressive or refractory brain tumors leukemia Acute lymphoblastic leukemia Acute myeloid leukemia CNS leukemia Mixed linear acute leukemia Philadelphia positive (Ph+) chronic myeloid leukemia Hodgkin lymphoma Non-Hodgkin lymphoma Anaplastic large cell lymphoma mature B cell NHL Hematopoietic stem cell mobilization for pediatric patients with malignancies eligible for autologous hematopoietic stem cell transplantation Melanoma Myelodysplastic syndromes Neuroblastoma Osteosarcoma Pediatric malignant tumors Refractory / recurrent malignant tumors Activation of the RAS / RAF / MEK signaling pathway in advanced, recurrent, or refractory solid tumors Relapsed or refractory solid tumors containing BRAF V600 activating mutations in the treatment of adolescent patients with unresectable or metastatic melanoma containing BRAF V600 activating mutations Recurrent or refractory tumors with dysregulated Erb-B1 or Erb-B2 pathways Rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas Ophthalmology conjunctivitis Allergic bacterial Newborns Intraocular pressure Postoperative inflammation after cataract surgery Retinopathy of Prematurity (ROP) Uveitis psychiatry Adolescent schizophrenia Attention Deficit Hyperactivity Disorder (ADHD) Autism and Autism Spectrum Disorders Core social impairment symptoms Bipolar disorder (mania associated with bipolar disorder) Depression / Major Depressive Disorder (MDD) Generalized Anxiety Disorder (GAD) Obsessive-Compulsive Disorder (OCD) Panic disorder Alzheimer's and Parkinson's Disease lung Allergic rhinitis asthma Bronchopulmonary dysplasia Bronchospasm (treatment and prevention) Treatment and prevention of bronchospasm in patients with obstructive airways disease Cystic fibrosis kidney disease Asthma due to chronic kidney disease (CKD) End-stage renal disease Hyperphosphatemia due to chronic kidney disease (CKD) Hyponatremia Rheumatology Familial Mediterranean fever (FMF) Juvenile idiopathic arthritis (JIA) / Juvenile rheumatoid arthritis (JRA) Polyarticular juvenile rheumatoid arthritis Managing Fibromyalgia Urology detrusor hyperreflexia Detrusor overactivity in neurological conditions

Claims

1. A composition suitable for delivery to the oral and / or nasal mucosa, said composition comprising at least one sulfated polysaccharide polymer and at least one hydrophobic or hydrophilic polymer partially cross-linked with at least one positively charged ion to a degree of cross-linking (DC) of at least about 1 percent; the composition is in liquid, semi-liquid or sprayable form; The composition has a substantially constant viscosity at room temperature (RT), thereby imparting to the composition the ability to transform into a uniform and continuous thin film upon contact with the oral and / or nasal mucosa.

2. The composition described in claim 1, wherein the DC is within the range of at least about 5 to 10, about 20 to 30, about 30 to 40, or about 40 to 50 percent.

3. 3. The composition of claim 1, wherein the at least one sulfated polysaccharide polymer is selected from sulfated galactans, ulvans, fucans, fucoidans, heparins, glucosamines, dextran, chitosans, chitins, and chondroitins.

4. 3. The composition of claim 1, wherein the at least one sulfated polysaccharide polymer is at least one carrageenan selected from iota carrageenan, kappa carrageenan, and lambda carrageenan.

5. The composition of claim 1 or 2, wherein the at least one hydrophobic or hydrophilic polymer is a hydrophilic polymer that is a polysaccharide or a protein.

6. The composition of claim 5 , wherein the polysaccharide is selected from dextran, alginate, chitosan, agarose, and pullulan.

7. 6. The composition of claim 5, wherein the protein is selected from albumin, gelatin, collagen, lectin, legumes, and vicilin.

8. 3. The composition of claim 1, wherein the at least one hydrophobic or hydrophilic polymer is a hydrophilic polymer that is alginic acid or an alginate.

9. The at least one positively charged ion is Ba ２＋ , Be ２＋ , Ca ２＋ , Co ２＋ , Mg ２＋ , Cu ２＋ , Ni ２＋ , Fe ２＋ and Zn ２＋ The composition of claim 1 or 2, wherein the divalent cation is selected from the group consisting of:

10. The at least one sulfated polysaccharide polymer is carrageenan, the at least one hydrophilic polymer is alginic acid, and the at least one positively charged ion is Ca ２＋ The composition according to claim 1 or 2,

11. The carrageenan is at a concentration ranging from about 0.1% to about 0.3%, the alginic acid is at a concentration ranging from about 2.0% to about 2.9%, and the Ca ２＋ The composition of claim 10, wherein the concentration ranges from about 0.0001% to about 0.005% (w / w).

12. The composition of claim 1 further comprising at least one additional therapeutic agent.

13. A pharmaceutical composition comprising a therapeutically effective amount of the composition of claim 1 and a pharmaceutically acceptable buffer, carrier, or excipient, The pharmaceutical composition is optionally adapted for oral and / or nasal administration in the form of a spray or gel, or adapted for oral and / or nasal inhalation in the form of particles or droplets.

14. A composition suitable for delivery to the oral and / or nasal mucosa, said composition comprising at least one sulfated polysaccharide polymer partially cross-linked by at least one positively charged ion and at least one hydrophilic polymer; the composition is in liquid, semi-liquid or sprayable form; the at least one sulfated polysaccharide polymer is carrageenan, the at least one hydrophilic polymer is alginate, and the at least one positively charged ion is Ca 2+ , provided at concentrations of about 0.005% to about 1%, about 0.1% to about 3%, and about 0.0001% to about 1% (w / w), respectively; The composition has a substantially constant viscosity at room temperature (RT), such that the composition transforms into a uniform and continuous thin film upon contact of the composition with the oral and / or nasal mucosa.

15. The composition of claim 1 for use in a method for treating, alleviating and / or preventing disorders or conditions associated with oral and / or nasal mucosal barrier dysfunction, comprising: Optionally, the disorder or condition is a microbial oral and / or nasal infection, or an aeroallergen-induced allergy and / or inflammation.

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